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English, Sciences, 1 season, 280 episodes, 2 days, 1 hour, 17 minutes
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The ASCO Daily News Podcast features oncologists discussing the latest research and therapies in their areas of expertise.
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Exploring CAR T Cells in GI Cancers at ASCO24

Dr. Shaalan Beg and Dr.Mohamed Salem discuss key abstracts that will be presented at the 2024 ASCO Annual Meeting, including hypoxia-response CAR T- cell therapy for solid tumors, GPC3-specific CAR T- cell therapy in hepatocellular carcinoma, and the promising efficacy of targeted therapies in GI cancers.  TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I am Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center. In today's episode, we'll be discussing some key abstracts in GI cancers that will be presented at the 2024 ASCO Annual Meeting. I'm delighted to welcome Dr. Mohammed Salem, a GI medical oncologist at the Levine Cancer Institute at Atrium Health, for this discussion. Our full disclosures are available in the transcript of this episode. Mohammed, it's great to have you back on the podcast. Dr. Mohamed Salem: Thank you, Dr. Beg. It's always a pleasure to be here. Thanks for having me.  Dr. Shaalan Beg: So we're seeing more and more exciting data emerge on the role of ctDNA in GI cancers. And that's a topic that we've covered fairly extensively on the podcast. This year, in Abstract 3513, investigators used a novel, highly sensitive HPV ctDNA assay to evaluate the clinical outcomes of HPV ctDNA status in people with localized anal cancer treated with chemoradiation. And we know that prior HPV infection is associated with 90% of anal cancers. Can you give us a summary of the study and why it's so important to the clinical care we're giving our patients today?  Dr. Mohamed Salem: Sure. So, as you already alluded to, in the current era of precision oncology or precision medicine in general, there is an effort to try to maximize treatment efficacy and minimize the side effects. We're trying to understand how to do that by developing more biomarkers. I think this was a very interesting study that was led by Dr. Morris of MD Anderson. As you mentioned, he tried to determine the correlation between that circulating tumor DNA at different timelines and also associated that with the relapse. Obviously, as we all know, HPV infection is linked to about over 90% of anal cancers, and anal cancer is increasingly common in the U.S.  The study design includes patients from stage 1, 2, and 3 anal cancer treated with curative intent concurrent chemo radiation and the plot sample to collect circulating DNA was taken at five weeks of treatment and then at various intervals, including 3months, 6  months, 9 months and 12 months, to detect the HPV circulating DNA. And the analysis was done to correlate detection of circulating DNA with a relapse.  So what they observed is after collecting the samples at the end of the treatment, which is 5 weeks, followed by 3 months, 6 months, 9 months, and 12 months following treatment using the correlation between the detection of circulating tumor DNA as well as the recurrence rate, they were able to identify that about 22% was seen at 5 weeks, 13% was seen at three months, then 10% was seen at 6 months, and 0% actually was seen at 12 months. In the final analysis, they concluded that detection of circulating DNA at 3 months was significantly associated with a relapse rate of those patients. And also, they looked at the baseline stage, T stage, end stage, age and other perhaps prognostic factors. But the clinical implication of that trial is this finding supports the potential of integrating now the circulating DNA analysis and routine post-treatment surveillance, which hopefully will help us identify those patients with high risk of relapse and whether they can be treated with adjuvant therapy  in context-free drug trial or even like more close surveillance. Obviously, this is a very novel study, so it needs validation. Also, we need to understand more about the platform used because with the immersion technology and how fast this field is moving, I think it's important to look at this platform or other platforms. I think as a concept it’s very interesting and hopefully will help us to identify patients with higher risk. So, I'm looking forward to hearing the full presentation. Dr. Shaalan Beg: Moving on to colorectal cancer, Abstract 3514 is a trial of hypoxia-responsive CEA CAR T-cell therapy for people with heavily pretreated solid tumors where this was administered intraperitoneally or intravenously. And you know, as a solid tumor oncologist or GI oncologist, we've been watching the hematologic space evolve so dramatically in the last five years with cellular therapies that it's exciting to see these CAR T-cell approaches being applied in solid tumors with some results. So can you talk about this study and whether you think it will influence clinical practice?  Dr. Mohamed Salem: Of course, I'm actually very excited to see this study because as you mentioned, CAR T-cell therapy has been utilized in hematological malignancies for the last several years and in fact it's becoming a center of care. As you know, it's very effective in certain tumors. Unfortunately, we did not see a similar result in solid tumors thus far. I know we are trying to make progress, but we are definitely not seeing the same efficacy in solid tumors. And also, of course, in CRC and many other tumors, we need more target options, so I was very excited to see this abstract. And I want to give a little bit of background why this abstract is important. Many solid tumors have a low oxygen level environment, hypoxia obviously, which can impact the effectiveness of CAR T therapy. So hypoxia can suppress the immune response, leading to poor performance of the immune cells like the T cell within the tumor. The investigators, to overcome that challenge, meaning hypoxia impacting the efficacy of the T cell, they were actually able to engineer a CAR T cell to be hypoxia responsive. And what does that mean? That the cells are designed to become more active in low oxygen conditions, which is more difficult in many of the solid tumors. The reason that's very interesting is because, one, it reduces exhaustion of the T cell, meaning like when you have the T cell active all the time, they get exhausted. So when you have the T cell in the resting state, until they reach the tumor environment and they get activated by the hypoxia status, now you reduce the expulsion of the T cell. But also that one overcomes the resistance. So once activated in the tumor hypoxic environment, this CAR T cell shows increased efficacy in targeting and killing the cancer cell.  Based on that concept, the investigators conducted a phase 1 dose escalation study in solid tumors. So this was a phase 1 open label group escalation study involving patients with tumor suppressed CEA and also had relapsed refractory second line treatment. The trial actually included 2 routes of administration, which I think was very interesting – IV versus intraperitoneal, IP, way of administration. And they enrolled about 40 patients between June of 2022 and January 2023. And 35 patients had colorectal cancer, 3 patients had gastric cancer, and 2 patients had non-small cell lung cancer. Overall, there was no surprising safety data. In terms of side effects, it was largely macrocystis, colitis. Unfortunately, they had 1 treatment that did not finish. But the interesting feature was the efficacy of that concept was demonstrated and in fact they were able to see more disease response and control at this rate with IP infusion, which I think is a very novel approach. I would look forward to trying and looking into this kind of delivery, especially in CRC and other tumors. Dr. Shaalan Beg: Because we've known that historically managing disease intraperitoneally has been challenging with cytotoxic chemotherapies and even surgical approaches that have been deployed can be fairly morbid as well. So looking at novel delivery mechanisms can help us understand, maybe be able to manage side effects of treatments in different ways and open doors for treatment in diseases that otherwise we couldn't manage. So definitely a very novel and exciting approach on this study.  Dr. Mohamed Salem: I agree. I think the idea of administering an IP route is a very interesting idea.   Well, Shaalan, there is another study in CRC, Abstract 3515. This is the first human study of ABBV-400, cMET–targeting antibody-drug conjugate in advanced solid tumors. Can you tell us about this promising data? Dr. Shaalan Beg: Yeah, so we've known that cMET is a very relevant biomarker across many cancers, particularly colorectal cancer, and it is overexpressed in a fairly large proportion of multiple diseases. But there hasn't been an effective regimen that has been found to be tolerable to target this specific biomarker. In this study, the investigators are evaluating an antibody drug conjugate, which takes the cMET targeting antibody telisotuzumab and conjugates it to a novel topoisomerase one inhibitor payload. And there's a phase one study that enrolled people across multiple different tumor types. This was presented at ASCO 2023. And this year, the investigators are coming in and giving the results of a colorectal cancer cohort within that study. Patients were enrolled in the dose escalation phase, and in the dose expansion phase, there were 122 colorectal cancer cases; so a fairly healthy size colorectal cancer population. And the median number of prior lines of therapy was 4, which is fairly consistent with what we would expect in our clinical population for people with colorectal cancer. So what they found in terms of efficacy is that the response rates, the confirmed overall response rates, were between 15 and 20%, depending on what dose of the medication the patients had received. They enrolled people regardless of cMET expression and then evaluated the response based on a higher or lower cMET expression. And those with higher cMET expression had an overall response rate of >30%, while those with lower cMET expression had a response rate of 10 to 15%. So they still had a response rate, which for fifth-line colorectal cancer is something to be aware of and it could be a marker of more significant clinical activity than other treatments that are out there.  And with the antibody drug conjugates, it's also important for us to keep an eye on the side effect profiles because a lot of these agents can have distinct side effect profiles that otherwise we wouldn't be familiar with. And in this study, 64% of participants had a grade 3 or above treatment emergent adverse events, and 41% had serious adverse events. So definitely something to think about. And most of these were hematologic toxicities, 30% had grade 3 or worse anemia. Neutropenia was seen, in grade three and above, was seen in 25%, leukopenia or grade three and above was seen in 12%, and thrombocytopenia again around 12%. And the non-hematologic toxicities were nausea, fatigue, vomiting and diarrhea. There was some interstitial lung disease, pneumonitis, which was seen in 7% of the total population, of which 2% had grade three or above. So definitely something to think about. From my perspective, I really am excited about this presentation because we're seeing evidence of clinical activity focused on cMET for refractory colorectal cancer compared to other agents that are out in the market. If this pans out in future studies, it could definitely change the way we deliver our treatments. Dr. Mohamed Salem: I totally agree that we actually need more therapy for those patients. And I'm not surprised that the myelosuppression, as you mentioned, was in fifth-line treatment. So this patient had large exposure to cytotoxic agents before.   So, looking at CAR T once more, there is a very interesting Abstract 4019, which is a study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR T, in patients with advanced hepatocellular carcinoma (HCC). What are your key takeaways from this study, Shaalan? Dr. Shaalan Beg: This is a first-in-human study. It enrolled people with advanced HCC who failed on one or more lines of prior therapy and they were given one single infusion of C-CAR031 after standard lymphodepletion and they enrolled 24 patients across 4 dose levels. If we look at the overall response rate, 50% of the 22 people who were eligible for response assessments had a partial response. This response rate varies based on the dose level itself and the investigators claim a 90% disease control rate. So definitely when we think about standard treatments for hepatocellular cancer after first line therapy, this is something which will catch a lot of people's attention. Again, with CAR T-cell therapy, we need to be aware of the risk of potential toxicities. There were no dose limiting toxicities and CRS or cytokine release syndrome was observed in 91% of patients, while a very small proportion, about less than 5%, had grade three CRS. Most of the side effects here were, again, lymphocytopenia, neutropenia, thrombocytopenia, and some transaminitis in 16% of patients. They did see tumor reduction in 90%, not only in the intrahepatic disease, but also in the extrahepatic disease. And again, these are people who had BCLC stage C disease. So this included people with hepatic and extrahepatic metastases. And in terms of prior lines of therapy, 96% of patients had either received immune checkpoint inhibitors and TKIs.  If we think about how some other immune therapy regimens are being developed in the GI cancer space, there is some indication that liver lesions may respond differently compared to extra hepatic disease. So in this case, they saw responses in both scenarios, which makes it very exciting, because even though we've seen many approvals of TKIs and immunotherapy, anti-androgenic therapy in hepatocellular cancer, the treatment of these patients is still extremely difficult because of their underlying hepatic dysfunction. And it'll be very interesting to see how this treatment unfolds.  Dr. Mohamed Salem: You summarized it very well, Shaalan. I echo your thoughts. What is also interesting about that study, it's actually targeted at the GPC strain, which is prevalent in HCC but not normal tissue, which goes back to your comment about the toxicity, and hopefully we can also manage treatment in the context of underlying liver disease.  Dr. Shaalan Beg: I guess it's fair to say that we're both very excited to see what's ahead in GI cancers at the Annual Meeting.   Mohamed, thanks as always for sharing your great insights with us on the ASCO Daily News Podcast.  Dr. Mohamed Salem: Thank you all for having me, and I'm looking forward to meeting you and all our colleagues in Chicago in a couple of weeks. Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcripts of this episode. I'll be back to cover late breaking abstracts and other key advances in GI oncology after the annual meeting, so please join me for more key insights from ASCO24 and on the ASCO Daily News Podcast. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers:  Dr. Shaalan Beg  @ShaalanBeg  Dr. Mohamed Salem  @SalemGIOncDoc    Follow ASCO on social media:  @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Shaalan Beg:  Consulting or Advisory Role: Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen  Speakers’ Bureau: Sirtex  Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics  Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune    Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca  Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck 
5/25/202417 minutes, 58 seconds
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Key Abstracts in GU Cancers at ASCO24

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss promising combination therapies and other compelling advances in genitourinary cancers in advance of the 2024 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of genitourinary cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode. Jeanny, it’s great to have you on the podcast. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal. It's a pleasure to be here. Dr. Neeraj Agarwal: So, Jeanny, let's start with some bladder cancer abstracts. Could you tell us about the Abstract 4509 titled, “Characterization of Complete Responders to Nivolumab plus Gemcitabine Cisplatin versus Gemcitabine Cisplatin Alone in Patients with Lymph Node Only Metastatic Urothelial Carcinoma from the CheckMate 901 Trial.”  Dr. Jeanny Aragon-Ching: Of course, Neeraj, I would be delighted to. First, I would like to remind our listeners that the CheckMate 901 trial was a randomized, open-label, phase 3 study, in which this particular sub-study looked at cisplatin-eligible patients with previously untreated, unresectable, or metastatic urothelial carcinoma who were assigned to receive the combination of gemcitabine and cisplatin, followed by up to 2 years of nivolumab or placebo. Based on the data presented at ESMO 2023 and subsequently published in the New England Journal of Medicine, which shows significantly improved progression-free survival and overall survival in patients receiving the combination of gemcitabine, cisplatin, and nivolumab, this regimen was approved in March 2024 as a first-line therapy for patients with unresectable or metastatic urothelial carcinoma.  In the abstract that will be featured at ASCO this year, Dr. Matt Galsky and colleagues present a post-hoc analysis that aims to characterize a subset of patients with complete response as well as those with lymph node-only metastatic disease. In patients receiving the experimental treatment, 21.7% achieved a complete response, while 11.8% of the patients in the control arm achieved a complete response.  Among these complete responders, around 52% had lymph- node-only disease in both arms. Furthermore, when characterizing the subgroup of patients with lymph-node-only disease, those receiving the combination of gemcitabine-cisplatin plus nivolumab had a 62% reduction in the risk of progression or death and a 42% reduction in the risk of death compared to those treated with gemcitabine-cisplatin alone.  The median overall survival in the experimental arm in this subgroup was around 46.3 months, while it was only 24.9 months in the control arm. The ORR in patients with lymph-node-only disease receiving gem-cis plus nivo was about 81.5% compared to 64.3% in those treated with gem-cis alone. Dr. Neeraj Agarwal: Thank you, Jeanny, for the excellent summary of this abstract. We can say that nivolumab plus gemcitabine-cisplatin induced durable disease control and clinically meaningful improvements in OS and PFS compared to gem-cis alone in patients with lymph- node-only metastasis, and deserves to be considered as one of the options for these patients.  In a similar first-line metastatic urothelial carcinoma setting, Abstract 4502, also reported data on a recently approved combination of enfortumab vedotin and pembrolizumab. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, as quick reminder to our audience, this regimen was tested in the EV-302 phase 3 trial, where patients with previously untreated, locally advanced or metastatic urothelial carcinoma were randomized to receive enfortumab vedotin, plus pembrolizumab or gemcitabine plus either cisplatin or carboplatin. These data were also first presented at ESMO 2023 and subsequently published in the New England Journal of Medicine. They showed that this immune based combination significantly improved both progression free survival and overall survival, which were the primary endpoints compared to chemotherapy. In this abstract, Dr. Shilpa Gupta from the Cleveland Clinic and colleagues present the results of patient reported outcomes based on quality-of-life questionnaires in this trial.  Time to pain progression and time to confirm deterioration were numerically longer in patients treated with EV plus pembro, and patients with moderate to severe pain at baseline receiving this combination had a meaningful improvement in the Brief Pain Inventory Short-Form worst pain from week 3 through 26. Dr. Neeraj Agarwal: Thank you, Jeanny. This means that patients treated with EV plus pembro did not only have improved survival compared with platinum-based chemotherapy, but also improvement in their quality-of-life and functioning, further supporting the value of this combination for patients with locally advanced or metastatic urothelial carcinoma. This is terrific news for all of our patients.   Before we wrap up the bladder cancer section, would you like to tell our listeners about Abstract 4565, which provides the data on the efficacy of trastuzumab deruxtecan in patients with bladder cancer? Dr. Jeanny Aragon-Ching: Yes, Neeraj; this is timely given the recent FDA approval, which we will talk about. The abstract is titled, “Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2 Expressing Solid Tumors: Results from the Bladder Cohort of the DESTINY-PanTumor02 Study.” And as a quick reminder, the DESTINY-PanTumor02 was a phase 2 open-label study where trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2 expression on cancer cells, was evaluated in patients with HER2-expressing locally advanced or metastatic disease who previously received systemic treatment or who had no other treatment options. The expression of HER2 was evaluated on immunohistochemistry by local or central testing.   The primary endpoint was confirmed objective response rate by investigator assessment. Secondary endpoints included duration of response, progression free survival, disease control rate, and safety. The primary analysis, which was published in the Journal of Clinical Oncology, showed an ORR of 37.1% and responses across all cohorts and the median duration of response was 11.3 months. Based on these results, fam-trastuzumab deruxtecan-nxki was just granted accelerated FDA approval for unresectable or metastatic HER2-positive solid tumors in April 2024.  So, back to this abstract; Dr. Wysocki and colleagues report the results of the bladder cancer cohort. This study included 41 patients with urothelial cancer and at a median follow up of around 12.6 months, the objective response rate among these patients was 39%, the median PFS was 7 months, and the duration of response median was 8.7 months. The disease control rate at 12 weeks was around 71%. Regarding the safety profile, 41.5% of patients experienced grade ≥3 drug related adverse events and interstitial lung disease or pneumonitis did occur in about 4 patients. Although there was no statistical comparison between different groups, the ORR was numerically highest among the HER2 3+ group with 56.3%.  Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data support consideration of trastuzumab deruxtecan as a salvage therapy option for pre-treated patients with HER2 expressing urothelial cancers and show that we are extending our treatment options to include therapies with novel mechanisms of action. This is definitely exciting news for patients with bladder cancer. Dr. Jeanny Aragon-Ching: Yes, absolutely, Neeraj. Now, let's switch gears a bit to prostate cancer. Could you tell us about Abstract 5005 which is titled, “EMBARK Post Hoc Analysis of Impact of Treatment Suspension on Health Quality-of-Life?” Dr. Neeraj Agarwal: Of course, I'd be happy to. So, enzalutamide was recently granted FDA approval for the treatment of patients with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high-risk of metastasis, based on the results of the EMBARK trial, which was a phase 3 study where patients with high-risk biochemical recurrence were randomized to receive either enzalutamide with leuprolide, enzalutamide monotherapy, or placebo plus leuprolide. The primary endpoint was metastasis-free survival with secondary endpoints including overall survival and safety.  Results showed that patients receiving enzalutamide alone or enzalutamide plus leuprolide had significantly improved metastasis-free survival compared to those treated with leuprolide alone while preserving health-related quality-of-life.   One important aspect in the design of the trial was that patients who achieved undetectable PSA at week 37 underwent treatment suspension. The treatment was resumed if PSA rose to more than 2 ng/ml for patients who underwent radical proctectomy or when PSA rose to more than 5 ng/ml for those who did not undergo surgery.  In this abstract, Dr. Stephen Freedland and colleagues present a post-hoc analysis of health-related quality-of-life outcomes after treatment suspension between weeks 37 and 205. They found that treatment was suspended in 90.9% of patients receiving enzalutamide plus leuprolide, 85.9% of those receiving enzalutamide monotherapy, and 67.8% of those receiving leuprolide monotherapy. Among those patients who stayed on treatment suspension, a trend toward numerical improvement in health-related quality-of-life after week 37 was seen in all 3 arms and this reached clinically meaningful threshold at week 205 in pain questionnaires, physical well-being, urinary and bowel symptoms. For hormonal treatment side effects, all arms reached clinically meaningful improvement at the subsequent assessments of week 49 to week 97. However, patients slowly deteriorated, with clinically meaningful deterioration at week 205 relative to week 37 in patients receiving the combination of enzalutamide and leuprolide and those treated with leuprolide.    Concerning sexual activity, a clinically meaningful improvement was reported only in patients receiving enzalutamide plus leuprolide, possibly because sexual function was better preserved prior to suspension in the enzalutamide monotherapy arm and thus there was less opportunity for “improvement” while on suspension.  Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for this great summary. This analysis confirms that treatment suspension in good responders might lead to a clinically meaningful improvements in health-related quality-of-life.   Now, moving on to patients with metastatic castration-resistant prostate cancer, what can you tell us, about Abstract 5008 titled, “Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore”?  Dr. Neeraj Agarwal: Sure, Jeanny. The PSMAfore trial was a phase 3 study that compared the efficacy of 177Lu-PSMA-617 versus an ARPI switch in patients with mCRPC and prior progression on a first ARPI, and not previously exposed to docetaxel chemotherapy. The primary endpoint was rPFS and OS was an important secondary endpoint. The primary analysis presented at ESMO 2023 showed a significantly prolonged rPFS in patients receiving lutetium. In the abstract that will be featured at the 2024 ASCO Annual Meeting, Dr. Johann De Bono and colleagues present an exploratory analysis regarding the associations between baseline circulating tumor DNA and outcomes.  ctDNA fraction was evaluated in all samples as well as alterations in key prostate cancer drivers prevalent in more than 10% of participants.  The investigators sought to interrogate the association of ctDNA fraction or alterations with rPFS, PSA response, and RECIST response at data cutoff. They showed that median rPFS was significantly shorter in patients with a ctDNA fraction >1% compared to those with a fraction 1% was also associated with worst RECIST response and PSA50 response. Regarding prostate cancer drivers, median rPFS was significantly shorter in patients with alterations in the AR, TP53 or PTEN in both treatment arms. There was no significant association between ctDNA alterations and PSA or objective responses. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that the presence of a ctDNA fraction >1% or alterations in AR, P53 and PTEN were all associated with worse outcomes regardless of treatment with lutetium or change in the ARPI. These data are definitely important for counseling and prognostication of patients in the clinic and may guide the design of future clinical trials. Let's move on to kidney cancer. Neeraj, do you have any updates for us?  Dr. Neeraj Agarwal:  Sure. In Abstract 4512 titled, “A Multi-institution Analysis of Outcomes with First-Line Therapy for 99 Patients with Metastatic Chromophobe Renal Cell Carcinoma,” Dr. Sahil Doshi and colleagues present a retrospective, multi-institutional study comparing survival outcomes, including time-to-treatment failure and overall survival, between different first-line treatment options in patients with metastatic chromophobe renal cell carcinoma, where limited clinical trial data exists to guide systemic therapy. They categorized patients into 4 treatment groups: and immune checkpoint inhibitors + targeted therapy doublets (such as ICI VEGF TKI); pure immune checkpoint inhibitor monotherapy and doublets (such as ipilimumab plus nivolumab); targeted therapy doublets (such as lenvatinib plus everolimus), and targeted monotherapy (such as sunitinib).  They identified 99 patients, of whom 54 patients received targeted monotherapy, 17 received ICI VEGF-TKI, 14 received targeted doublet, and 14 patients received only ICI therapies. So the patients treated with any doublet containing a targeted agent had a 52% decrease in the risk of treatment failure and a 44% decrease in the risk of death compared to those treated with targeted monotherapy. The median time to treatment failure was 15 months with IO-targeted doublet, and the median overall survival was 56 months. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that targeted doublet regimens resulted in a longer time to treatment failure and overall survival compared to any monotherapy in patients with chromophobe metastatic RCC and definitely provides valuable insights on treatment selection, albeit I would say there's still a small number of patients that were included in this retrospective analysis. Dr. Neeraj Agarwal: I completely agree this is a relatively small number of patients, but I decided to highlight the abstract given how rare the cancer is, and it is highly unlikely that we'll see large randomized clinical trials in patients with metastatic chromophobe renal cell carcinoma.  So, before we wrap up the podcast, what would you like to tell us about Abstract 5009 which is titled, “A Phase II Trial of Pembrolizumab Platinum Based Chemotherapy as First Line Systemic Therapy in Advanced Penile Cancer: HERCULES (LACOG 0218) Trial.” Dr. Jeanny Aragon-Ching: I'm glad you brought this up, Neeraj. As our listeners may know, advanced penile squamous cell carcinoma has a poor prognosis with limited treatment options. From this perspective, the results of the LACOG 0218 trial are very important. As you mentioned, this was a phase 2 single-arm study evaluating the addition of pembrolizumab to platinum-based chemotherapy as first-line treatment in patients with metastatic or locally advanced penile squamous cell carcinoma not amenable to curative therapy. Patients enrolled received chemotherapy, namely 5-Fluorouracil with cisplatin or carboplatin and pembrolizumab 200 mg IV every 3 weeks for 6 cycles, followed by pembrolizumab 200 mg IV every 3 weeks up to 34 cycles. The primary endpoint was confirmed overall response rate by investigator assessment.  In the 33 patients eligible for the efficacy analysis, the confirmed ORR by investigator assessment was 39.4% and included one complete response and 12 partial responses. The confirmed ORR was 75% in patients with high TMB and 55.6% in patients positive for HPV16, making TMB and HPV16 potential predictive biomarkers for efficacy in this study. Concerning the toxicity profile, any grade treatment-related adverse events were reported in around 92% of patients, and grade 3 or more treatment-related adverse events occurred in 51% of patients. 10.8% of patients discontinued treatment due to adverse events.  Dr. Neeraj Agarwal: Thank you, Jeanny. I would like to add that HERCULES is the first trial to demonstrate the efficacy of an immune checkpoint inhibitor in advanced penile squamous cell carcinoma with a manageable safety profile. Thus, the combination of ICI with platinum-based chemotherapy is a promising treatment for advanced penile squamous cell carcinoma and warrants further investigation.  Dr. Jeanny Aragon-Ching: I agree, Neeraj. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Jeanny, I really want to thank you for your participation and valuable insights. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. It was a pleasure.  Dr. Neeraj Agarwal:  As we bring this podcast to an end, I would like to acknowledge the significant advances happening in the treatment of patients with genitourinary cancers. During our upcoming 2024 ASCO Annual Meeting, there will be an array of different studies featuring practice-changing data presented by researchers and physicians from around the globe. I urge our listeners to not only participate in this event to celebrate these achievements, but to also play a role in sharing these cutting-edge data with healthcare professionals worldwide. Through our collective efforts, we can surely optimize the benefits of patients on a global scale.   And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you very much.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers:  Dr. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:   @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:    Dr. Neeraj Agarwal:     Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:  Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers’ Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 
5/25/202426 minutes, 4 seconds
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Novel Approaches in Hematologic Malignancies at ASCO24

Dr. John Sweetenham and Dr. Marc Braunstein look ahead at key abstracts across the spectrum of hematologic malignancies that will be presented at the 2024 ASCO Annual Meeting, including the OPTIC trial in chronic myeloid leukemia, treatment options for transplant-ineligible patients with multiple myeloma, and the 7-year analysis of the ECHELON-1 trial in classical Hodgkin lymphoma. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and the host of the ASCO Daily News Podcast. I'm delighted to be joined again this year by Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center in New York. We're going to be discussing some of the key abstracts in hematologic malignancies that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.  Marc, it's great to have you back on the podcast. Dr. Marc Braunstein: It's a pleasure to be back, John.  Dr. John Sweetenham: There are some exciting abstracts to be presented at this year's meeting, and I would like to begin, if we can, with Abstract 6501. As you know, this reports the four-year results from the OPTIC trial of ponatinib in patients with chronic-phase CML and the T315I mutation. Can you tell us about the trial and about these latest follow-up results? Dr. Marc Braunstein: Sure. Well, we've made tremendous progress in managing patients with CML in the past two decades using these oral tyrosine kinase inhibitors such as ponatinib. Ponatinib is a third-generation TKI that has activity in both Philadelphia-positive ALL as well as CML, and can overcome the resistance mutation you mentioned, called the T315I mutation, which is sometimes found following prior TKI therapy. The OPTIC study is a multicenter phase 2 randomized study of various doses of ponatinib in 283 chronic phase CML patients who had received 2 or more prior lines of therapy or those who had the presence of a T315I mutation, with the current analysis examining the major remission at 48 months, PFS, as well as OS. Of note, in this study, after patients have achieved a major remission with a transcript level of 1% or less, the study allowed for dose reduction of ponatinib from the original dose of either 45 milligrams or 30 milligrams to a reduced dose of 15 milligrams.  So, when we look at the results, we find that the patients who had the highest overall response rates and higher rates of molecular remission were those who received the 45-milligram dose. And remember, these patients were allowed to be dose-reduced to the 15-milligram dose once they achieved a molecular remission of 1% or less. In addition, the rates of overall survival were highest in the 45-milligram dose as well. When looking at the T315I subgroup, the rates of molecular remission, the depth of remission, and the rates of progression-free survival, in general, were lower in that subgroup, but still higher in the 45-milligram dose than the 35- milligram dose.  Furthermore, when looking at the rates of treatment-emergent adverse events leading to discontinuation, they were 8% in the 45-milligram dose compared to 14% in the 30-milligram dose and 5% in the patients who only received the 15-milligram dose. The authors have concluded that the 45-milligram dose, with the potential to be reduced to 15 milligrams after achieving 1% or less of the BCR-ABL transcript level, seems to be the right balance between efficacy and safety.  Dr. John Sweetenham: Thanks, Marc. In the longer term, do you think that this study will, in any way, affect the position of ponatinib in the treatment algorithm for CML? Is it going to remain as a second or third-line option, or do you think there's any chance it will be moved up? Dr. Marc Braunstein: Well, that's a great question. There are other TKIs, such as asciminib, that also target the T315I mutation, and that mutation tends to develop after prior first-line or second-line TKI therapy. But given its activity in both ALL and CML, I think it's certainly reasonable to expect that ponatinib will be used in earlier lines of therapy given its efficacy in later lines. Dr. John Sweetenham: Let's change gears and move the focus to acute myeloid leukemia. There has been a lot of discussion around frailty in many different malignancies, but the impact of frailty on outcomes in AML is maybe something that hasn't been quite so well studied. In Abstract 6506, investigators did a population-based study in Ontario, Canada, that assessed the patient's frailty risk and the impact that might have on outcomes. What are your takeaways from this study, and how do you think these data will help optimize treatment decisions?  Dr. Marc Braunstein: Yeah, I'm glad we're talking about this abstract John, because frailty scores are increasingly being used in hematologic malignancies to help guide goals and intensity of care. And as opposed to using age or performance status alone, these composite frailty assessment tools, such as the MFI tool that they used in this particular study, take into account multiple variables that are both physiologic, such as the patient's comorbidities, as well as social, and what kind of support system do they have, and things of that nature. And that accounts for their overall fitness. So, in this retrospective cohort study that was a population-based study in Ontario between 2006 and 2021, they looked at 5,450 patients retrospectively with acute leukemia and grouped those patients into 3 categories based on this frailty index. Patients who are either fit, somewhere in the middle between fit or frail, which they call pre-frail, or frail. And they looked at outcomes such as overall survival, comparing patients who got intensive chemotherapy regimens for induction or those who got non-intensive therapy for induction. Patients in either group could have been assigned to either fit, pre-frail, or frail although there are much more fit patients than those who got intensive induction.  And so, looking at their findings, it was noted that patients who were in the frail category, not entirely unexpectedly, had lower overall survival when compared to those who were fit or pre-frail. I think the value of a study like this is not just to highlight the benefit of frailty scores to help predict which patients may ultimately have a shorter survival, but also to help potentially guide which patients may be more suitable for intensive versus less intensive induction. I will note that this study was conducted in an era where we didn't have the same sorts of less intensive induction that are very effective in less fit patients, such as the combination of azacytidine and venetoclax, which is commonly used in less fit patients nowadays. So, the study may encompass patients who didn't have access to that therapy because it wasn't available during that time. But I think it still, overall, does highlight the fact that assessing fitness or frailty in acute myeloid leukemia is important for predictive value. Dr. John Sweetenham: I agree. Marc, I don't know what your thoughts are on this, but it goes either way. I mean, I think that, if I remember the numbers correctly, 25% of fit patients received non-intensive therapy. So, is there a missed opportunity there for that group of patients who actually may have tolerated the intensive therapy but it was never offered? Dr. Marc Braunstein: That's an excellent point, John, and I think that highlights the importance of frailty indices because they take into account much more than one particular factor, or even just a subjective assessment of the patient in real time when they’re first presenting. And they may have disease-specific features that are decreasing, say one element of their assessment such as their performance status. So, really taking these composite fitness scores into account may actually allow you to escalate therapy in a patient who may actually be fit but maybe perceived as less fit when they present. Dr. John Sweetenham: Yeah. So, I think, as you mentioned, there are better treatment options out there now maybe than there were at the time this study was conducted. Nevertheless, there may still be that opportunity for more intensive therapy for some of these patients when they are more holistically assessed.  Let's move on and switch gears once again and talk about a study in multiple myeloma, the so-called IMROZ study, which is Abstract 7500. So, this is a study looking at treatment options for transplant-ineligible patients with newly diagnosed multiple myeloma. Some of these patients may not have a chance for subsequent therapy if they are not eligible for transplant. What are your thoughts on this study? Do you think we're closer to a new standard of care for patients who are not going to proceed to an autologous stem cell transplant?  Dr. Marc Braunstein: It seems like every year there's a new standard of care for newly diagnosed multiple myeloma because there's so much data emerging, which is just wonderful. So, I think as background, at the 2023 ASH meeting, the IsKia study was presented, which is a randomized phase 3 study in newly diagnosed transplant-eligible patients. And that was using isatuximab with carfilzomib, lenalidomide, and dexamethasone upfront and that study did show a benefit in terms of reducing minimal residual disease compared to carfilzomib, lenalidomide, and dexamethasone alone. But that study was looking at fit newly diagnosed patients who were going on to stem cell transplant. Right now, the standard of care for patients who are not eligible for transplant is generally to use a 2 or 3-drug regimen, such as daratumumab, lenalidomide, and dexamethasone, based on the phase 3 MAYA study. But this study is really unique in that it looks at using a quadruplet regimen in patients who are transplant ineligible or not intended to go for transplant.  So, the phase 3 IMROZ study was a randomized study of 446 patients that compared isatuximab, bortezomib, lenalidomide, and dexamethasone to bortezomib, lenalidomide, and dexamethasone alone. So, a quad versus a triplet regimen. The primary endpoint in this study was progression-free survival, but they also looked at secondary endpoints, such as complete response rate and minimal residual disease negativity.   Just to quickly highlight the results and then discuss the standard of care, the median duration of treatment in this study was 53 months in the quad regimen and 31 months in the control arm. At a median follow-up of about 60 months, the progression-free survival was not reached with the quad regimen versus 54 months in the triplet, and that was a significant difference. In addition, the safety profile was pretty much consistent with the class, there were a bit more grade three or higher treatment-emergent adverse events with the ESA-containing regimen, 92% versus 84%, but no difference in adverse events leading to discontinuation in either arm.   So, this study is certainly compelling in terms of using quadruplet-based regimens that contain an anti-CD38 monoclonal antibody for newly diagnosed patients who are not intended to undergo transplant. I think at the meeting, I will be interested to see the patient population that was included. Patients who are over the age of 80, for example, are excluded. So, I would like to know more about their fitness level and performance status. But I think it’s clear, John, that using quad regimens over triplet regimens is just consistently superior in terms of efficacy outcomes. Dr. John Sweetenham: Right. I guess that, even though maybe we can’t focus on the specific agents right now, it looks as if quad regimens are going to be the standard of care regimens for the future in this group. Do you think that is fair?  Dr. Marc Braunstein: Very likely. Dr. John Sweetenham: Absolutely. Well, that's a pretty challenging group of patients.   And so to move on again, let's talk about another, perhaps equally challenging group - patients with mantle cell lymphoma, particularly those who carry certain mutations. The so-called SYMPATICO study, which is reported in Abstract 7007, presents data on the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who carry a TP53 mutation. We know that this mutation confers a high risk of early progressive disease and poorer outcomes when these patients are treated with standard chemoimmunotherapy for mantle cell. Trials to date have been limited to small single-arm studies. Can you tell us a little bit about this study and the outcomes and what you think it means for the future?  Dr. Marc Braunstein: As a background, although BTK inhibitors such as ibrutinib have yet to be approved for newly diagnosed mantle cell lymphoma, acalabrutinib and zanubrutinib, which are second-generation BTK inhibitors, are FDA-approved for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market. The lead author of this abstract, Dr. Michael Wang, had presented a late-breaking data from the phase 3 SYMPATICO trial at ASH last year, in which 267 patients with relapsed or refractory mantle cell lymphoma after one to five prior lines of therapy were randomized to receive the combination of ibrutinib plus the BCL-2 inhibitor venetoclax or ibrutinib plus placebo. That study showed there was a 32 versus 22-month progression-free survival with a hazard ratio of 0.65 at a median follow-up of 51 months, indicating the PFS benefit of the combination of ibrutinib and venetoclax compared to ibrutinib with placebo.   So that leads us to this subgroup analysis in the current study being presented at ASCO, in which they looked at a subgroup of patients with mantle cell lymphoma who are at very high risk for treatment failure and early relapse - those are patients who have a mutation in TP53, which again is high risk for treatment failure. This abstract examined an open-label cohort of 44 first-line patients, as well as 75 patients who were in the relapse/refractory cohort, and compared to patients who either did or did not have the P53 mutation. When we look at the progression-free survival outcomes, the median progression-free survival in the first-line cohort of patients who did not have a P53 mutation was not reached, whereas those with the P53 mutation had a median progression-free survival of 22 months, which is still meaningful but still less than those who did not have a P53 mutation. Which again is not entirely unexpected. But the overall response rate of the combination of ibrutinib and venetoclax was very high at 90%, and the median duration of response was about 21 months.  Now comparing this to the relapse/refractory cohort, in those without a P53 mutation, the progression-free survival of the combination of ibrutinib and venetoclax was about 47 months versus those who don’t have the P53 mutation was about 21 months with an overall response rate of 80%. I think one takeaway looking at this comparison of the first-line and relapse/refractory setting is that patients seem to do very similar in terms of overall response rate and progression-free survival, whether they were in the first line or in the later lines of treatment if they had the P53 mutation, which says that the combination of ibrutinib and venetoclax is effective no matter which phase of the disease the patient might be in, indicating its overall activity and being strong.    Dr. John Sweetenham: Yeah, I thought that was an interesting observation, actually, how similar the outcomes were in those two groups.  Dr. Marc Braunstein: No, I agree. And I think although patients with TP53 mutations did comparatively worse than those without the mutation according to progression-free survival, overall response rate, or complete remission rates, they did seem to be similar whether a patient was in first-line or relapsed refractory if they were P53 mutant and were treated with this combination. So, I think we need further data in the first line, such as the data that's awaiting publication from the TRIANGLE study, which is examining upfront ibrutinib. But certainly, BTK inhibitors have significant activity in either the first line or the relapse setting of mantle cell lymphoma.  Dr. John Sweetenham: Great. Thanks, Marc.  Let's wind up with one more abstract, and this is Abstract 7053. It's a 7-year analysis of the so-called ECHELON-1 study. This was a study comparing the standard of care, ABVD, with the same regimen with bleomycin substituted by brentuximab vedotin for patients with previously untreated advanced-stage classical Hodgkin lymphoma. The study at the time it was originally reported, resulted in a significant practice change in the first-line therapy of Hodgkin’s lymphoma. We now have mature follow-up. What are your take-homes from this study? Dr. Marc Braunstein: The ECHELON-1 study has certainly been a practice-changing clinical trial where, as you said, brentuximab with the backbone of AVD was compared to ABVD, which was the prior standard. And this was examined in newly diagnosed patients with classical Hodgkin lymphoma who were at advanced-stage, stage 3 or 4. The publication, first of the progression-free survival, and more recently, in the New England Journal of Medicine in 2022, where we saw the 6-year overall survival was 94% with the brentuximab-containing arm versus 89% in the control arm, established the brentuximab AVD, or otherwise called AAVD, as the standard of care in advanced stage newly diagnosed classical Hodgkin lymphoma. The current study is now reporting 7-year follow-up on about 1,300 randomized patients who were enrolled in this impressive study.   Though at a median follow-up of 89 months now, the 7-year overall survival was quite similar, 94% versus 89%, again favoring the brentuximab-containing arm. In particular, this was driven by patients who had stage 4 disease or those patients who were aged less than 60 in subgroup analyses. So, what I take away from this abstract in the 7-year follow-up of the ECHELON-1 is that brentuximab with AVD remains the standard of care for previously untreated advanced-stage classical Hodgkin lymphoma. It is worth noting that the SWOG S1826 study that was presented at ASCO last year compared nivolumab with AVD compared to brentuximab AVD and did show a slight PFS advantage of 94% versus 86% with nivolumab AVD. Obviously, these were different studies with different patient populations enrolled, so we're really just cross-comparing different studies. But I think brentuximab AVD, given the survival benefit that is retained now at seven years in the current abstract, still remains the standard of care for advanced-stage classical Hodgkin lymphoma. The role of immune checkpoint inhibitors like nivolumab is making headway in terms of treating newly diagnosed patients as well. Dr. John Sweetenham: Yeah, thanks, Marc. I mean, one of the observations that I thought was of interest in this study was the outcome for patients who were PET-2 positive, when you compare AAVD and ABVD. It does seem as if even in those patients who are PET-2 positive, having had AAVD, they still apparently have a better outcome than those who received ABVD in that situation who were PET-2 positive. So, I think that's another interesting observation. I'm not quite sure what it means, except speaking to the overall superior efficacy of that regimen. Dr. Marc Braunstein: You make a great point, John, because it's worth noting that in ECHELON-1, a PET scan was done after cycle 2, but the study was not PET-adapted. So even if you had a positive PET, you continued for the full six cycles of treatment. But PET-2 status is often used in various studies of Hodgkin lymphoma to guide whether to give additional cycles or escalate therapy. So, I think the benefit of presenting those subgroups is that even if you were PET-2 positive, you still did better by continuing on the brentuximab-containing regimen. Dr. John Sweetenham: Yeah, exactly. I mean, the other important takeaway message, I think, is that the outcome for patients with advanced Hodgkin lymphoma seems to continue to steadily improve, which is great news and also really remarkable. And I'm excited to see there may be some additional data presented at one of the late-breaking abstracts in this year's meeting, so it will truly be interesting to see what that shows us as well.  Dr. Marc Braunstein: Incredible. Dr. John Sweetenham: Well, Marc, as always, thank you for sharing your insights with us today on the ASCO Daily News Podcast. We look forward very much to hearing the updated data from these abstracts at the meeting.  Dr. Marc Braunstein: As do I and thank you so much for inviting me again.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s guest: Dr. Marc Braunstein @docbraunstein   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures:  Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness   Dr. Marc Braunstein: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp Speakers’ Bureau: Janssen Oncology Research Funding (Institution): Janssen, Celgene/BMS
5/24/202422 minutes, 33 seconds
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ASCO24: The Future of Personalized Immunotherapy

Dr. Diwakar Davar and Dr. Jason Luke discuss key abstracts from the 2024 ASCO Annual Meeting that explore triplet therapy in advanced melanoma, TIL cell therapy in immune checkpoint inhibitor–naive patients, and other novel approaches that could shape the future of immunotherapy in melanoma and beyond.  TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I am your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to have my friend and colleague, Dr. Jason Luke, on the podcast today to discuss key abstracts in melanoma and immunotherapy that will be featured and highlighted at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapeutic Center, as well as the associate director for clinical research at the University of Pittsburgh's Hillman Cancer Center.  You will find our full disclosures in the transcript of this episode.  Jason, as always, it's a pleasure to have you on this podcast to hear your key insights on trials in the immunotherapy space and melanoma development paradigm, and to have you back on this podcast to highlight some of this work.  Dr. Jason Luke: Thanks so much for the opportunity to participate. I always enjoy this heading into ASCO.  Dr. Diwakar Davar: We're going to go ahead and talk about three abstracts in the melanoma space, and we will be starting with Abstract 9504. Abstract 9504 essentially is the RELATIVITY-048 study. It describes the efficacy and safety of the triplet nivolumab, relatlimab, and ipilimumab regimen in advanced PD-1 naive melanoma. So in this abstract highlighted by Dr. Ascierto and colleagues, they report on the results of this phase 2 trial in this setting. By way of background, PD-1 inhibitors and immune checkpoint inhibitors starting in PD-1 and CTLA-4, as well as PD-1 and LAG-3, are all FDA-approved on the basis of several pivotal phase 3 trials, including KEYNOTE-006, CheckMate-066, CheckMate-067, and most recently, RELATIVITY-047. Jason, can you briefly summarize for this audience what we know about each of these drugs, at least the two combinations that we have at this time?  Dr. Jason Luke: For sure. And of course, these anti PD-1 agents, became a backbone in oncology and in melanoma dating back to more than 10 years ago now, that response rates in the treatment-naive setting to anti PD-1 with either pembrolizumab or nivolumab are roughly in the range of mid-30s to high-40s. And we've seen clinical trials adding on second agents. You alluded to them with the seminal study being CheckMate-067, where we combined a PD-1 antibody and CTLA-4 antibody or nivo + ipi. And there the response rate was increased to approximately 56%. And more recently, we have data combining PD-1 inhibitors with anti-LAG-3. So that's nivolumab and relatlimab. Now, in that trial, RELATIVITY-047, the overall response rate was described as 43%. And so that sounds, on a first pass, like a lower number, of course, than what we heard for nivolumab and ipilimumab. We have to be cautious, however, that the cross-trial comparison between those studies is somewhat fraught due to different patient populations and different study design. So I think most of us think that the response rate or the long-term outcomes between PD-1, CTLA-4, and PD-1 LAG-3 are probably roughly similar, albeit that, of course, we have much better or much longer follow up for the nivo + ipi combo.  The one other caveat to this, of course then, is that the side effect profile of these two combinations is distinct, where the incidence of high-grade immune-related adverse events is going to be roughly half with nivolumab and relatlimab, a combination of what you would see with the nivolumab and ipilimumab. So that has caused a lot of us to try to think about where we would use these different combinations. But we do see that all of these treatments can land a durable long-term response in the subset of patients that do have an initial treatment benefit. The landmark, I think, for the field has been the 7-and-a-half-year median overall survival that we've seen with PD-1 plus CTLA-4, nivo + ipi; of course, we don't have such long-term follow up for PD-1 and LAG-3. But I think that's the setting for thinking about the rationale for combining a triplet regimen of PD-1, CTLA-4, and LAG-3. Dr. Diwakar Davar: So, Jason, in your mind, given the difference in the disparity and durability of the responses for the 067 regimen of nivo-ipi, and the RELATIVITY-047 regiment of nivo-rela, what is the standard of care in the U.S., and how does it change in the rest of the world, knowing that nivo-rela is not necessarily approved in all jurisdictions? Dr. Jason Luke: So this is a major complication in our field, is that there is perhaps not complete agreement across the world in terms of what the frontline standard of care should be. I think most United States investigators, or those of us that really treat melanoma most of the time, would suggest that a combination regimen, given the enhanced response rate and longer-term outcomes, should be the consideration for the majority of patients. In fact, in my practice, it's hard to think of who I would treat with a monotherapy PD-1 approach in the PD-1 naive setting. So either nivo + ipi or nivo + rela. As you alluded to however, in other regulatory settings throughout the world, combinations might not actually even be approved at this point. So PD-1 monotherapy would be the backbone of that setting. It does set up some complications when you think about a comparator arm; say you were going to look at various combinations, probably PD-1 monotherapy would be the worldwide comparator. You have to understand though, in the United States, I think that that's a less attractive option. Dr. Diwakar Davar: So in RELATIVITY-047, Dr. Ascierto and his colleagues are looking at generating a triplet. And in this case, they looked at this in the context of frontline metastatic melanoma, 46 patients. Very interestingly, the dose of ipilimumab studied here was 1 mg/kg through 8 weeks, not the 3 mg/kg every three weeks times four doses using 067, or even the low dose ipilimumab regimen that you studied in the second line setting, which was 1 mg/kg every 3 weeks for 4 doses. So let's talk about the results and specifically the implications of potentially studying lower doses of ipi. Dr. Jason Luke: I appreciate you raising that point. I think it's really important as we think about this dataset because this triplet regimen is not by any means the only version of a triplet that could be developed using these agents. So just to give the high-level numbers from the abstract, we see from these data that the overall response rate is described as 59% and 78%, a disease control rate with patients having an unreached link. So duration of response of unreached, and then the progression-free survival at about 5 months. So those are really interesting data. But as was alluded to, it's not totally clear to me that that's the best that we could do with this regimen.   Now, you alluded to this low-dose ipilimumab schedule at 1 mg/kg every 8 weeks, and it's really important to note that we have no benchmark for that regimen in melanoma oncology. And in fact, the one study that used that regimen, which was the adjuvant study of nivolumab and ipilimumab, known as CheckMate915, is in fact the only immune checkpoint inhibitor study in melanoma oncology that was actually negative. That study noted no benefit to adding ipilimumab at 1 mg/kg every 8 weeks on top of nivolumab, again, the adjuvant setting. So it's a little bit curious to then understand what it means in this study to have that amount of ipilimumab added to the rela-nivo backbone. And that manifests in a few different ways. We see the response rate here at 59%. Again, if you compare that just against the standard nivo + ipi dosing schedule, it's about the same. So is that really an advantage to having the triplet as compared to just doing standard nivo + ipi?   We do see that it manifests in a slightly lower rate of grade 3/4 immune-related adverse events, at 39%. That's a little bit lower than what we'd expect for standard nivo + ipi. But again, I think that that emphasizes to me the possibility that some efficacy was left on the table by using this very low dose ipilimumab regimen. I think that's really a concern. It's not clear to me that these triplet data really differentiate from what we'd expect with the already approved regimen of nivo + ipi. Therefore, it makes it difficult to think about how would we really want to move this regimen forward, or should there be more work done about dose and schedule to optimize how we might want to do this?  Dr. Diwakar Davar: As far as triplet therapy in the context of frontline metastatic melanoma, meaning triplet immune therapy, because there are at least several targeted therapy triplets that are FDA-approved, [but] not necessarily widely utilized. How would you summarize the future for triplet therapy? Do you think it's potentially attractive? Do you think it's very attractive with some caveats? Dr. Jason Luke: Well, I think it's attractive, and we have 3 independently active agents. And so I do think it's a priority for the field to try to figure out how we could optimize the therapy. We've had such a revolution in melanoma oncology, talking about 7.5-year median survival from CheckMate-067, but that still implies that 7.5 years, half the patients have passed away. There's more to do here. And so I do think it should be a priority to sort this out. I guess I would be cautious, though, about advancing this regimen directly to a phase 3 trial because it doesn't seem clear to me that this is optimized in terms of what the outcome could be. If we're willing to tolerate higher rates of toxicity from other dose schedules of nivo-ipi alone, then I think we should do a little bit more here to potentially explore the space that might be possible to increase that overall response rate a little more without getting into a completely exaggerated toxicity profile that would be unacceptable. So, I do think it's exciting, but there’s possibly more to do before really think about going big time with this. Dr. Diwakar Davar: Great. So now we'll switch gears and move from frontline metastatic melanoma to the second line and beyond looking at a new agent and contextualizing the effects of that actually in the frontline settings. So Abstract 9505 describes the efficacy and safety of lifileucel, which is essentially autologous tumor-infiltrating lymphocyte cell therapies, also known as TIL, in combination with pembrolizumab in patients with ICI naive, so not necessarily pretreated, but ICI naive metastatic or unresectable melanoma. This is data from the IOV-COM-202 Cohort 1A oral abstract presented by Dr. Thomas and colleagues. In this abstract, Dr. Thomas and colleagues are presenting data from the 1A cohort, which is the phase 2 portion of the frontline trial that is evaluating autologous TIL with pembro in checkpoint inhibited naive metastatic melanoma.  By way of background, TIL is FDA approved on the basis of several cohorts from a phase 2 trial. The data has been presented multiple times now by Drs. Sarli, Chesney, and multiple colleagues of ours. And essentially autologous TIL, which is generated from a surgical procedure in which a patient undergoes a surgery to extract a tumor from which T cells are then grown after ex vivo expansion and rapid expansion protocol. The entire procedure was essentially pioneered by several colleagues at the NCI, primarily Dr. Steve Rosenberg, and this approach produces objective response rates of approximately 31% to 36%. And the most recent publication demonstrated that at median follow up of approximately 2 years, the median duration of response was not reached. The median OS was about 14 months and PFS was about 4 months or so. So, can you contextualize the results of the abstract in the frontline setting? And then we'll talk a little bit about where we think this is going to go. Dr. Jason Luke: So I think this is a timely study given the recent approval. And in the abstract presented here, we see an early data cut from the PD-1 naive study, as you alluded to. So here we had 22 patients and distributed across various states of advanced melanoma. Ten out of the 22 had M1C, but there also were smatterings of earlier M1A and M1B at 18.2% and 9.1%. So this is important, as we think who the treatment population is that's going to be optimized with a TIL procedure. The median sum of diameters, meaning how much tumor burden the patients have, was about 5.5cm, and I'll note that that's a relatively modest amount of tumor burden, albeit not that unusual for an early-stage trial. So of the patients that participated, 8 had BRAF mutations so that's 36%. That's not that high, but it's reasonable. And I think the important overlying number, the response rate so far in the study, with about 17 months of follow up, was 63.6%, and that includes 22% or 23% having complete response. So those are interesting data.  And another point that was made in the abstract, which we've all seen, is that responses to TIL, all of immunotherapy but especially TIL, do seem to mature over time, meaning they deepen over time. So it's possible the response rate could go up some extent as we watch this study advance. So I think these are exciting data on some level. Also, a 63.6% response rate sounds pretty impressive, but we do have to put that in the context of a double checkpoint blockade, which we just got done discussing, gives you almost a 60% response rate, 59% response rate. So then the question really is: Is it worth the amount of effort that we could go into generating a TIL product in a treatment naive patient, and put them through the lymphodepletion that is associated with TIL and the high dose interleukin 2 treatment that accompanies the reinfusion of the TIL, if you're going to get a response rate that's roughly the same as what you would get if you gave them off the shelf nivo plus ipilimumab?  At this point it's a little bit hard to know the answer to that question. I think it could be possible that the answer is yes, because we don't know exactly which populations or patients are most likely to benefit from each of these therapies. And if it could be teased out who's not going to benefit to nivo + ipi from the get-go, then of course, we would want to offer them a therapy that has that frontline potential, durable, long-term response. But I have to say, on a one-to-one with TIL therapy, you get a lot of toxicity initially with the treatment; with nivo + ipi on the back end, you get a fair amount of toxicity with the treatment. How are we going to judge those two things? And I think we probably need a larger dataset to really have a good handle on that.  So these are interesting early data, but it's not totally clear to me that even if this holds up all the way through the trial, and we're going to talk about the design of the registration trial here in a second, a 60% response rate on its own without further biomarker stratification is a little bit hard for me to see in clinical practice why we would want to do that, given we can already just go off the shelf and give checkpoint inhibitors. Dr. Diwakar Davar: So that brings us to TILVANCE-301. So TILVANCE is a phase 3 trial. It's a registration intent trial by our Iovance colleagues evaluating the pembro-TIL regimen versus pembrolizumab alone. So in this phase 3 trial, approximately 670 patients will be randomized to either arm A, which is lifileucel + pembro. And in this arm A, patients are going to be getting lifileucel with the tumor resection, non-myeloablative lymphoid depletion, the lifileucel and abbreviated course of high-dose IL-2, and thereafter, continued pembro for the study mandated duration versus arm B, where patients will be getting just pembrolizumab monotherapy per label. Arm B patients, per the design, may cross over to receive TIL monotherapy at the time of central-blinded, radiology-confirmed disease progression.   The study design otherwise is fairly routine and, per most of our registration trials these days, patients have actually been permitted to receive neoadjuvant and adjuvant therapy, including checkpoint inhibitors, as long as the receipt of the therapy was more than 6 months prior to the inclusion of the patient in that registration trial. The dual primary efficacy endpoints as stated are BICR-assessed objective response rate as well as PFS, and the key secondary endpoint is overall survival.   So Jason, what are your thoughts on the study design and potentially the regulatory implications, particularly given, one, the control arm of pembro monotherapy, and two, the role of TIL crossover to receive TIL monotherapy at the time of BICR mandated progression for arm B? Dr. Jason Luke: So this goes to a few points that we've touched on already in the discussion here. When we think about the primary endpoints for this study, with one of them being overall response rate, one has to assume that that's a given that they would get that. I feel like that's a low bar. And we go back to that cross-trial comparison. If their results end up being that the response rates are about 60%, I don't know that that differentiates necessarily from what's already available in the field with combination immune checkpoint blockade. For the purposes of the study that would mean it's a positive study, so I think that would probably be good. But again, the comparator to pembrolizumab monotherapy, I think some of us would argue, isn't really consistent with what we would do with a patient in our clinic. So it's not that it's bad per se, but I think there's going to be a whole lot of cross-trial comparison. So if the study is positive, that would be good for getting the drug available. It's still a bit hard though, based on the preliminary data that I've seen, to imagine how this would have uptake in terms of utilization as a frontline therapy.  You alluded to the crossover, and I think there, the assumption is that patients who get TIL therapy as a second line perhaps would have an attenuated benefit. But I'm not sure that's really true. It certainly looks from the data that we have, like the patients who benefit most from TIL are going to be those who didn't respond to anti PD-1 in the front line. So I'm not sure how much difference there's going to be between first- and second-line TIL therapy, but those data will kind of wait to be seen. So I think it's an important study. Of course, the accelerated approval of TIL as a later line therapy is dependent on this trial being positive. So there is some risk that if this trial ended up not being positive, that that could have regulatory implications on the utility or availability of TILs, a subsequent line therapy. But all of these, I guess we'll have to wait to see the results. We do hope for a positive trial here, although I think it'll be nuanced to sort of interpret those data given that pembrolizumab monotherapy control arm.  Dr. Diwakar Davar: Fantastic. So we've learned a lot about TIL, both its use in the second-line setting and this very exciting but potentially risky frontline trial that is ongoing at some centers in the United States and certainly a lot of ex-U.S. enrollment.   So we'll now pivot to a related product which actually belongs to a much larger class of agents that are antigen specific T-cell therapies in a variety of different formats. And that is Abstract 9507, which is the “Phase 1 safety and efficacy of IMC-F106C, a PRAME × CD3 ImmTAC bispecific, in post-checkpoint cutaneous melanoma (CM).” Now, in this abstract, Dr. Omid Hamid and colleagues reported the results of this phase 1 trial. As a disclosure, I'm an investigator and the last author on this manuscript. Jason, it would be important for our audience, for us to maybe firstly, outline the PRAME as a target, and then the ImmTAC as a platform prior to discussing these results. So let's start with the target PRAME, which I think is a target that you know well. So why don't you start with the target and we'll talk a little bit about that and then the platform? Dr. Jason Luke: Yeah, so I think for the audience, being aware of PRAME, or the Preferentially Expressed Antigen in Melanoma, is going to be quite important moving into the future. So PRAME as a therapeutic target is a cancer testis antigen that's overexpressed in tumor tissues. And of course the name has melanoma in it, but it's not uniquely present in melanoma. So the expression patterns of PRAME as a target are very high in melanoma. So in cutaneous disease, this is upwards of almost 100%, somewhere between 95% and 100%, in metastatic melanoma tissues. And PRAME has several different roles on a molecular level, although I don't think for our purposes here, it's so much important to be aware of them, but rather that this is a very highly expressed target, which then can make it attractive for using T cell receptor-based therapies. And so in the case we're talking about here on the ImmTAC platform, that's a CD3 PRAME×CD3 bispecific approach. But of course there are other approaches that can also be taken, such as TCR T cells that directly go after PRAME itself. Dr. Diwakar Davar: Let's now talk about the platform and how it differs from some of the other antigen targeting platforms that you have just alluded to. I think the Immtac platform is basically a fusion protein comprising engineered TCRs with a CD3 specific short chain variable fragment. And then the engineered TCR therefore binds antigens in an HLA dependent fashion. But you know quite a lot about some of these alternative platforms, and I think it'll be important to contextualize for the audience the difference between ImmTAC, which is a prototype drug that is already approved in the context of tebentafusp. But how does this differ from some of the other more nuanced platforms, such as the Immatics TCR or TCR platform and TScan TCRT nanoplasmonic platform.  Dr. Jason Luke: Right. So the ImmTAC platform as alluded to is already approved on the market with tebentafusp, which is the gp100-CD3 bispecific molecule. And the advantage of that approach is infusion off the shelf of a drug. The downside of it is that it is a weekly dosing strategy as it stands now. And there are some complicated disease kinetics associated with treatment response, which we'll come back to in the context of the PRAME bispecific. Those are, in contrast with T-cell receptor-transduced T cells, as an alternative strategy, which is a form of adopted cell transfer. So we just got done talking about TIL therapy, which of course, is trying to take lymphocytes out of the tumor and grow them up and then give them back. Here with TCR-transduced T cells, we're talking about taking leukopak from the blood and then using different transfection approaches to try to insert into the lymphocytes of the patient a T cell receptor that recognizes to a certain cancer antigen, in this case, PRAME.  So you alluded to a couple of different companies that have different platforms to do this. Immatics has a molecule called IMA 203, for which there have been data disclosed in the past year, again showing some very interesting responses in patients who have highly refractory melanoma. That process, though, again, does require lymphodepletion before you reinfuse the cells. Again, in contrast, the ImmTAC, which is an off the shelf revenue administer, there you have to make the product and then bring the patient back, lymphodeplete, and give the cells back. Immatics platform uses a viral transfection vector. The T scan approach that you alluded to before uses an approach of a mixed system on multiple HLA backgrounds to try to get past HLA-A*02:01 only, and in this case, uses a plasmid-based transfection syndrome that perhaps can be more broadly utilized given the lack of a lentiviral vector.   So this is a complicated area of technology that starts to get into immune engineering, and I think for the purposes of this discussion, we don't want to belabor it. But both of these technologies, talking about the CD3 bispecific with the off the shelf aspect of it and the adoptive cell transfer, each of these using a T cell receptor-based therapy to try to go after PRAME, I think have very high upsides, and I think we'll initially see it in melanoma over the next year or so. But this is likely to be relevant to multiple tumor types beyond melanoma.  Dr. Diwakar Davar: So let's discuss the results of this phase 1 trial. IMC-F106C, like all other ImmTAC, is administered intravenously and does require step-up dosing. You alluded to the fact that the tebentafusp was approved, and it's one of those drugs that is fortunately otherwise administered weekly, which can be difficult for the patient and requires at least the patient spend the first 3 doses overnight under some kind of monitoring, whether it's in the hospital or extended outpatient monitoring, for at least 23 hours. The efficacy of this agent and this platform appears to be surprising in that you tend to see a relatively low RECIST response rate. We'll have you comment a little bit on why that is the case and what may be the role of ctDNA, as opposed to conventional RECIST in assessing response.   At least in this trial, they mandated pre-testing, but did not require it for study enrollment. And pre-positivity was defined using immunohistochemistry with a relatively low H-score of 1%. And the molecular response definition was a 0.5 log or a 68% ctDNA reduction just prior to the first imaging assessment. So how do you contextualize the results? But maybe before you talk a little bit about the results, the ctDNA aspect, that was a recent publication by Drs. Rich Carvajal, Alex Shoushtari, and I think you are also involved in that.  Dr. Jason Luke: So, I think an interesting observation around tebentafusp has been that ctDNA may be a better predictor of long-term outcomes. And how you define ctDNA response is still something that the field is grappling with, albeit that I think is going to be an important consideration as we think about these novel therapies, these ImmTACs and other CD3 engagers moving into the future. But for the purposes of the abstract here, we see that in the population of patients treated, there were 46 patients with cutaneous melanoma. The majority got monotherapy with IMC-F106C, and that's the PRAME bispecific. So 40 patients that got monotherapy and six who got a combination with checkpoint inhibitor. All these patients had prior treatment with immunotherapy, and most of them had PD-1 and CTLA-4 antibody with a small spanner that also had BRAF inhibitors.  In terms of that PRAME testing that you alluded to, based on the immunohistochemistry H-score greater than 1%, 35 out of 40 patients were positive, so they defined 5 as negative. And we could come back if we have time, but there are other ways to do PRAME testing as well that I think may become unique for different agents, maybe an important biomarker. In the data, 31 out of the 46 patients were RECIST evaluable. The outcomes of those patients were to note that the response rate was 13%, which was four partial responses. But 35% of patients had tumor regression with a disease control rate at 65%. It was clear that there was an enrichment by PRAME positivity for both progression free and overall survival. So those patients who had obvious positivity essentially had a doubling of the PFS and more than the doubling of the OS, 2.1 to 4.1 months for TFS and landmark OS, 40% to 94%. So I think these are quite intriguing data.  It does suggest that for the vast majority of patients, we do see some induction of the antitumor effect, albeit that RECIST might undercall the effect. And so this may become another area where the ctDNA monitoring might be able to help us to understand who is likely to have really long-term benefit from this therapy. And given the number of emerging treatments that we have for melanoma, we might be able to really focus in on that group of patients in terms of optimizing how we would use this drug moving into the future. Dr. Diwakar Davar: So you talked about a response rate, and at first glance, this response rate is a little underwhelming. We're talking about 4 out of 31 RECIST evaluable patients, 13%. So it's in the double digits, but barely. So how enthusiastic are you about the results? How does it contrast with at least the publicly known data from other brain targeting approaches, such as the IMA203 agent, understanding that while they may be all targeting somewhat the same target, they are actually extraordinarily different platforms. One’s off the shelf, one’s highly customized. How do you contextualize the results? How would it contrast with other cellular approaches?  Dr. Jason Luke: I think it's important, again, to emphasize the point you made, which is that they're very different kinds of treatments. So even though they both target PRAME, they're going to be differently useful, and they could be quite useful for different groups of patients. And so here we see that there is a subfraction of patients who are deriving long-term benefit. And we commonly have an argument in our field about, is overall response rate really a useful monitor that describes a patient-centric outcome? While, of course, patients like to know their tumors are shrinking, what they want the most is for the tumors not to get worse and for them not to pass away from cancer. So I think I'm enthusiastic about these results, but emphasizing the point that we need to better understand who is going to benefit the most from this CD3 bispecific PRAME approach and how we're going to be able to harness that into long term benefit for patients because there's no doubt that an off the shelf therapy has a high degree of value relative to adoptive cell transfer, which sort of requires a big wind up.   So when you say, what does it contrast with? Well, the data for IMA203 has shown more than a 50% response rate in patients with more than 5 lines of therapy for metastatic disease. That really looks quite exciting. And several of those patients are now out for quite an extended period, meaning 2 years or more given only a single dose of IMA203. But again, the caveat being, you have to make the cell product for the patient, and that takes time. You lymphodeplete the patient, not all patients can tolerate that in the refractory disease setting, and then they have to be able to tolerate the reinfusion of the cells. And so this drug, IMC-F106C, looks very promising. Moving into the earlier phase trial that we'll talk about, I think the TCR T cell program has a lot of upsides for patients, especially with refractory disease. And so I think these two different approaches are really on parallel tracks. They both target PRAME, but I don't think they necessarily need to be compared one to one, as if they're going to go head-to-head with each other. Dr. Diwakar Davar: So now we'll talk a little bit about the frontline setting, because on the basis of some of these results, Immunocore is now exploring IMC-F106C frontline melanoma. This trial is actually being presented as a trial in progress at this meeting by Georgina Long and colleagues. Some of us are co-authors in that abstract. And in this study, HLA-A*02:01 positive patients with advanced unresectable melanoma will be randomized one to one to the combination of IMC-F106C, which actually, I think after this meeting will be known as bre-ni in combination with nivolumab versus nivolumab regimens, which will either be nivo or nivo-rela, investigators choice and likely dependent on region. So what do you think of the challenge of this trial? We talked about some of the challenges of the TILVANCE trial earlier. But what is going to be the challenge of this trial and in this setting, particularly given the response rates that we've seen so far? Dr. Jason Luke: Yeah, so, similar to comments we had before, thinking about what the optimal control arm is for a study like this is difficult, and so that'll be important as we think about interpreting the results. One has to assume for the purpose of this conversation that it is a positive trial, and that adding the PRAME bispecific theory does lead to an improvement in progression free survival relative to those in checkpoint alone approaches. And I think the magnitude of that difference is going to be of some relevance. And then I think importantly, also figure out who needs this treatment and who's going to benefit long term are going to be really important considerations.  We alluded to how this drug requires an intensive dosing period at the get go, and so telling patients that they need to come in weekly or bi-weekly initially for some number of weeks before they switch to a longer-term intermittent regimen, that comes with real world considerations for patients, their families, their finances, etc. So the benefit has to be clearly obvious that makes it worthwhile doing that, again, because a default could be giving drugs that we've had for 10 years with the nivolumab and ipilimumab. So there's going to be a lot of cross-trial comparison that is going to necessarily have to take place here to think about what these results really mean in the context of other available therapies.  I think the study is reasonable to do. I think this is a very active agent. There's no doubt there's a subset of patients who seem to benefit a lot from it. And I would just emphasize the point that that's probably going to be the most important thing to really drill down on is under the assumption there's a positive trial, we need to know who those people are so we could optimize giving this kind of a treatment to them. Dr. Diwakar Davar: I guess one important point to underscore what Jason said about potential predictive biomarkers, I think as part of the presentation, Dr. Hamid and colleagues will be talking about a candidate predictive biomarker of this agent, which is potentially class specific and not necessarily agent specific of a T cell signature that potentially could define patients who are more likely to benefit from this agent.  So, Jason, as always, thank you for sharing your expertise and insights with the team today. We certainly look forward to catching up again for our wrap up episode after the annual meeting where we'll talk about some of the data that we could not talk about, particularly the late breaking abstracts and other key advances that will shape the future of, certainly the field of immunotherapy and melanoma, potentially the field of cancer immunotherapy at large. Dr. Jason Luke: Oh, thanks very much for the opportunity. Dr. Diwakar Davar: And thank you to our listeners today. You'll find the links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. So thank you, and we'll see you soon.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:       Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Jason Luke:    Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio      
5/24/202434 minutes, 42 seconds
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ASCO24: The Era of the ADCs in NSCLC

Drs. Vamsi Velcheti and Nathan Pennell discuss key lung cancer abstracts from the 2024 ASCO Annual Meeting, including data from LUMINOSITY and ADAURA, novel therapies in KRASG12C-mutant advanced NSCLC, and the need for effective adjuvant therapies for patients with rare mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at Perlmutter Cancer Center at NYU Langone Health. Today, I'm delighted to welcome Dr. Nathan Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Dr. Pennell is sharing his valuable insights today on key abstracts in lung cancer that will be presented at the 2024 ASCO Annual Meeting. You'll find our full disclosures in the transcript of the episode.  Nate, it's great to have you here on the podcast. Thank you for being here. Dr. Nathan Pennell: Thanks, Vamsi, for inviting me. I'm always excited for the ASCO Annual Meeting, and we have a tremendous amount of exciting lung cancer abstracts. I know we're not going to discuss all of them on this podcast, but even exciting Plenary presentations coming up.  Dr. Vamsi Velcheti: So, one of the abstracts that caught my attention was Abstract 103, the LUMINOSITY trial, which will be presenting the primary analysis at the meeting. So, there's a lot of buzz and excitement around ADCs. Can you comment on this abstract, Nate, and what are your thoughts on key takeaways from this abstract?  Dr. Nathan Pennell: Absolutely, I agree. This is really an exciting new potential target for lung cancer. So historically, when we think about MET and lung cancer, we think about the MET exon 14 skipping mutations which are present in 3% or 4% of adenocarcinoma patients. And we have approved tyrosine kinase inhibitors, small molecule inhibitors that can be very effective for those. What we're talking about here is actually an antibody drug conjugate or ADC telisotuzumab vedotin, which is targeting the MET protein over expression in non-squamous EGFR wild type advanced non-small cell lung cancer. The LUMINOSITY was a single arm, phase 2 study of teliso, and first of all, I think we have to define the patient population. So, these were MET over expressing non-small cell lung cancer by immunohistochemical staining. So, it included both what they considered MET high expression and MET intermediate expression, both of which had to be 3+ IHC positive on 25% to 50% of cells in the intermediate and 50% or higher in the high expressing group. They were treated with the ADC and had pretty promising results, a response rate of 35% in the MET high group and 23% in the intermediate group. Duration of response at nine months and 7.2 months in those two groups, and the PFS was five and a half and six months. So I would say in a previously treated population, this was relatively promising and potentially defines a completely new and unique subgroup of biomarker defined patients. So, Vamsi, I'm curious, though, if this ends up moving forward to further development, what your thoughts are on adding yet another biomarker in non-small cell lung cancer? Dr. Vamsi Velcheti: Yeah, I think it's certainly exciting. I think for this population, we really don't have a lot of options beyond the second line, and even in the second line, docetaxels are low bar. So,I think having more options for our patients is certainly outcome development. And I think MET IHC is relatively easy to deploy in a clinical setting. I think we already test for MET PD-L1 IHC routinely, and now recently, as you know, HER2 IHC given approval for ADCs, HER2 ADCs there in that space. So, I think from a technical standpoint, I don't see a big barrier in terms of adding an additional IHC marker. And usually, the IHC testing is pretty quick. And I think if you have a therapeutic approval based on IHC positivity, I think certainly from an operational standpoint, it shouldn't be a very complicated issue. Dr. Nathan Pennell: Yeah, I agree. This is cheap. It's something that can be done everywhere in the world. And as you said, in addition to diagnostic IHC, we're already looking at PD-L1, and probably moving towards doing that for HER2. This is really wonderful that we're moving into kind of the era of the ADCs, which is opening up a whole new therapeutic group of options for patients. Dr. Vamsi Velcheti: So, the other abstract that caught my attention was like, the Abstract 8005. This is the molecular residual disease MRD analysis from the ADAURA trial. The ADAURA trial, as you all know, is the trial that led to the FDA approval of adjuvant use of osimertinib in patients with EGFR mutant stage 1B through 3A non-small cell lung cancer. And in this trial, osimertinib demonstrated significant improvements in DFS and OS. And in this particular study, Abstract 8005, the authors looked at the role of MRD in predicting DFS in the study. And after 682 patients who were randomized, 36% of the patients had samples to look at MRD post- surgery. And in the trial the MRD status predicted DFS or event free survival at 36 months with a hazard ratio of 0.23. And the MRD status had a median lead time of 4.7 months across both the arms, both osimertinib and the placebo arm. So, suggesting that MRD could potentially identify high risk subgroups of patients post-surgery to tailor personalized approaches potentially in this population. So, Nate, in your practice, of course, we don't have a clinically validated approach yet to kind of use MRD in this setting, but if we have an option to use an MRD based assay, do you think that would potentially be an opportunity to perhaps escalate or de-escalate adjuvant strategies with TKIs in the adjuvant setting? Do you see value in using MRI assays post- surgery? Dr. Nathan Pennell: Yeah, I think this is a really important study because this is such an important topic around adjuvant targeted treatment. So, of course, ADAURA really changed how we treated people with EGFR mutant lung cancer who underwent surgical resection, because we know that the three years of osimertinib significantly improved disease-free survival and overall survival. But there's still a lot of questions being asked about, is that affordable? Obviously, we're putting a lot of resources into three years of treatment, and not everyone necessarily needs it. There may well be people who are cured with surgery alone and adjuvant chemotherapy. And then what about duration? Is three years enough? Do we need even longer treatment, or do we need shorter treatment? And up to date, we haven't really been able to tell people at risk of recurrence other than the pure odds-based risk based on their stage.   And the assay that was used in the ADAURA study was a personalized tumor informed assay based on the resected tumor. It's unclear to me whether this was just a subgroup of people that had this done or whether they tried to do it in all 600 patients and only, it looks like they were successful in about 32% of people. Maybe about a third were able to successfully have a tumor informed assay. So, the first question is, “Can you use this to help guide who needs treatment or not?” And I think what they showed was only about 4% of people in osimertinib arm in 12% had MRD positive at baseline after surgery. So probably, upfront testing is not really going to be all that helpful at determining who's at high risk and needs to be treated.   Interestingly, of those who were positive, though, most of them, or 80% of them, did go MRD negative on osimertinib. And what I found really interesting is that of those who did have a recurrence, 65% of them did have the MRD test turn positive. And as you mentioned, that was about five months prior to being picked up radiographically, and so you can pick them up sooner. And it also looks like about two thirds of recurrences can be identified with the blood test. So that potentially could identify people who are recurring earlier that might be eligible for a more intensive treatment. The other thing that was really interesting is of those who recurred in the osimertinib arm, 68% of them happened after stopping the osimertinib, suggesting that for the majority of patients, even those not necessarily cured, they seem to have disease control while on the osimertinib, suggesting that maybe a longer duration of treatment for those patients could be helpful. The problem is it still isn't necessarily helpful at identifying who those people are who need the longer duration of treatment. So, definitely an important study. I think it could be useful in practice if this was available clinically, especially at monitoring those after completion of treatment. I think as the sensitivity of these MRD assays gets better, these will become more and more important. Dr. Vamsi Velcheti: I think it's a little bit of a challenge in terms of standardizing these assays, and they're like multiple assays, which are currently commercially available. And I think the field is getting really complicated in terms of how you incorporate different assays and different therapeutics in the adjuvant space, especially if you're kind of looking at de-escalating immunotherapeutic strategies at the adjuvant setting, I think, makes it even more challenging. I think exciting times. We definitely need more thoughtful and better studies to really define the role of MRD in the adjuvant space. So, I guess more to come in this space. Dr. Nathan Pennell: Vamsi, I wanted to ask you about another really interesting Abstract 8011. This is a subgroup of the AEGEAN perioperative study for early-stage resected non-small cell lung cancer. This abstract is specifically looking at baseline N2 lymph node involvement in stage 2A-3B with N2 positive patients in an exploratory subgroup analysis. What are your key takeaways from the study?   Dr. Vamsi Velcheti: I felt this was a very interesting abstract for a couple of reasons. As you know, this is the AEGEAN trial, the phase 3 trial that was reported earlier last year. This is a perioperative study of durvalumab plus new adjuvant chemotherapy versus new adjuvant chemotherapy alone and adjuvant durvalumab plus placebo. The study obviously met its primary endpoint, as we all saw, like the event-free survival. And here in this abstract, the authors present an exploratory subgroup analysis of patients who had N2 lymph node involvement prior to study enrollment. So, in this study, they were focusing on perioperative outcomes. And one of the issues that has come up multiple times, as you know, in a lot of these preoperative studies, is the impact of neoadjuvant chemo immunotherapy on surgery or surgical outcomes. And consistently, across a lot of these trials, including the CheckMate 816, about 20% of patients don't end up making it to surgery. So in that light, I think this study and the findings are very interesting. In this study, they looked at patients who had N2 nodal involvement and of the patients with N2 nodal involvement, the surgical operability or the number of patients who completed surgery was similar in both the groups. So, there was no significant difference between patients who received durva versus chemotherapy and also among patients who had N2 subgroup who had surgery, similar proportions of durvalumab and placebo arms had open versus minimally invasive versus pneumonectomy. So durvalumab didn't have a negative impact on the type of surgery that the patients had at the time of surgery. So overall, the findings were consistent with other trials, perioperative trials that we have seen. So, the surgical outcomes were not negatively impacted by adding immunotherapy in the neoadjuvant perioperative space. So, this is consistent with other trials that we have seen. And also, the other issue, Nate, I'd like to get your opinion on is, across the board, in all the perioperative trials we have seen that about 20% of the patients actually don't end up making it a surgery. And of course, most of these perioperative trials, a lot of these patients are stage 3 patients. And my take on this was that there’s probably a little bit of a patient selection issue. We generally tend to err on the side of operability when we have a stage 3 patient discussed in the tumor board, sometimes feel like the patient may downstage and could potentially go to surgery. But even in the real world, in stage 3 operable patients, what proportion of patients do you think don't end up going to surgery? Dr. Nathan Pennell: That is such an important question that I don't think we have the best answer to. You're right. All of these perioperative studies have a relatively high- sort of 20% to 30% of people who enroll on the studies don't necessarily go to surgery. And I don't think that they've done as great a job as they could in all of these trials describing exactly what happens to these patients. So in the real world, obviously not everyone would be fit enough to go to surgery or might progress in the time between when they were diagnosed and the time as planned for surgery. But probably more of them would go to surgery if they weren't getting neoadjuvant treatment, because that would be their initial treatment. The question is, of course, is that the right choice? If someone gets 12 weeks or nine weeks of neoadjuvant treatment and then a restaging scan shows that they've had progression with metastatic disease, are those really the people that would have been optimally treated with surgery upfront, or would they just have had recurrence on their first postoperative scan? So, it's really an important question to answer. I think the bigger one is, is the treatment preventing them through toxicity from going to treatment? And I think the studies have generally felt that few patients are missing out on the option of surgery because of toxicity being caused by the IO. And in the AEGEAN study, for example, in this subgroup, a slightly numerically higher percentage of patients in the durvalumab arm actually underwent surgery compared to those who got neoadjuvant chemo. So, it doesn't seem like we're necessarily harming people with the neoadjuvant treatment. But I know that this is a concern for patients and doctors who are undergoing this approach. Dr. Vamsi Velcheti: Definitely, I think having multiple data sets from perioperative trials, looking at the relative impact of IO on the safety and the nature of the surgery is going to be important, and this is a very important study for that reason. Dr. Nathan Pennell: Can I ask you another thing that I thought really interesting about this particular one is they looked at the difference between those with single station N2 and multi station N2. And I know this is one of those, should we be operating on people who have multi station N2 disease? And the AEGEAN study did include people who had multiple N2 stations where perhaps in the pre-IO era, these would have been treated with definitive chemoradiation and not surgery at all. But the disease-free survival hazard ratio was essentially the same for multi station N2 as it was in the overall population. So, has that changed the way we're approaching these patients in these multidisciplinary discussions? Dr. Vamsi Velcheti: Absolutely, Nate. I think surgical operability is in the eye of the beholder. I think it depends on which surgeon sees the patient or how the discussion goes in the tumor boards, as you know. Certainly, I think with this optionality of having a chemo IO option and potential for downstaging, kind of pushes, at least in our practice, more of these patients who are multistation, who would have otherwise gone down the chemoradiation route are now actually going through neo adjuvant chemo IO and with the hope that they would make it to surgery. So, I think it's an interesting change in paradigm in managing our locally advanced patients. So, I think it's certainly interesting, but I guess to your point, there clearly are some patients who probably should just have chemoradiation upfront, and we may be kind of like delaying that definitive chemoradiation approach for at least a subset of patients. So, at the end of the day, I think it's a lot of clinical decision-making and I think there's going to be a little bit of art to managing these patients and it's going to be really hard to define that population for a clinical trial.  Dr. Nathan Pennell: Yeah, clearly, multidisciplinary discussion, still very important for earliest age non-small cell lung cancer patients. If we move back to metastatic lung cancer, let's talk about Abstract 8510 looking at one of our newer, exciting biomarkers, which are the KRASG12Cmutant non-small cell lung cancer. So this is a study of a second generation KRASG12Cinhibitor, olomorasib, which was combined with pembrolizumab, the anti PD-1 antibody, in patients with advanced KRASG12C mutant non-small cell lung cancer. This is something that has been tried before with first generation G12C inhibitors, with some concerns about how safe it was to do that. So, Vamsi, what did you learn from this abstract? Dr. Vamsi Velcheti: Definitely, I think one of the concerns that we've had in other trials is like the cumulative toxicity of adding checkpoint inhibition to G12C inhibitors, especially the sotorasib CodeBreaK trial, where we see increased rates of grade 3, 4 transaminitis. So, it is encouraging to see that some of the newer agents have less of those issues when it comes to combining the checkpoint inhibition. So especially with KRASG12C, as you know, these are patients who are smokers, and often these are patients who have high PDL-1 could potentially also benefit from immunotherapy. In order for these KRASG12C inhibitors, in order to move these targeted therapy options for these patients to the front line, I do think we need to have substantial comfort in combining the checkpoint inhibitors, which is a standard treatment approach for patients in the frontline setting. I think this is exciting, and I think they're also like, as you know, there are other KRASG12C inhibitors also looking to combine with checkpoint inhibition in the frontline settings. So, we'll have to kind of wait and see how the other agents will perform in the setting. Dr. Nathan Pennell: Yeah, I completely agree. I think this is such an important area to explore specifically because unlike our other targeted oncogenes like EGFR and ALK, we have multiple options for these patients, both immunotherapy and targeted treatments. And if we could think about sequencing them or even combining them and if it could be done safely, I think that would be well worth investigating. There still was significant toxicity in this trial; 30% of people had diarrhea, even at the reduced dose, and there was transaminitis at sort of about 20% or so, although probably at a manageable level. But the response rate was really quite promising. And these are all previously IO and mostly G12C TKI pre-treated patients still had a response rate of 63%. And in those who were naive to IO and TKIs, it was 78% response rate. So, if it could be done safely, I think it's definitely worth pursuing this in further trials. Dr. Vamsi Velcheti: And also, there's some data, preclinical data, like looking at G12C inhibition. And also we have known with MET inhibition for a long time that it could potentially augment immune responses and could be having some synergistic effect with IO. So, we'll have to wait and see, I think. But safety is really the top in mind when it comes to combining these agents with checkpoint inhibitors. So, it's really encouraging to see that some of the newer agents may be more combinable IO. Now moving on to the next abstract, and moving on to, again, the early-stage setting. So, Abstract 8052 from our colleagues in Princess Margaret reported outcomes in early-stage non- small cell lung cancer in patients with rare targetable mutation. This is actually becoming increasingly more relevant because we are seeing at least, like with the ALINA data, with the ALK and EGFR, now with ADAURA, we know that these patients don't benefit with adjuvant immunotherapy, especially some of these rare oncogene living mutations, other than like G12C. So I always struggle with this. When you have early-stage patients, with, let's say, a ROS or a RET, where we just don't have data, and we know that those are poor actors because biologically these are aggressive tumors. So, there's a really odd clinical question to ask in terms of, what is the role of adjuvant immunotherapy? Of course, this trial and this abstract are not really addressing that. But what is your take on this abstract? If you could just summarize the abstract for us. Dr. Nathan Pennell: Sure. Well, I think this is incredibly important, and this is an area near and dear to my own heart. And that is, of course, the whole landscape of how we manage early-stage patients has changed with both ADAURA, because we now have effective treatment in the adjuvant setting for EGFR mutant patients, and now more recently with the ALINA trial for adjuvant alectinib for ALK positive patients now being FDA-approved. So, what that means is we actually have to be testing people at diagnosis even before they would be getting adjuvant treatment, and potentially before even surgery to look for these targets. We need the PD-L1 status, we need EGFR and ALK. And if you're going to be looking at these biomarkers, I think there is a reasonable argument to be made that you should be doing broad testing for all of the targetable oncogenes in these patients. There are some studies suggesting that there's value to this and identifying them for treatment at the time of recurrence. But we also know that these patients are at high risk of recurrence and probably need to be investigated, at least in trials for the adjuvant setting. So, this particular study looked at 201 resected, mostly adenocarcinoma patients, and then they basically sequenced them for all of the targeted oncogenes. And they were quite common, perhaps even more common than you might expect in an advanced population. So, 43% of them had KRASG12C mutations, 13% had EGFR Exon 20 mutation, ERBB2 or HER2 mutations found in 11%, MET mutations in 10%, ALK in 7%, ROS1 in 6%, BRAF in 5%, and RET in 2%. So quite common to find these targetable oncogenes in this particular population, perhaps a somewhat biased population at Princess Margaret Hospital, but very common. And then they looked at the outcomes of these patients without targeted adjuvant treatment. And what they found was there was a very high rate of recurrence. So, relapse-free survival was pretty high in these patients across different stages, and generally their prognosis was worse than the more common KRASG12C patients. Most of these, in particular the HER2 mutant patients, seem to have a significantly worse relapse free survival. Interestingly enough, though, that did not carry over to overall survival. Overall survival was better in those who had targetable oncogenes. And my guess is that that probably had to do with the availability of targeted treatments at the time of recurrence that may have impacted overall survival. But I do think that this particularly highlights the need, the unmet need for effective adjuvant treatment in these patients. And most of them, with the exception of KRAS and perhaps BRAF, perhaps MET unlikely to benefit from adjuvant immunotherapy, as you mentioned. And so, I think we really need to be investing in trials of adjuvant targeted treatments in these populations.  Dr. Vamsi Velcheti: Yeah, this is an area that we really don't have a lot of data. But Nate, a question for you. So tomorrow you have a patient with RET fusion, stage 2, N1 disease. What would you do? Would you offer them an adjuvant RET inhibitor? Dr. Nathan Pennell: I think I would search really hard for a trial to give them access. But if you really want to know what I think, and I'm usually willing to tell people what I think, I think the proof of concept is there. I think we know that in the setting of highly effective and very tolerable adjuvant targeted treatment in the EGFR space with osimertinib, in the ALK space with alectinib, if anything, drugs like selpercatinib and pralsetinib in RET fusion positive lung cancer in the advanced setting are just as well tolerated and easily as effective and long lasting. And so, I think if you did a trial and they are doing trials looking at these drugs in the adjuvant space, almost certainly you're going to see the same really dramatic disease-free survival benefit from these treatments, which, at least in the EGFR space, seems to have translated into an improvement in overall survival. And so if I had a stage II or a resected stage 3, especially a RET fusion positive patient today, I would definitely talk to them about off-label use of a RET inhibitor if I could not find a trial. Now, I understand that there are going to be reimbursement issues and whatnot associated with that, but I think the extrapolation is worth discussing. Dr. Vamsi Velcheti: Yeah, I think it's really challenging because some of these fusions are so rare and it's hard to really do large adjuvant trials for some of these rarer subgroups. Nate, fascinating insights. Our listeners will find links to the abstracts we discussed today in the transcript of the episode. And Nate, I look forward to catching up with you at the Annual Meeting, and again after the meeting for our wrap up podcast to discuss the practice-changing lung cancer abstracts and highlights from the Plenary Session. Thank you so much for joining us and sharing your insights today. Dr. Nathan Pennell: Thanks for inviting me. Vamsi. I look forward to touching base after we get to see all the late-breaking abstracts. Like I said, this is, I think, a year for lung cancer with a lot of exciting data, and I know we'll have a lot to talk about. Dr. Vamsi Velcheti And thank you so much to all our listeners for your time. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate and review and subscribe wherever you get your podcast.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers: Dr. Vamsi Velcheti @VamsiVelcheti   Dr. Nathan Pennell @n8pennell   Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures: Dr. Vamsi Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 
5/23/202426 minutes, 7 seconds
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Spotlight on Breast Cancer at ASCO24

Dr. Allison Zibelli and Dr. Megan Kruse discuss the potential benefit of endocrine therapy in ER-low breast cancer; the efficacy and tolerability of triplet therapy in PIK3CA-mutated, HER2-negative locally advanced or metastatic breast cancer; and more key research that will be featured at the 2024 ASCO Annual Meeting.  TRANSCRIPT Dr. Allison Zibelli: Hello, I'm Dr. Allison Zibelli, your guest host of the ASCO Daily News Podcast today. I am an associate professor of medicine and a breast medical oncologist at the Sidney Kimmel Cancer Center of Jefferson Health in Philadelphia. My guest today is Dr. Megan Kruse, a breast medical oncologist and director of breast cancer research at the Cleveland Clinic Taussig Cancer Institute. We'll be discussing key abstracts in breast cancer that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod.  Megan, it's great to have you back on the podcast. Dr. Megan Kruse: Thanks, Alison. Happy to be here. Dr. Allison Zibelli: So, let's begin with Abstract 505. This was another analysis of the SWOG S1007 (RxPONDER) trial, which was the trial that was looking at premenopausal women with intermediate risk oncotype scores. And do they benefit from chemotherapy? If you analyze the whole group, they do benefit from chemotherapy, but what this study questions is whether we can pull out the subset of these patients that actually benefit from chemotherapy? And what they tried doing was measuring various endocrine reproductive hormones and found that anti-mullerian hormone over 10 was the only one that predicted for chemotherapy benefit. What are your key takeaways from this study? Will it help us figure out who is truly postmenopausal biochemically? Dr. Megan Kruse: I think this is really promising. This is one of the toughest situations in clinic, honestly, when you have a premenopausal woman who has an intermediate oncotype risk. We know that chemotherapy is not going to make a huge difference potentially in their breast cancer outcomes, but it may add to some small differential benefit. I think that many of our patients are really afraid about leaving any impactful therapy on the table. And so, it'd be nice to have another marker to help sort out who in this group will really benefit. And the AMH levels, I think, are something that are very accessible for most practices, easily orderable. And it seems like this cutoff of 10 is a very well-known cut point in the AMH interpretation, and a pretty clear-cut point. So, I think it gives a little bit more objective view of who may actually benefit or not.  When you look at the results shown in this abstract, for the women in the recurrence score less than 25 receiving chemotherapy followed by endocrine therapy, they had a benefit in five-year invasive disease-free survival of 7.8%. When you look at those oncotype reports and they suggest how much benefit you might get, that's right around the same number you see. So, I think that's supporting that this is the subgroup that's benefiting.  When you look at those patients with AMH less than 10, they actually had a negative 1.7% difference in overall survival. So, you wonder, are we harming these patients by giving them chemotherapy? I think that's too far of a stretch to say. I wouldn't be worried about harm. But hopefully, we can stop giving chemotherapy to patients who truly are not going to benefit if we have an additional biomarker of response. That's what the promise is for this.  So again, another potentially actionable abstract that we can put into practice pretty quickly. It’s going to be hard to know how to use this, also in the context of the upcoming OFSET study or BR009, which is of course the study in the same group of premenopausal patients with node-negative or 1-3 lymph nodes involved, and intermediate oncotype scores, randomizing them to endocrine therapy with ovarian suppression versus chemoendocrine therapy. It would be kind of nice to see the AMH levels incorporated into that model to see if the same trend holds true. But I think we go back to the TAILORx and RxPONDER studies many times as good quality data, and the trend here is really striking.  Dr. Allison Zibelli: I really like this study because one of the things I often struggle with in the clinic as a practicing breast oncologist is who's really in menopause. And we end up having these fights with the gynecologists where sometimes our opinions differ. And it would be really nice to have something this clear cut to say, “You’re in biochemical menopause or you're not.” So, I look forward to seeing this used in a lot of different ways in the future.  Dr. Megan Kruse: Yeah, I agree. And I think it's based on the other markers we have with estrogen levels, with FSH levels. If you're checking those sequentially in patients, we know they go up and down, and it's really hard to tell what we are capturing at this single point in time. And maybe that's what we're seeing in this analysis is that the AMH is a little bit more stable and reliable marker. So, I really love that. And I don't know about you, but in clinical practice it can be really hard. A lot of our patients have had uterine ablations or hysterectomies but have intact ovaries. And so, figuring out ovarian function status is actually much, much harder than it may seem superficially.  Dr. Allison Zibelli: Okay, so let's focus on Abstract 513. I thought this was really interesting. It's a group of patients that we don't have much data for, and that's women that are ER-low, with an ER of 1% to 10% in early-stage breast cancer. Right now, national guidelines are sort of on the fence about whether these women benefit from endocrine therapy. So that's what this study tried to focus on. How will this study change how we approach this group of patients? Dr. Megan Kruse: This study really gave me pause and made me rethink what I'm doing on a day-to-day basis, because here, what the authors found in a very large NCDB analysis was that for women with ER-low status, so ER 1% to 10% positive, they actually did have benefit receiving endocrine therapy, it seems. What they found, after you adjust for many other confounding factors like age, comorbidity, and PR status, is that patients with ER-low breast cancer when they did not receive endocrine therapy actually had worse overall survival outcomes with a hazard ratio of around 1.2 to 1.3.  This is a group where I have typically not pushed endocrine therapy very strongly. I think the patients, especially now, are receiving such intense therapy with chemoimmunotherapy in the preoperative setting, by the time they reach their adjuvant phase with immunotherapy, maybe with capecitabine, maybe with a PARP inhibitor, endocrine therapy seems, “Oh, why bother after we've done all of this?” And we know that the toxicities of endocrine therapy are real and can be very problematic. And so, I have often felt like it's the least important part of therapy and questioned whether we should even bother. But I think this analysis really challenges that and makes us think twice. And I think it speaks to a theme that we're seeing more and more about the heterogeneity of these breast cancer subtypes. And again, talking about clear-cut points in analysis, nothing is truly black and white. So maybe that little bit of expression does mean something.   It does kind of stand in contrast to what we see in studies of ER-low behaving a bit more triple-negative like, but maybe they're their own category, and maybe it gives us a place to look for other therapy synergy in the future. But it certainly will make me stop and think again when I see a ER 4% patient. Should I talk to them about endocrine therapy?  Dr. Allison Zibelli: Yeah, I totally agree with everything you said there. And we know that this is a biologically different group of patients than the ER strongly positive group, but maybe not as different as we once thought. Dr. Megan Kruse: Yeah. And I think there's still a lot of unknowns here about what if they’re ER truly negative and PR a little bit positive. So, these clinical situations don't come up that frequently, but when they do, they're humbling, because I think we really, as much data as we have in breast cancer, it’s pretty limited for these types of patients.  Dr. Allison Zibelli: So, let's move on to Abstract 1003, which was a new combination in the INAVO120 trial. It was palbociclib plus fulvestrant with either inavolisib or placebo in patients with PIK3CA-mutated hormone receptor-positive, HER2-negative, locally advanced metastatic breast cancer in the second line, who relapsed within 12 months of adjuvant endocrine therapy completion. This is a big group of patients for us. Can you tell us about the study? And does this triple therapy, in your mind, represent a new standard of care? Dr. Megan Kruse: Yeah, this study was initially presented at our 2023 San Antonio Breast Cancer Symposium, and there I felt like it was a little bit of a surprise. There's been so much talk about PI3K-AKT-PTEN pathway impactful drugs and targetable mutations. We've heard a lot about alpelisib and capivasertib, and how these drugs are fitting into our practice. Then all of a sudden, we have this data with inavolisib that I wasn't really expecting to see. And perhaps I think one of the reasons that this study came about so suddenly, seemingly, and so quickly is because it looks at a really high-risk patient population. And so, these are those patients that are having relapses of their breast cancer within their initial, while on adjuvant AI therapy or within 12 months of stopping. And so, having a marker of this patient group that is developing, I think, early endocrine resistance and it's another space where it's kind of hard to identify who these patients are upfront. And so their response to therapy tends to be one of the best markers of risk moving forward.   So, when this trial was originally presented, what was quite striking is that the progression-free survival was more than doubled for the triplet combination compared to the control arm. And those numbers were PFS of 15 months versus 7.3 months for the triplet versus the control. The response rate was also significantly improved, with the triplet going above 50%, versus a response rate in the control of about 25%. So, the results were really striking. But they clearly come with some caveats, which are that this is a very defined patient population of risk. Of course, they have to have the biomarker of a PIK3CA mutation, and in the control arm here, there was no PIK3-targeted medication. And so you wonder, are we just getting better results by including that more specific targeted therapy earlier on? It's hard to know, but I think that could certainly be a big part of this.  And the other caveat, when I'm looking at the data, is how might we think about this in our real population? Because as we know, drugs that impact this pathway tend to have a lot of toxicity concerns, primarily hyperglycemia, diarrhea, and rash. And with this particular agent, there was also notable stomatitis, which is something we've seen with everolimus, of course, in this pathway, but not maybe as much with alpelisib and capivasertib. When you're thinking about all of those toxicities, keep in mind that this trial population included patients with a pretty tight fasting blood sugar requirement, A1c of less than 8, and not requiring insulin. So all of that being said, I think this combination seems really intriguing for efficacy. This is a patient population I'm worried about, because we know that these patients are likely not going to get the same upfront benefit of CDK4/6 inhibitor-based therapy, like maybe we see for a patient with long disease-free survival or de novo metastatic breast cancer. But I think it's going to have some meaningful issues in clinic regarding tolerability. And then, of course, the regimen is more complex. We're talking about two different oral agents and an intramuscular injection, which could be hard for some patients, and it's going to have some decent financial toxicity associated with it.  So, I think it's really, really exciting and has the potential to make an impact in first-line therapy. But I don't envision it being the standard of care first-line therapy for everyone, particularly in light of some of the other data we have in the first line questioning, like from the SONIA trial, how important is CDK for everyone? Again, this is I think where we’re starting to get subsets within subsets of this first-line patient population of who needs escalation of therapy and who may benefit from more de-intensified therapy. Dr. Allison Zibelli: I agree, these agents have significant toxicity, and especially financial toxicity is something that we at the academic setting frequently forget about because a lot of our patients are on trials. So, it will be interesting to figure out how we’re going to use these agents in real life.  So, for our final abstract, I wanted to discuss Abstract 10508, which was a prevention trial. I think pretty much everybody’s patients are going to be asking them about this because it's about GLP-1 inhibitors. We know that bariatric surgery does prevent obesity-associated cancers. This study explored whether the GLP-1 agonists could offer a similar result to bariatric surgery in patients with BMIs over 35. What do you think about this study?  Dr. Megan Kruse: I thought this was such an interesting and timely study and question. These drugs are out there – Ozempic, Mounjaros, and Wegovy – and our patients ask about them. And I think there has been a lot of interest for years now about the impact of lifestyle factors on cancer incidence, particularly in breast cancer, where we know that obesity does seem to be related to cancer incidence. And with all of our concerns about hormonal exposure and extra weight, extra adipose tissue being a source of potential extra estrogen, this is a really key topic.   Talking about financial toxicity, again, I think that is honestly probably the bigger hurdle because this study does reinforce that patients who are receiving GLP-1 receptor antagonists and those who have had bariatric surgery do benefit in terms of cancer-related survival and all-cause related survival. So, I think the impact on metabolic factors is making a difference in cancer incidence and outcomes. But access and equity will be the big issue here, right? Dr. Allison Zibelli: Yes. Dr. Megan Kruse: Can we get patients on these drugs? I certainly have had patients with a history of breast cancer who have been on these medications, and they have done great with them in terms of weight loss. We know that our therapies, many times, do have the side effect of weight gain. So, I wonder if there is a part of weight management that maybe we haven’t talked about so much as oncologists that we need to talk about moving forward and would be very welcome by our patients. But it’ll have its own caveats, of course. Not only the financial issue but there’s the durability issue. And I think when you look at the degree of impact of these medications versus bariatric surgery, you do see a greater impact from bariatric surgery, in not only the degree of weight loss but also the sustainability of that weight loss. So, I think for the right patient at the right time, bariatric surgery may still be the better option, but that’s not going to be an option for a lot of patients. It is a huge shift in lifestyle and medications and many ways might be easier, so more to come.   I also wonder about looking at this data through the lens of different cancer types. What will we find out? Is the trend for colon cancer going to be different from the trend for breast cancer? Will the trend within breast cancer be different for breast cancer subtypes? I would very much welcome more data in this space, and it is nice to see a first step forward. Dr. Allison Zibelli: I thought the most interesting thing about this study was that while bariatric surgery patients lost more weight, GLP-1 patients had a higher decrease in obesity-related cancer risk. So, it shows to me that there is something beyond just weight. It is something in metabolism that is driving these cancers.  Dr. Megan Kruse: Yes, and I think that that goes back to some things we have thought about for a long time with insulin levels and insulin-like growth factor, and all of these things that I think when our patients look at more metabolic approaches to cancer control, this is probably what we are trying to get at. We have just never had great ways to measure it or influence it, and perhaps now we finally do. I would love to see some partnering work here in the future with oncologists and endocrinologists and digging into these patients who have great responses to see what we are actually seeing at the hormone level. Dr. Allison Zibelli: Well, thank you so much, Megan, for your great insights today on the ASCO Daily News Podcast. We really appreciate you coming to talk with us again. Dr. Megan Kruse: Thank you. It has been a great conversation. Thank you for opening my eyes to these abstracts, and I am happy to see what else ASCO brings. Dr. Allison Zibelli: And thank you to our listeners for joining us today. You will find links to all the abstracts we discussed today in the transcript of this episode. Finally, if you value the insights you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. It really helps other people find us. Thank you for listening.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. The guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers: Dr. Allison Zibelli Dr. Megan Kruse @MeganKruseMD   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Allison Zibelli: None Disclosed   Dr. Megan Kruse: Consulting or Advisory Role: Novartis Oncology, Puma Biotechnology, Immunomedics, Eisai, Seattle Genetics, Lilly
5/23/202420 minutes, 16 seconds
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Optimizing Novel Therapies and Surgery in Early-Stage NSCLC

Doctors Vamsi Velcheti, Sandip Patel, and Michael Zervos discuss recent updates on the management of early-stage non-small cell lung cancer (NSCLC), including the optimization of neoadjuvant and adjuvant treatment options for patients and the role of surgery in the era of targeted therapy and immuno-oncology in lung cancer. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I am a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. On today's episode, we'll be discussing recent updates on the management of early-stage non-small cell lung cancer (NSCLC), including the optimization of neoadjuvant and adjuvant treatment options for our patients, and the evolving role of surgery in the era of targeted therapy and immuno-oncology in lung cancer.  Today, I am delighted to be joined by two renowned experts in this space, Dr. Sandip Patel and Dr. Michael Zervos. Dr. Patel is a professor of medicine and a medical oncologist specializing in lung cancer at UCSD. Dr. Mike Zervos is the clinical chief of the Division of Robotic Thoracic Surgery and Director of General Thoracic Surgery at NYU Langone. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod. Dr. Patel and Dr. Zervos, it's a great honor to have you on the podcast today. Welcome aboard. Dr. Sandip Patel: Great to be joining you.  Dr. Vamsi Velcheti:  Let's get started with Dr. Patel. As you know, over the last decade we've had dramatic advances in systemic therapy options for patients with metastatic non-small cell lung cancer, in both the realms of targeted therapy and immunotherapy. These have significantly improved outcomes for our patients with metastatic lung cancer. What's exciting is that more recently, we've seen the incorporation of these agents, both targeted therapies and immunotherapies, in early-stage non-small cell lung cancer. Dr. Patel, can you tell our listeners about these exciting recent advances and why do you think it's so important to incorporate these personalized systemic therapy options for our early-stage patients? Dr. Sandip Patel: I think it's a great point and a great question. And so, I think one thing to understand is that non-small cell lung cancer is actually multiple diseases. We give it one name based on how it looks under the microscope, but the vast majority of our advances to improve outcomes for patients have come from our ability to understand specific subgroups.  Many of our therapies have had activity in the advanced setting. We have our patients with metastatic or more widespread disease, which naturally led to the thought that could we utilize these therapies in earlier stage disease and potentially increase the rate of cure for many of our patients, lung cancer being the most common cancer killer worldwide. And so to your point, trying to understand how to best treat a patient really involves personalized medicine, typically driven by understanding the genomic profile of their tumor and two of the genes that have graduated from being tested for in the metastatic setting and now in the localized setting are EGFR and ALK. And these in particular are mutations that confer sensitivity to small molecule inhibitors, EGFR with osimertinib, ALK in the localized setting with alectinib based on the data that we've seen.  And so, one of the areas that's been particularly exciting is our ability to maximize a patient's chance for durable remissions by integrating these therapies after surgery, after chemotherapy when appropriate, and continuing generally for a finite amount of time, two to three years depending on the agent in the study we're discussing for these patients. Additionally, immunotherapy, which has revolutionized our treatment of patients with metastatic disease, may be particularly well-suited for the localized setting of non-small cell lung cancer as well. Dr. Vamsi Velcheti: Excellent points, Sandip. You're absolutely right, in the metastatic setting, we've all come to accept molecular testing, sequencing, and biomarker profiling as a standard, but unfortunately, that hasn't quite yet percolated into the early-stage setting. Can you talk about some of the challenges that we face as we have these therapeutic options available now for more early-stage patients? Dr. Sandip Patel: So, I think there are 3 flavors of localized therapy in non-small cell lung cancer. One is the advanced, unresectable stage 3, for which the approach is often concurrent chemo-radiation followed by some form of consolidated therapy. We're about to hear the results of LAURA, which is the study looking at EGFR-mutated non-small cell lung cancer.  For other patients, historically, the treatment has been durvalumab, an anti-PD-L1 directed immunotherapy. The other two are operative treatment of localized cancer: adjuvant treatment after surgery, or neoadjuvant or perioperative, in which chemoimmunotherapy begins before surgery. And testing depends on the settings. For the stage 3 patient who's likely getting concurrent chemo-radiation, they may have a very small amount of tissue, and so often these are done by pulmonary EBUS biopsies and that’s how we pathologically confirm that advanced stage 3B. There may not be a lot of tissue available for molecular testing. In fact, if you look at the PACIFIC analysis, just looking at PD-L1, which is just an IHC off a single slide, a third of patients weren't able to even get a PD-L1, let alone a genomic result. And so, I think that's one of the areas of LAURA that's going to be particularly interesting to see as we try to implement it into our practice after seeing the full data.  I think in the adjuvant setting, we're lucky because our surgeons, Dr. Mike Zervos here, will get us a large amount of tissue in the surgical resection specimen, so we tend to get enough tissue to do genomics while they're under chemotherapy, there tends to be time to wait for their genomic result. Where this really gets complicated is in the neoadjuvant or perioperative setting, where time is everything.  The most important thing we can do for a patient in the localized space is get them to the operating room, get them started on radiation, their curative local modality, and that’s where we have a time pressure but also a sample pressure because that is a diagnostic biopsy. It’s a very small piece of tissue. Initially, there are multiple stains that have to be done to identify this lung cancer as opposed to another tumor. And so that’s an area that I think we’re going to need additional approaches given that cell-free DNA tends to have lower yield in lower stage disease in giving us a result. Dr. Vamsi Velcheti: Great points, Sandip. How do you deal with this issue in San Diego? The challenge is now we have a lot of trials, we’ll talk about those neoadjuvant immunotherapy trials, but we know that immunotherapy may not be as effective in all patients, especially those with EGFR or ALK or some of these non-smoker, oncogene-driven tumors. So, we don’t want to be giving patients treatments that may not necessarily be effective in the neoadjuvant space, especially when there is a time crunch, and we want to get them to surgery and all the complications that come with giving them targeted therapy post-IO with potential risk for adverse events. Dr. Sandip Patel: Absolutely. It is a great point. And so, the multidisciplinary team approach is key, and having a close relationship with the interventional pulmonary oncs, interventional radiology surgery, and radiation oncology to ensure that we get the best treatment for our patients. With the molecularly guided therapies, they are currently more on the adjuvant setting in terms of actually treating. But as you mentioned, when we’re making a decision around neoadjuvant or perioperative chemo IO, it’s actually the absence of EGFR now that we’re looking for because our intervention at the current time is to give chemoimmunotherapy. Going back to the future, we used to use single gene EGFR within 24 hours, which was insufficient for a metastatic panel, but it often required five slides of tissue input. ALK can be done by IHC, and so some of these ‘oldie but goodie’ pathologic techniques, and that pathologists, if I haven’t emphasized, understanding what we’re trying to do at a different context is so key because they are the ones who really hold the result. In the neoadjuvant and perioperative setting, which many of us favor, especially for stage 3A and stage 2B disease, understanding how we can get that result so that we can get the patient to the operating room in an expeditious way is so important. There is a time pressure that we always had in the metastatic setting, but I think we feel much more acutely in the neoadjuvant and perioperative setting in my opinion. Dr. Vamsi Velcheti: Fascinating insights, Dr. Patel.  Turning to Dr. Zervos, from a surgical perspective, there has been an evolution in terms of minimally invasive techniques, robotic approaches, and enhanced recovery protocols, significantly improving outcomes in our patients post-surgery. How do you see the role of surgery evolving, especially with the increasing complexity and efficacy of these systemic therapies? How do you envision the role of surgery in managing these early-stage patients, and what are the key considerations for surgeons in this new era? Dr. Michael Zervos: Thanks, Vamsi. Thanks, Sandip. Thank you for having me on the podcast. Obviously, it's an honor to be a part of such a high-level discussion. I have to say, from a surgeon's perspective, we often listen to you guys talk and realize that there’s been a lot of change in this landscape. And I think the thing that I've seen is that the paradigm here has also changed. If we were having this discussion 10 years ago, a lot of the patients that I am operating on now, I would not be operating on. It really has been amazing. And I think the thing that stands out to me the most is how all of this has changed with neoadjuvant chemotherapy checkpoint inhibition. I think, for us as surgeons, that's really been the key. Whether it's CheckMate 816 or whatever you're following, like PACIFIC, the data supports this. And I think what we're seeing is that we're able to do the surgery, we’re able to do it safely, and I think that the resectability rates are definitely high up there in the 90% range. And what we’re seeing is pretty significant pathologic responses, which I think is really amazing to me.  We're also seeing that this has now shifted over to the oligometastatic realm, and a lot of those patients are also being treated similarly and then getting surgery, which is something that we would not have even thought of ever. When you look at the trials, I think a lot of the surgery, up to this point, has been done more traditionally. There's a specific reason why that happens, specifically, more through thoracotomy, less with VATS, and less with robotic. Sandip, I think you guys have a pretty robust robotic program at UCSD, so I'm sure you're pretty used to seeing that.   As you guys have become so much more sophisticated with the treatments, we have also had to modify what we do operatively to be able to step up to the plate and accept that challenge. But what we are seeing is yes, these treatments work, but the surgeries are slightly more complicated. And when I say slightly, I’m minimizing that a little bit.  And what's complicated about it is that the treatment effect is that the chemo-immune check inhibition actually has a significant response to the tumor antigen, which is the tumor. So it's going to necrose it, it’s going to fibrose it, and wherever there is a tumor, that response on the surgical baseline level is going to be significant. In other words, there are going to be lymph nodes that are stuck to the pulmonary artery, lymph nodes that are stuck to the airway, and we've had to modify our approaches to be able to address that.   Now, fortunately, we've been able to innovate and use the existing technology to our advantage. Personally, I think robotics is the way we have progressed with all this, and we are doing these surgeries robotically, mainly because I think it is allowing us, not only to visualize things better, but to have sort of a better understanding of what we're looking at. And for that matter, we are able to do a better lymph node dissection, which is usually the key with a lot of these more complicated surgeries, and then really venturing out into more complicated things, like controlling the pulmonary artery. How do we address all this without having significant complications or injuries during the surgery? Getting these patients through after they’ve successfully completed their neoadjuvant treatment, getting them to surgery, doing the surgery successfully, and hopefully, with minimal to no morbidity, because at the end, they may be going on to further adjuvant treatment. All of these things I think are super important. I think although it has changed the landscape of how we think of things, it has made it slightly more complicated, but we are up for the challenge. I am definitely excited about all of this. Dr. Vamsi Velcheti: For some reason, like medical oncologists, we only get fixated on the drugs and how much better we're doing, but we don't really talk much about the advances in surgery and the advances in terms of outcomes, like post-op mortality has gone down significantly, especially in larger tertiary care centers. So, our way of thinking, traditionally, the whole intergroup trials, the whole paradigm of pneumonectomies being bad and bad outcomes overall, I think we can't judge and decide on current treatment standards based on surgical standards from decades ago. And I think that's really important to recognize.  Dr. Michael Zervos: All of this stuff has really changed over the past 10 years, and I think technology has helped us evolve over time. And as the science has evolved for you with the clinical trials, the technology has evolved for us to be able to compensate for that and to be able to deal with that. The data is real for this. Personally, what I'm seeing is that the data is better for this than it was for the old intergroup trials. We're able to do the surgery in a better, more efficient, and safer way. The majority of these surgeries for this are not going to be pneumonectomies, they are going to be mostly lobectomies. I think that makes sense. I think for the surgeons who might be listening, it doesn't really matter how you’re actually doing these operations. I think if you don't have a very extensive minimally invasive or robotic experience, doing the surgery as open is fine, as long as you’re doing the surgery safely and doing it to the standard that you might expect with complete lymph node clearance, mediastinal lymph node clearance, and intrapulmonary lymph node clearance. Really, I think that’s where we have to sort of drive home the point, really less about the actual approach, even though our bias is to do it robotically because we feel it’s less morbidity for the patient. The patients will recover faster from the treatment and then be able to go on to the next phase treatments. Dr. Vamsi Velcheti: In some of the pre-operative trials, the neoadjuvant trials, there have been some concerns raised about 20% of patients not being able to make it to surgery after induction chemo immunotherapy. Can you comment on that, and why do you think that is the case, Sandip?  Dr. Sandip Patel: Well, I think there are multiple reasons. If you look, about half due to progression of disease, which they might not have been great operative candidates to begin with, because they would have early progression afterwards. And some small minority in a given study, maybe 1% to 2%, it's an immune-related adverse event that’s severe. So, it’s something that we definitely need to think about. The flip side of that coin, only about 2 in 3 patients get adjuvant therapy, whether it be chemotherapy, immunotherapy, or targeted therapy. And so, our goal is to deliver a full multimodal package, where, of course, the local therapy is hugely important, but also many of these other molecular or immunologically guided agents have a substantial impact.  And I do think the point around neoadjuvant and perioperative is well taken. I think this is a discussion we have to have with our patients. I think, in particular, when you look at higher stage disease, like stage 3A, for example, the risk-benefit calculus of giving therapy upfront given the really phenomenal outcomes we have seen, really frankly starting with the NADIM study, CheckMate816, now moving on into studies like KEYNOTE-671, AEGEAN, it really opens your eyes in stage 3. Now, for someone who’s stage 1/1b, is this a patient who’s eager to get a tumor out? Is there as much of an impact when we give neoadjuvant therapy, especially if they’re not going to respond and may progress from stage 1 and beyond? I think that’s a reasonable concern. How to handle stage II is very heterogeneous. I think two points that kind of happen as you give neoadjuvant therapy, especially chemo-IO that I think is worth for folks to understand and this goes to Mike’s earlier point, that is this concept if they do get a scan during your neoadjuvant chemo immunotherapy, there is a chance of that nodal flare, where the lymph nodes actually look worse and look like their disease is progressing. Their primary tumor may be smaller or maybe the same. But when we actually go to the OR, those lymph nodes are chock-full of immune cells. There’s actually no cancer in those lymph nodes. And so that’s a bit of a red herring to watch out for.   And so, I think as we’re learning together how to deliver these therapies, because the curative-intent modality is, in my opinion, a local modality. It’s what Mike does in the OR, my colleagues here do in the OR. My goal is to maximize the chance of that or really maximize the long-term cure rates. And we know, even as long as the surgery can go, if only 2 or 3 patients are going to get adjuvant therapy then 1 in 10, of which half of those or 1 in 20, are not getting the surgery and that’s, of course, a big problem. It’s a concern. I think better selecting towards those patients and thinking about how to make these choices is going to be hugely important as we go over. Because in a clinical trial, it’s a very selective population. A real-world use of these treatments is different. I think one cautionary tale is that we don’t have an approval for the use of neoadjuvant or perioperative therapy for conversion therapy, meaning, someone who’s “borderline resectable.” At the time at which you meet the patient, they will be resectable at that moment. That’s where our best evidence is, at the current time, for neoadjuvant or perioperative approaches.  Dr. Vamsi Velcheti:   I think the other major issue is like the optimal sequencing of immune checkpoint here. Obviously, at this point, we have multiple different trial readouts, and there are some options that patients can have just neoadjuvant without any adjuvant. Still, we have to figure out how to de-escalate post-surgery immunotherapy interventions. And I think there’s a lot of work that needs to be done, and you’re certainly involved in some of those exciting clinical trials. What do you do right now in your current clinical practice when you have patients who have a complete pathologic response to neoadjuvant immunotherapy? What is the discussion you have with your patients at that point? Do they need more immunotherapy, or are you ready to de-escalate?  Dr. Sandip Patel: I think MRD-based technologies, cell-free DNA technologies will hopefully help us guide this. Right now, we are flying blind along two axes. One is we don’t actually know the contribution of the post-operative component for patients who get preoperative chemo-IO. And so this is actually going to be an ongoing discussion. And for a patient with a pCR, we know the outcomes are really quite good based on CheckMate816, which is a pure neoadjuvant or front-end only approach. Where I actually struggle is where patients who maybe have 50% tumor killing. If a patient has only 10% tumor killing ... the analogy I think in clinic is a traffic light, so the green light if you got a pCR, a yellow light if you have that anywhere from 20%-70% residual viable tumor, and then anything greater than that, you didn’t get that much with chemo-IO and you’re wondering if getting more chemo-IO, what would that actually do? It’s a bit of a red light. And I’m curious, we don’t have any data, but my guess would be the benefit of the post-op IO is because patients are in that kind of yellow light zone. So maybe a couple more cycles, we’ll get them an even more durable response. But I am curious if we’re going to start relying more on MRD-based technologies to define treatment duration. But I think it’s a very complicated problem. I think folks want to balance toxicity, both medical and financial, with delivering a curative-intent therapy. And I am curious if this maybe, as we’re looking at some of the data, some of the reasons around preferring a perioperative approach where you scale it back, as opposed to a neoadjuvant-only approach where there’s not a clean way to add on therapy, if you think that makes sense. But it’s probably the most complicated discussions we have in clinic and the discussion around a non-pCR. And frankly, even the tumor board discussions around localized non-small cell lung cancer have gone very complex, for the benefit of our patients, though we just don’t have clean data to say this is the right path.   Dr. Vamsi Velcheti: I think that the need for a really true multidisciplinary approach and discussing these patients in the tumor board has never been more significant. Large academic centers, we have the luxury of having all the expertise on hand. How do we scale this approach to the broader community is a big challenge, I think, especially in early-stage patients. Of course, not everyone can travel to Dr. Zervos or you for care at a large tertiary cancer centers. So, I think there needs to be a lot of effort in terms of trying to educate community surgeons, community oncologists on managing these patients. I think it’s going to be a challenge. Dr. Michael Zervos: If I could just add one thing here, and I completely agree with everything that has been said. I think the challenge is knowing beforehand. Could you predict which patients are going to have a complete response? And for that matter, say, “Okay. Well, this one has a complete response. Do we necessarily need to operate on this patient?” And that’s really the big question that I add. I personally have seen some complete response, but what I’m mostly seeing is major pathologic response, not necessarily CR, but we are seeing more and more CR, I do have to say. The question is how are you going to predict that? Is looking for minimal residual disease after treatment going to be the way to do that? If you guys could speak to that, I think that is just tremendously interesting.  Dr. Vamsi Velcheti: I think as Sandip said, MRD is looking very promising, but I just want to caution that it’s not ready for primetime clinical decision making yet. I am really excited about the MRD approach of selecting patients for de-escalation or escalation and surgery or no surgery. I think this is probably not quite there yet in terms of surgery or no surgery decision. Especially for patients who have early-stage cancer, we talk about curative-intent treatment here and surgery is a curative treatment, and not going to surgery is going to be a heavy lift. And I don’t think we're anywhere close to that. Yet, I’m glad that we are having those discussions, but I think it may be too hard at this point based on the available technologies to kind of predict CR. We’re not there.  Dr. Michael Zervos: Can I ask you guys what your thought process is for evaluating the patient? So, when you're actually thinking about, “Hey, this patient actually had a good response. I'm going to ask the surgeons to come and take a look at this.” What imaging studies are you actually using? Are you just using strictly CT or are you looking for the PET? Should we also be thinking about restaging a lot of these patients? Because obviously, one of the things that I hate as a surgeon is getting into the operating room only to find out that I have multiple nodal stations that are positive. Which really, in my opinion, that's sort of a red flag. And for me, if I have that, I'm thinking more along the lines of not completing that surgery because I'm concerned about not being able to provide an R0 resection or even having surgical staple lines within proximity of cancer, which is not going to be good. It's going to be fraught with complications.  So, a lot of the things that we as surgeons struggle with have to do with this. Personally, I like to evaluate the patients with an IV intravenous CT scan to get a better idea of the nodal involvement, proximity to major blood vessels, and potentially even a PET scan. And though I think in this day and age, a lot of the patients will get the PET beforehand, not necessarily get it approved afterwards. So that's a challenge. And then the one thing I do have to say that I definitely have found helpful is, if there's any question, doing the restaging or the re-EBUS at that point to be particularly helpful.  Dr. Sandip Patel: Yeah, I would concur that having that pathologic nodal assessment is probably one of the most important things we can do for our patients. For a patient with multinodal positive disease, the honest truth is that at our tumor board, that patient is probably going to get definitive chemoradiation followed by their immunotherapy, or potentially soon, if they have an EGFR mutation, osimertinib. For those patients who are clean in the mediastinum and then potentially have nodal flare, oftentimes what our surgeons will do as the first stage of the operation, they'll actually have the EBUS repeated during that same anesthesia session and then go straight into surgery. And so far the vast majority of those patients have proceeded to go to surgery because all we found are immune cells in those lymph nodes.  So, I think it's a great point that it's really the pathologic staging that's driving this and having a close relationship with our pathologists is key. But I think one point that I think we all could agree on is the way that we're going to find more of these patients to help and cure with these therapies is through improved utilization of low-dose CT screening in the appropriate population in primary care. And so, getting buy-in from our primary care doctors so that they can do the appropriate low-dose CT screening along with smoking cessation, and find these patients so that we can offer them these therapies, I think is something that we really, as a community, need to advocate on. Because a lot of what we do with next-generation therapies, at least on the medical oncology side, is kind of preaching to the choir. But getting the buy-in so we can find more of these cases at stage 1, 2 or 3, as opposed to stage 4, I think, is one of the ways we can really make a positive impact for patients. Dr. Vamsi Velcheti: I just want to go back to Mike's point about the nodal, especially for those with nodal multistation disease. In my opinion, those anatomic unresectability is a moving target, especially with evolving, improving systemic therapy options. The utilization for chemo radiation has actually gone down. I think that's a different clinical subgroup that we need to kind of think differently in terms of how we do the next iteration or generation of clinical trials, are they really benefiting from chemo-IO induction? And maybe we can get a subset of those patients in surgery. I personally think surgery is probably a more optimal, higher yield to potentially cure these patients versus chemo radiation. But I think how we identify those patients is a big challenge. And maybe we should do a sequential approach induction chemo-IO with the intent to kind of restage them for surgery. And if they don't, they go to chemo consolidation radiation, I guess. So, I think we need to rethink our approach to those anatomically unresectable stage 3s. But I think it's fascinating that we're having these discussions. You know, we’ve come to accept chemo radiation as a gold standard, but now we're kind of challenging those assumptions, and I think that means we're really doing well in terms of systemic therapy options for our patients to drive increased cures for these patients. Dr. Michael Zervos: I think from my perspective as a surgeon, if I'm looking at a CT scan and trying to evaluate whether a patient is resectable or not, one of the things that I'm looking for is the extent of the tumor, proximity to mediastinal invasion, lymph nodes size. But if that particular patient is resectable upfront, then usually, that patient that receives induction chemo checkpoint inhibition is going to be resectable afterwards. The ones that are harder are the ones that are borderline resectable upfront or not resectable. And then you're trying to figure out on the back end whether you can actually do the surgery.  Fortunately, we're not really taking many patients to the operating room under those circumstances to find that they're not resectable. Having said that, I did have one of those cases recently where I got in there and there were multiple lymph node stations that were positive. And I have to say that the CT really underestimated the extent of disease that I saw in the operating room. So, there are some challenges surrounding all of these things. Dr. Sandip Patel: Absolutely. And I think for those patients, if upfront identification by EBUS showed multi nodal involvement, we've had excellent outcomes by working with radiation oncologists using modern radiotherapy techniques, with concurrent chemo radiation, followed by their immunotherapy, more targeted therapy, at least it looks like soon. I think finding the right path for the patient is so key, and I think getting that mediastinal pathologic assessment, as opposed to just guessing based on what the PET CT looks like, is so important. If you look at some of the series, 8% to 10% of patients will get a false-positive PET on their mediastinal lymph nodes due to coccidioidomycosis or sarcoidosis or various other things. And the flip side is there's a false-negative rate as well. I think Mike summarized that as well, so I think imaging is helpful, but for me, imaging is really just pointing the target at where we need to get pathologic sampling, most commonly by EBUS. And getting our interventional pulmonary colleagues to help us do that, I think is so important because we have really nice therapeutic options, whether it's curative-intent surgery, curative-intent chemo radiation, where we as medical oncologists can really contribute to that curative-intent local therapy, in my opinion.  Dr. Vamsi Velcheti: Thank you so much Sandip and Mike, it's been an amazing and insightful discussion, with a really dynamic interplay between systemic therapy and surgical innovations. These are really exciting times for our patients and for us. Thank you so much for sharing your expertise and insights with us today on the ASCO Daily News Podcast.   I want to also thank our listeners today for your time. If you value the insights that you hear today, please take a moment to rate, review, and subscribe to the podcast wherever you get your podcasts. Thank you so much. [FH1]   Dr. Sandip Patel: Thank you. Dr. Michael Zervos: Thank you.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers: Dr. Vamsidhar Velcheti @VamsiVelcheti Dr. Sandip Patel @PatelOncology Dr. Michael Zervos   Follow ASCO on social media: @ASCO on X (formerly Twitter) ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Vamsidhar Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Sandip Patel: Consulting or Advisory Role: Lilly, Novartis, Bristol-Myers Squibb, AstraZeneca/MedImmune, Nektar, Compugen, Illumina, Amgen, Certis, Eli Lilly, Roche/Genentech, Merck, Pfizer, Tempus, Iovance Biotherapeutics. Speakers’ Bureau: Merck, Boehringer Ingelheim Research Funding (Inst.):Rubius, Bristol-Myers Squibb, Pfizer, Roche/Genentech, Amgen AstraZenece/MedImmune, Fate, Merck, Iovance, Takeda   Dr. Michael Zervos: No relationships to disclose
4/25/202431 minutes, 31 seconds
Episode Artwork

A Revolution in Immunotherapy for Cervical and Endometrial Cancers

Doctors James Ferriss, Linda Duska, and Jayanthi Lea discuss the promise and the challenges of targeting the immune system with immune checkpoint inhibitors, or ICIs, in cervical and endometrial cancers. They also examine emerging data that support the use of ICIs in recurrent cervical cancer, the potential for curing some patients with advanced endometrial cancer, and molecular factors that make cervical cancer a good target for immunotherapy. TRANSCRIPT Dr. James Stuart Ferriss: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. James Stuart Ferriss, your guest host of the ASCO Daily News Podcast today. I'm an associate professor of gynecology and obstetrics and the Gynecologic Oncology Fellowship Program Director at Johns Hopkins Medicine. In today’s episode, we'll be discussing the use of immunotherapy in cervical and endometrial cancers to advance the treatment of these malignancies. I'm delighted to be joined by two acclaimed experts in this space, Dr. Linda Duska and Dr. Jaya Lea.   Dr. Duska is a professor of obstetrics and gynecology and serves as the associate dean for clinical research at the University of Virginia School of Medicine. Dr. Lea is a professor of obstetrics and gynecology and chief of gynecologic oncology at the University of Texas Southwestern Medical Center.  Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod. Drs. Duska and Dr. Lea, it's great to have you on the podcast today.  Dr. Linda Duska: Thanks, Dr. Ferriss.  Dr. Jayanthi Lea: Thanks, Dr. Ferriss.  Dr. James Stuart Ferriss: So, let's get started. In recent years, we've had a revolution in the treatment of advanced endometrial and cervical cancers with improved outcomes for patients treated with immunotherapy. And when we say immunotherapy, we're specifically talking about immune checkpoint inhibitors today. A few of these agents have actually been approved in the United States for the management of these diseases. In our discussion, I'd like to review the promise and challenges of targeting the immune system in patients with advanced endometrial and cervical cancers, as well as review the most recent evidence we have in these spaces.  Let's start with cervix. We've had a lot of improvements in outcomes here, Dr. Lea, and with cervical cancer, we've seen improved overall survival with the incorporation of immunotherapy along with chemotherapy and anti-angiogenic therapy for advanced and recurrent disease. Can you remind us why cervical cancer is a good target for immunotherapy?  Dr. Jayanthi Lea: Yes, Dr. Ferriss. Immunotherapy for cervical cancer is supported by several molecular factors. And I think first and foremost, it's so important to remember that the majority of cervical cancers are HPV-positive. And HPV-positive cancers can induce a high level of inflammation, but this high level of inflammation actually contributes to evasion of immune surveillance. What it also does is that it’s responsible for the induction of PD-L1. And we've seen several studies that have shown that cervical cancers express PD-L1 anywhere from 50 to 90 percent of cases. Other pertinent factors to consider are that cervical cancer can be considered a tumor with a high tumor mutational burden. So, the number of somatic mutations that we see in the DNA can be considered as a proxy for neoantigens. And so the higher the level of neoantigens, the more immunogenic the tumor. And then lastly, about 1 in 10 cervical cancers present with microsatellite instability, which is an already established key biomarker for the response team in care.  Dr. James Stuart Ferriss: So, thinking about targeting PD-L1, what clinical evidence do we have that supports the use of immune checkpoint inhibitors in recurrent cervical cancer?  Dr. Jayanthi Lea: We now have several studies that have shown a benefit for immune checkpoint inhibitors. For example, KEYNOTE-158 was a phase 2 basket [trial] that investigated the antitumor activity of pembrolizumab, which is a PD-1 inhibitor, in multiple cancer types. And specifically for patients with previously treated advanced cervical cancer, we were able to see an overall response rate of about 15% in those patients who had PD-L1 positive. And similarly, the EMPOWER CERVICAL-1 study, which was a phase 3 randomized trial that investigated the efficacy of cemiplimab, which is another PD-1 inhibitor, versus investigator's choice of single agent chemotherapy, showed a significant difference in median overall survival and progression-free survival in the cemiplimab group. There are several other studies that have investigated the efficacy of PD-1 or PD-L1 inhibitors in cervical cancer. One specific PD-1 inhibitor is nivolumab. In CHECKMATE-358, nivolumab was associated with an overall response rate of 26% in women who had recurrent/metastatic cervical cancer.  Dr. James Stuart Ferriss: Dr. Duska, do you have any thoughts?  Dr. Linda Duska: I'm really interested in PD-L1 as a biomarker because in the KEYNOTE-A18 study, which we’re going to get to, 95% of patients were PD-L1 positive by CPS, which is the scoring system that we use in cervix cancer. And some of the studies that you already mentioned, including BEATcc, which we’re also going to talk about, reported results where PD-L1 wasn’t even considered. And so it begs the question, since PD-L1 is actually – again, depending on when in the course of disease you look at it, but more recent studies suggest 95% of cervical cancers express PD-L1, and – agnostic is the word I was looking for – it seems at least in BEATcc and similar trials that PD-L1 is agnostic, but I wonder if PD-L1 is really a good biomarker for response to checkpoint inhibitor therapy and I wonder what your thoughts are.  Dr. Jayanthi Lea: I think that's an excellent question. To your point, that's correct that we saw in KEYNOTE-A18 that more than 90% of the patients had PD-L1 positivity and the result is sort of generalizable to all comers. That's still a matter of debate as to how we see PD-L1 as a biomarker to incorporate checkpoint inhibitors in the treatment of patients.  Dr. James Stuart Ferriss: So, let's talk about the use of immune checkpoint inhibitors in the frontline setting. Until recently, we haven't seen much improvement in overall survival since the introduction of anti-angiogenic therapy to the chemotherapy backbone, and that was in GOG 240. Let's talk about the changes that have recently occurred in this space.  Dr. Jayanthi Lea: So, we've had some very exciting data specifically from initially KEYNOTE-826 and its primary metastatic or first line salvage settings. So, KEYNOTE-826, which was a phase 3 randomized, controlled trial was very practice-changing for us because it showed that incorporation of pembrolizumab to the first-line treatment of patients with metastatic or recurrent cervical cancer, really changed the landscape for treatment in this group of patients. So, keep in mind that prior to the study, the standard of care was carboplatin, or cisplatin with paclitaxel plus or minus bevacizumab, which yielded a median overall survival range in anywhere from 13 to 17 months depending on whether you use bevacizumab or not. And then adding pembrolizumab to that regimen, increase the median overall survival to 24 months, which is very promising.  Dr. James Stuart Ferriss: If I remember correctly, KEYNOTE-826 allowed investigators choice, use of bevacizumab, and initially we were unsure about which regimen was best. Has there been additional data since?  Dr. Jayanthi Lea: There has been additional data since. And another study that was done in the same vein was the BEATcc trial, which also looked at the different checkpoint inhibitors, atezolizumab in combination now with bevacizumab and platinum-based chemotherapy. And the control arm for this study was the GOG 240 regimen, which included bevacizumab. And this study showed both a progression-free and overall survival difference. The median overall survival in this study was 32 months with the incorporation of the checkpoint inhibitor to the bevacizumab and platinum-based chemotherapy. So, the way that I look at it is that the BEATcc trial basically confirmed the findings of KEYNOTE-826 and highlights that it is important for us to incorporate checkpoint inhibition with immunotherapy along with bevacizumab when we’re treating patients with a recurrence.  Dr. James Stuart Ferriss: Also, folks with primary advanced treatment for cervical cancer, this would be a great regimen, is that right?  Dr. Jayanthi Lea: Absolutely. Primary advance, we would want to use the same regimen for that.  Dr. James Stuart Ferriss: Okay. What about locally advanced in primary treatment? What advances have we seen?  Dr. Jayanthi Lea: So we've had some major changes in that field as well, especially with the recent KEYNOTE-A18 data where pembrolizumab was administered in combination with external beam radiation and concurrent chemotherapy. And this study showed that there was significant and clinically meaningful improvement in progression-free survival compared to chemoradiation alone. Specifically, the progression-free survival at 24 months using pembrolizumab with chemoradiation was 68%, and 57% when in the placebo group. The hazard ratio for disease progression was 0.7 and no new safety signals were observed, which is fantastic, especially given the 0.7 hazard ratio that received PFS.  Dr. James Stuart Ferriss: Yeah, absolutely. These patients with locally advanced cervical cancer often are quite symptomatic, and the prospect of adding chemo, radiation, and now immunotherapy on top of that is really encouraging to see that it was such a well-tolerated regimen. I believe that there were patient-reported outcomes recently reported at SGO.  Dr. Jayanthi Lea: Absolutely. So, the safety profile of pembrolizumab and chemoradiation was consistent with the known profile of the individual treatment components. And no new safety signals emerged in the pembrolizumab chemoradiation arm. So, you’re right. It was very well tolerated.  Dr. James Stuart Ferriss: What would you say are the takeaways for folks who are seeing these patients in the community? These locally advanced cervical cancer patients that are now adding immunotherapy in a space that we have not used routinely in the past in terms of combining it with chemo radiation in gynecologic cancer. What are some things they should be looking out for?  Dr. Jayanthi Lea: Well, I think that with the hazard ratio of 0.7 and the patient-reported outcomes showing no new signal, I think we can say that there is a positive benefit-to-risk profile of adding pembrolizumab in combination with chemoradiation, and that we should feel comfortable using this regimen. Now, of course, we have individualized patient care, and be able to know when to use bevacizumab, when to use immunotherapy. So, taking the whole patient into consideration becomes important. But for those individuals who are able to receive these drugs who don’t have concrete issues to not receive these drugs [then I’d say we could] incorporate them since the safety profile is set.  Dr. Linda Duska: I would add to that, Dr. Ferriss, that right now we only have FDA approval in the U.S. for stage 3-4A disease, and that’s 2014 staging. Mind you, we are now in 2018, so we should be very careful in and follow the correct FIGO staging. But the FDA only gave approval for stage 3-4A disease, even though the study included patients with earlier stage disease and positive nodes.  Dr. James Stuart Ferriss: That's a great point, thank you.  So, Dr. Duska, thinking about endometrial cancer and advanced endometrial cancer, we have seen a similar revolution in the care of patients over the past few years, with major shifts in our approach. Can you remind us how we got here?  Dr. Linda Duska: Yes, I would say in the ‘90s and before, and maybe even in the early 2000s, we used a lot of radiation for endometrial cancer as adjuvant therapy following surgery. The general consensus and what we were all taught was that this was a chemotherapy-resistant disease. And then we learned from a variety of GOG at the time, Gynecologic Oncology Group trials, that this disease is actually chemosensitive. And we went through a series of chemotherapy drugs, ranging from adriamycin cisplatin to taxel adriamycin cisplatin, and finally to taxel and carboplatin, demonstrating that this disease is actually quite chemosensitive.  With this realization came the idea that maybe it would be important to combine chemotherapy and radiation particularly in high-risk endometrial cancer cases, so those with positive nodes or patients with high-risk histology such as clear cell or serous cancers. So two very important trials were done, one of them was PORTEC-3 and the other was GOG-258, which looked at combining chemo and radiation together to see if we could do better than one or the other alone. And they were very different trials, and they looked at different populations of patients and they looked at different things. For example, PORTEC-3 randomized patients to receive chemotherapy and radiation versus radiation alone, while 258 looked at chemotherapy and radiation versus chemotherapy alone. Without going into a great amount of detail, I think what we learned from both of those studies, and I think surprised many of us, that the arms that included chemotherapy, those patients did better.  In fact, the results of GOG-258 can be interpreted – and this is somewhat controversial – but can be interpreted that many of these high-risk patients don’t need radiation at all, or perhaps need tumor-directed radiation. For example, chemotherapy followed by tumor-directed radiation either to the vaginal cuff, because the vaginal cuff is at risk for recurrence, or perhaps to an area of concern, maybe the cervix if there were cervical involvement or if there is a particular concern for local recurrence in a particular patient. So, I think the pendulum has swung from almost always using radiation alone to, in more modern day, using chemotherapy and using radiation much more sparingly, and then comes immunotherapy.  Dr. James Stuart Ferriss: So, update us on the results of NRG-GY018 and RUBY?  Dr. Linda Duska: So, we've already talked about the KEYNOTE basket trials, which really contributed a lot to our understanding of the importance of MMR deficiency and microsatellite unstable disease. The KEYNOTE-158 study and the GARNET study showed us how important it was for women with MMRd and MSI endometrial cancer to receive checkpoint inhibition, and actually with remarkable response rates to women who had already been pretreated. But we also learned from the GARNET trial, which included MMRp patients, that the response rates in MMRp were not that great. And that led to KEYNOTE-775, which looked to combine pembrolizumab with a VEGF inhibitor, lenvantinib, to see if we could make the cold tumor hot. And indeed, we could. And not only could we improve the response rate in patients with MMRp tumors, but we could also improve the response rate in patients with MMRd tumors. They did better with the combination than they did with pembro alone.  That led to the idea of combining checkpoint inhibitors with chemo upfront. The idea there was we were going to take paclitaxel and carboplatin, which were our backbone for advanced or recurrent endometrial cancer, and add immunotherapy to that. And to your point, GY018 and RUBY trials did just that. And they allowed MMRd and MMRp patients and combined paclitaxel and carboplatin, either with dostarlimab in the case of RUBY, or pembrolizumab in the case of GY018. These studies, both of which were reported and published in the New England Journal of Medicine last year, showed remarkable findings in the upfront setting and potentially in the curable setting. And the OS data for RUBY were presented at SGO this year and were remarkable for MMRd patients. In the whole population, in the whole group in RUBY, there was a 16.4-month improvement in overall survival with the addition of dostarlimab which is just huge.  When you look at the MMRd group, I think Dr. Powell described the overall survival improvement as unprecedented. I believe that was the word that he used. Also, he called it very robust, with a hazard ratio of 0.32 for the group that got dostarlimab, and a median OS that was not reached. So really remarkable. In addition, in the MMRp group, there was a seven-month improvement in OS that was significant. So that's really amazing in the RUBY trial. It's also of note that the RUBY trial allowed carcinosarcomas, whereas the GY018 study did not. So, I think it's fair to say that these results apply to carcinosarcomas.  It's also really important to note that many of the patients in the immunotherapy group who received placebo, 41% of them got IO in a later treatment line, and these OS data still stand. So that's really interesting and hypothesis-generating. For GY018, we don't have mature OS data yet, so we can't talk about OS. But we saw a similar improvement in PFS in both arms, in the d and the pMMR, with an OS trend in both arms that was also reported at SGO. GY018 was a little bit different though, because they unblinded at the time of the PFS reporting last year, and so those patients were unblinded a lot earlier than the RUBY patients were. So, to interpret the data in that vein, the OS data is not mature, but we anticipate looking at the PFS curves and the preliminary OS curves, that the OS data will also be statistically significantly improved in core pembrolizumab in GY018.  What's also really interesting, and we haven't talked about molecular subtypes, is that when we look at the molecular subtypes in RUBY, and I'm sure we're going to see data on the molecular subtypes in GY018 coming up, different molecular subtypes of endometrial cancer respond differently to IO. And so, there's going to be lots of really interesting data coming our way soon that we're really excited to see, and that will help us triage patients appropriately into treatment regimens.  Dr. James Stuart Ferriss: Dr. Lea, did you have a thought?  Dr. Jayanthi Lea: Yeah, I just wanted to comment that looking at the dMMR survival curve in the file that was presented recently, one thing that really strikes me is the importance of adding the IO at the time of initial treatment. The separation of the curves persists. And, like you just mentioned, Dr. Duska, I mean, some of those patients who received placebo then later on went to get an IO treatment, but at the same time, we still see a vast separation of those curves. So, I think it's really important to note that immunotherapy should be used upfront, especially in dMMR.  Dr. Linda Duska: Yeah, I completely agree with that. And I think that might be– I mean, this is just a hypothesis, but I think that that might be why we saw a difference with the addition of immunotherapy in the MMRp group, because it's possible that the chemotherapy created an immune environment that made the checkpoint inhibitor work more successfully than it would have otherwise. So, a really good point. You definitely need to include dostarlimab or pembrolizumab with the chemotherapy and then as maintenance therapy after.  Dr. James Stuart Ferriss: So, you mentioned, we're increasingly thinking about endometrial cancer in smaller and smaller buckets of patients with very prescribed molecular profiles. We don't yet have enough information to specifically tailor treatment. How are you approaching that today in patients that you see in clinic?  Dr. Linda Duska: Well, the MMR, and I'm interested in what you both are doing also, it's easy with the MMRd and MSI high patients. Those patients all should receive a checkpoint inhibitor, no question. The patients that are p53 mut, I test them for HER2, because we do have data to suggest that atezolizumab or TDX-d might be useful in those individuals, HER2 positive. And then the remaining patients, also called the NSMPs. That's a difficult group. I'm interested to know how you all manage them. I think that's the group where more clinical research is really needed to determine what the best treatment regimen for them is. But I'm interested in both of your thoughts on that.  Dr. James Stuart Ferriss: Dr. Lea?  Dr. Jayanthi Lea: I would have to say that I do exactly like you do, Dr. Duska.  Dr. James Stuart Ferriss: And I would say our approach is very similar. And we have a robust discussion always about the use of immunotherapy with chemotherapy and in patients who are proficient MMR. But I think that most of us believe that the PFS data is certainly compelling. And now the OS data from RUBY, very compelling in both groups. And so, we are routinely recommending the use of immunotherapy along with chemotherapy in these advanced patients.  Dr. Linda Duska: I've heard the argument made that GY018 required measurable disease, and so does not necessarily apply to patients without measurable disease. I'm not sure that I agree with that. I think there were clinical trial reasons why that was a requirement rather than biologic reasons. In addition, as we already discussed, RUBY included carcinosarcomas and GY018 did not. I don't think there's a reason to only use dostarlimab for carcinosarcomas, but that said, I don't know that pembrolizumab has an indication for carcinosarcomas. The devil's in the details, don't get too lost in the weeds. I think the take-home message here is that it's really important to use IO, particularly for the MMRd patients with endometrial cancer, upfront. And based on the OS that we saw in both RUBY and preliminarily in GY018, we may be curing some people with this regimen, and I think we should focus on that. The overall survival for advanced endometrial cancer is not great, and if we can improve that and potentially cure some people, that's a huge advance for our patients.  Dr. James Stuart Ferriss: Do you envision a day that we might even ask the question, “Do we need to do surgery?”  Dr. Linda Duska: So, the rectal data would support that assertion. I'm not sure that endometrial cancer and rectal cancer are the same thing. And I think that taking out a postmenopausal woman's uterus is a lot less morbid than potentially radiating or taking out somebody's rectum. I think a different question would be, is there a day when we would stop doing no dissection? We could definitely debate that, but I don't see that happening. Do you see that happening anytime soon? A stopping of hysterectomy for endometrial cancer? Dr. Jayanthi Lea: I don't see that happening anytime soon. And I think, as you said, taking out the uterus, tubes, and ovaries, it does provide us with some information about whether you're even dealing with a secondary primary. But also, it’s from a quality-of-life standpoint. If a woman has a large uterus, that’s uncomfortable. Postmenopausal bleeding, avoiding bleeding during the course of treatment, so many reasons why I wouldn't be in too much of a hurry to want to not do surgery for these patients. Dr. James Stuart Ferriss: So, we'll put a plug in for our fellow gynecologic oncologists that we still have a role to play in the incorporation of treatment regimens for patients with advanced uterine cancer. So it's not just medicine, there's still a role for surgery.  Dr. Linda Duska: I think that's very fair, yeah. Dr. James Stuart Ferriss: Okay. I think that's all the time we have for today.  I want to thank our listeners for their time, and you'll find the links to all the studies we've discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you.  Dr. Linda Duska: Thank you. Dr. Jayanthi Lea: Thank you. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers: Dr. James Stuart Ferriss Dr. Linda Duska @LDuska Dr. Jayanthi Lea   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. James Stuart Ferriss: Honoraria: National Board of Medical Examiners Dr. Linda Duska: Consulting or Advisory Role: Regeneron, Inovio Pharmaceuticals, Merck, Ellipses Pharma Researching Funding (Inst): GlaxoSmithKline, Millenium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Syndax, Pfizer, Merck, Genentech/Roche, Cerulean Pharma, Ludwig Institute for Cancer Research, Leap Therapeutics Patents, Royalties, Other Intellectual Property: UpToDate, Editor, British Journal of Ob/Gyn Dr. Jayanthi Lea: Consulting or Advisory Role: Roche
4/18/202426 minutes, 18 seconds
Episode Artwork

How ctDNA Is Advancing Care for Patients With GI Cancers

Drs. Shaalan Beg and Aparna Parikh discuss the role of ctDNA as a powerful prognostic biomarker for GI cancers, along with its impact on risk stratification and the detection of recurrence. They highlight key studies in ctDNA that were featured at the 2024 ASCO GI Cancers Symposium, including COBRA, GALAXY, and BESPOKE in CRC, as well as the promise of ctDNA testing in the preoperative detection of iCCA. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Shaalan Beg, your guest host for the ASCO Daily News Podcast today. I am an adjunct associate professor at UT Southwestern's Harold Simmons Comprehensive Cancer Center in Dallas. On today's episode, we will be discussing the emergence of circulating tumor DNA (ctDNA) technology in GI cancers. I am delighted to be joined by Dr. Aparna Parikh, an assistant professor of medicine at Harvard University and the director for colorectal medical oncology at the Massachusetts General Hospital Cancer Center, where she also serves as the medical director of the Young Adult Colorectal Cancer Center. Dr. Parikh will share her insights on key research on this hot topic in GI oncology that was featured at the recent ASCO Gastrointestinal Cancers Symposium.  Our full disclosures are available in the transcripts of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod.  Dr. Parikh, it's great to have you on the podcast today. Dr. Aparna Parikh: Thanks so much, Dr. Beg.  Dr. Shaalan Beg: In recent years, it has become evident that liquid biopsy and other emerging ctDNA technologies are changing how we treat GI cancers, and colorectal cancer (CRC) is in the forefront of this space. Before we dive into key studies, can you briefly highlight for our listeners how ctDNA is advancing the field and how it can influence the care that we deliver to our patients in the future? Dr. Aparna Parikh: Absolutely, ctDNA is certainly a hot topic. What we have learned over the years is that ctDNA has emerged across many solid tumor types as one of the most powerful, if not the most powerful, prognostic biomarker we have to date. ctDNA has improved risk stratification. We have learned a lot about the role in what is called minimal or molecular residual disease in patients with early-stage disease, and ctDNA being a biomarker of recurrence for those patients, with ctDNA, we have a better understanding of tumoral heterogeneity, both spatially and temporally, getting a better glimpse of what is happening in a given patient with multiple metastases, as well as genomic evolution of tumors over time. So certainly many, many roles and areas where ctDNA is emerging. Dr. Shaalan Beg: This was a hot topic at the 2024 ASCO GI Cancers Symposium, and we're going to take a deep dive into some of the abstracts that were presented. Let's start with the COBRA study, which is the NRG-GI005. That was Abstract 5 at the ASCO GI Cancers Symposium, and the GALAXY study, which was Abstract 6 at the symposium. So, the COBRA study reported results of ctDNA as a predictive biomarker in adjuvant chemotherapy for people with colon cancer. At a high level, it was a negative study, but there are some important lessons for us to learn. Similarly, in the GALAXY study, investigators from Japan presented an updated analysis on the correlation of ctDNA dynamics with outcomes in colorectal cancer with minimal residual disease. How do you synthesize all this information and help the listeners understand our current state for ctDNA applications in colorectal cancer? Dr. Aparna Parikh: Yeah. Let's take the COBRA study first. Let's talk a little bit about the design of COBRA. COBRA was intended to look at patients that were resected, stage 2 colorectal cancer patients, or colon cancer patients who were 2A. These are patients where the treating physician would, at the outset, decide that there was no adjuvant chemotherapy indicated. These are patients where active surveillance would be entirely appropriate as the standard of care. Patients were randomized to arm 1, which was active surveillance, or randomized to arm 2, which was assay-directed therapy. If there were ctDNA positive in arm 2, then they were given chemotherapy, FOLFOX or CAPOX. And if they were “ctDNA not detected,” then they would also go on to active surveillance.   And so, the plan was that nearly 1,500 patients are to be recruited, and at the time of this data cut, they had around 630-some patients. The primary objective was to look at the clearance rates of ctDNA between the ctDNA-positive cohorts, remember, the chemotherapy and the active surveillance cohorts at 6 months. They had around a 5% detection rate of ctDNA patients. Ultimately, that was around 16 patients. The reason that the study shut down was that what they found was that in the surveillance arm, the arm that was not getting any treatment, they had a ctDNA clearance of 43% versus 11% in the chemotherapy arm. They had an interim analysis to look at the clearance rate between the 2 arms, and what was surprising to the investigators and the community was what was happening in terms of clearance. Why do we have a 43% clearance rate in patients that were not getting anything? And so, because of that, the study was shut down as it did not meet its prespecified interim look at clearance in those 2 arms.   Many things came up in terms of learnings from COBRA. Number one was the characteristics of the assay. And so, you take an assay in a low-risk patient population that has a fixed specificity, and when your baseline prevalence of recurrence is so low, for example, in low-risk stage 2 patients, your composite predictive value is very susceptible to small changes in that specificity. And so, your PPV is going to be a lot lower in a low-risk patient population than a higher-risk patient population. The COBRA study used an older version of a tumor-uninformed assay, so it definitely called into question some characteristics of the assay. Is one-time-point clearance sufficient, and is that the right endpoint? We have seen now, including the GALAXY study that we'll talk about here, previously reported just spontaneous clearance happening in 5%, 10% of patients. The question with that spontaneous clearance is: Was it actually clearance, or was chemotherapy just perhaps in a low ctDNA shedding state? Are you just suppressing the ctDNA below the level of limited detection?  And then in this study, the clearance draw was actually done in the chemotherapy arm right before the last cycle of chemotherapy, again to that point of, are you just suppressing the ctDNA with chemotherapy? There is also stochastic sampling error that can happen in patients with very low residual tumor volume. So, I think this is a disappointing study in the sense that it is still a really important question. There are still 2A patients that recur, but maybe [this was] not the right test, or maybe single-time-point testing wasn't enough. And so, lots of lessons to be learned from this study in terms of test and design, but hopefully more to come. I think certainly stage 2 patients remain an area where I think, hopefully, ctDNA still plays a factor for those patients.  Dr. Shaalan Beg: And how was the patient population for the GALAXY study? That was Abstract 6, compared to the COBRA study. Could you summarize those findings for us?  Dr. Aparna Parikh: Yeah, so GALAXY was part of a large study in Japan that includes an observational cohort plus therapeutic cohorts as well. And so, GALAXY was just further reporting of the observational cohort. So unlike COBRA, which is a low-risk, stage 2 study that was actually asking that interventional question: Can you use it to guide therapy? The GALAXY and the updated GALAXY just continues to show more clinical validity data rather than clinical utility data. And it was nearly 3,000 patients, pan stages. Again, the lion’s share were stage 2 and 3 patients, but there were also stage 1 and stage 4 patients as well. And what they showed was that ctDNA is undoubtedly prognostic. They showed very consistent Kaplan-Meier curves, which we've seen time and time again, where if you're ctDNA-positive, you don't do as well.  What they showed was, not surprisingly, with longer-term follow-up – this is 24-month follow up, so longer-term follow up than was published in their paper last year – was that when you test at one time point, so landmark testing, the sensitivity of detecting recurrence was around 48%, and that fell from the publication last year which was around 58%, 59%, which is not surprising as you follow more people. I think single time point testing soon after surgery may miss those late recurrences, but it's still prognostic and showed a specificity of around 94%.   They also continued to show that if you continued to test with serial testing, your sensitivity improves, but what was really interesting and new, what they presented this time, was a clearance analysis. And showing, again, comparable to COBRA, in many ways, in the sense that clearance can be a little bit finicky, especially at one time point, is what they showed is that patients who had sustained clearance, and these are patients that had at least two time points with their ctDNA remained to be negative, they did very well. But if you had transient clearance, and again, the definition was a little bit broad, at least having one negative and then one positive, those patients ultimately, at 24 months, the curves came together with the no clearance curve. So initially, they did better than the people that didn’t have any clearance. But if you transiently cleared at two years, the curves came back together.   And what was interesting is that in those patients that sort of transiently clear by 9 to 12 months, 80% of those are actually having a rapid return of ctDNA. And so this begs the question of was chemotherapy just suppressing that ctDNA or maybe if you have a better test you could have actually improved it.  These were some of the updated, interesting learnings from GALAXY, which remains incredibly prognostic. And then the concept of clearance, which I think we have to look into a little bit more as a field, and understanding that maybe just one time point clearance isn't sufficient.  Dr. Shaalan Beg: Yeah, and one of the most important applications for ctDNA can be its ability to inform adjuvant chemotherapy. Its ability to not only identify more people who may benefit from chemotherapy, but maybe even identify people who don't need chemotherapy. And along those lines, Abstract 9, the BESPOKE study, looked to understand the role of ctDNA-based detection of molecular residual disease to inform adjuvant therapy for stage 2 and 3 colorectal cancer. And they presented interim data at the GI ASCO this year. What were your takeaways from this study? Dr. Aparna Parikh: Exactly. Beyond the prognostic implications, I think what was really interesting was that there was the initial data looking at the benefit of adjuvant chemotherapy. So, what they did was they said, “Okay. We’re going to take the MRD-positive patients and look at the benefit of adjuvant chemotherapy and then the benefit of adjuvant chemotherapy in the MRD-negative patients.” And again, remember, this is a prospective observational study, so it's not looking at negative and positive to guide therapy, but it's just looking prospectively and observationally at how those patients are doing. But what they showed again is that indeed, in the adjuvant chemotherapy group, the benefit of adjuvant chemotherapy again with the follow-up to date on the study was different in the MRD-positive patients.  First of all, I guess taking a step back, the DFS in the ctDNA-negative patients at 2 years was very good. So negative patients had over 98% 2-year DFS in both the adjuvant chemotherapy and observational group. And there was no real difference between adjuvant or not. But in the positive patients, not surprisingly, the DFS was worse. But what was reassuring to see is that you can make an impact with adjuvant chemotherapy in the positive patients. And the difference in DFS between the positive and negative patients, with adjuvant or not, was 42% versus 12.5%, in the observational patients. So, it is benefitting the patients who are positive so it does give us more data that, again, at least in the positive patients, you may be able to reverse the recurrences there with adjuvant chemotherapy. And maybe if you’re negative, eventually, we'll get to a point of de-escalation of care. Again, keeping in mind the kinds of sensitivity limitations as well.  Dr. Shaalan Beg: Wonderful. And one of the other malignancies in the GI space where precision therapies and molecular biomarkers are making a huge difference are intrahepatic cholangiocarcinoma. Genomic profiling using ctDNA is increasingly being used in this population to inform precision oncology approaches and determine mechanisms of resistance to targeted therapies as well. In Abstract 528, investigators looked at the role of preoperative ctDNA testing for resectable intrahepatic cholangiocarcinoma. What are your thoughts on that study?  Dr. Aparna Parikh: Yeah, it's such an important area, as you mentioned, in the metastatic space – FGFR, IDH1, all these alterations that are emerging in intrahepatic cholangios. This was a very small study, it was preoperative, and so the tumor was intact, and around 14 patients. They used a tumor-informed approach just for detection and quantification of ctDNA. So this was not a study that was looking at a next-generation sequencing approach where you’re going to actually be able to detect the alterations, but it’s actually looking for the detection and quantification of ctDNA rather than genomic characterizations. And patients had about a month or so where they had their baseline blood detected. And I think what was reassuring to say was that ctDNA was actually detected in all the patients with the primary tumor intact, except for one patient who was a very low-risk stage 1A patient. There was some correlation, against a small number of patients, between the concentration of ctDNA in patients that had the lower stage and then the higher stage groups. Small numbers were actually hard to characterize and correlate with recurrence or mortality, but at least, some correlation with pathologic tumor size, they were able to because it was a bespoke panel and you’re sampling the tissue and then looking in the blood, IDH1 and 2 were mutations that were tracked based on the genomic profiling and a couple of the patients were able to have their IDH mutations tracked.  So it gives us a sense, a little bit, that ctDNA, we know has a lot of variable shedding across disease states and tumor locations, but gives us some promise that it is reliably detected with the tumor-informed approach, at least preoperatively in cholangios. So may again open some more opportunities for MRD testing in cholangiocarcinoma as well.  Dr. Shaalan Beg: Thank you. That's a wonderful review of ctDNA applications in gastrointestinal cancers from the 2024 ASCO GI Cancers Symposium. Thank you, Dr. Parikh, for sharing your valuable insights with us on the podcast today. Dr. Aparna Parikh: Thank you so much for having me. Dr. Shaalan Beg: Thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Aparna Parikh @aparna1024   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Aparna Parikh: Consulting or Advisory Role (An Immediate Family Member): PMV Consulting or Advisory Role: Checkmate Pharmaceuticals, Guardant Health, Foundation Medicine, Abbvie, Value Analytics Labs, Bayer, Taiho Oncology, Delcath, Seagen, CVS, SAGA Diagnostics, Scarce, Illumina, UpToDate, Takeda, AstraZeneca, Takeda, Pfizer, Kahr, Xilio Therapeutics, Sirtex Research Funding: PMV Pharma, Erasca, Inc, Syndax Research Funding (Institution): Bristol-Myers Squibb, Genentech, Guardant Health, Array, Eli Lilly, Novartis Pharmaceuticals UK Ltd., PureTech, Mirati Therapeutics, Daiichi Sankyo, Karkinos Other Relationship: C2i Genomics, Xgenomes, Parithera, Cadex
4/4/202417 minutes, 21 seconds
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New Machine Learning Framework Uses EHR Data to Assess ICI Effectiveness, Toxicity

Drs. Shaalan Beg and Travis Osterman discuss a machine learning model, recently featured in JCO Clinical Cancer Informatics, that uses electronic health record data to accurately predict the effectiveness and toxicity of treatment with immune checkpoint inhibitors. The new AI model can be used to provide a personalized risk-benefit profile, inform therapeutic decision-making, and improve clinical trial cohort selection.   TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host for today. I am an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center.  Cancer immunotherapy has transformed the treatment landscape by providing new and effective treatment options for many solid and hematologic malignancies. But while many patients experience a remarkable response to immune checkpoint inhibitors, other patients can suffer life-threatening immune checkpoint toxicities. Today, we will be discussing a machine learning solution that can assess a patient's immune checkpoint inhibitor risk-benefit profile based primarily on routinely collected structured electronic health record data. This novel AI solution was recently featured in JCO Clinical Cancer Informatics, and I am delighted to welcome one of the report's authors, Dr. Travis Osterman. He is an associate vice president for research informatics and associate professor in the Department of Biomedical Informatics and the Division of Hematology Oncology at Vanderbilt University Medical Center in Nashville, Tennessee. Dr. Osterman also serves as the director of cancer clinical informatics at the Vanderbilt Ingram Cancer Center.  Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod.  Dr. Osterman, it's great to have you on the podcast today.   Dr. Travis Osterman: Thanks, Shaalan. It's great to be here. Thank you for the invitation.   Dr. Shaalan Beg: Congratulations on your recently published article in the JCO CCI titled "Prediction of Effectiveness and Toxicities of Immune Checkpoint Inhibitors Using Real World Patient Data." Why did you decide to address this specific problem?   Dr. Travis Osterman: I am a practicing medical oncologist at Vanderbilt, I specialize in thoracic malignancies. Immunotherapy has been a significant part of my practice from the beginning. And I think for all of us, we have patients in our practices that are tremendous responders. I have stories of my patients, a few of which, at least, are able to get years of benefit even after stopping therapy, and potentially some even stage 4 patients that are amazingly seemingly cured after their treatments. But I also have patients that experience severe toxicities, some of those are life-threatening or life ending, but many of those carry morbidity. In my population, I see a lot of pneumonitis, and that really alters patients' quality of life. And the biggest conversation I have with patients is: “How do I know which of these outcomes I’m going to have, if I’m going to get benefits from these therapies or am I going to get one of these side effects or toxicities?” And we set out to try to answer that question with data.   Dr. Shaalan Beg: When electronic medical records started to make their way into the clinic, I remember all of us thinking about the wonderful applications where we could use the data to help guide the clinical care, assign the right treatment for the right patient at the right time, and learn from other patients' experiences to improve the care of the person who’s in front of us. And my personal opinion is that we haven’t realized our electronic medical records’ potential to that extent. And efforts like the one you published in JCO CCI is the culmination of one of the efforts, and I can only imagine how much time and effort it must have taken to develop that and we’re hoping is the first of many more to come. For our listeners, can you talk us through the steps required to develop such a tool, and why now is the right time, and why we’re starting to see these evolve?   Dr. Travis Osterman: This project would not have been possible 20 years ago. It relies on having what we would call structured data available for our patients that are receiving cancer care, so that’s vital signs, laboratory values, and diagnoses, all of the things that we routinely collect in the electronic health record. So that is step 1. This project required that those systems be not just in place at academic centers but be widely available because our goal is to set up systems that will be able to transform cancer care, not just at academic institutions, but for the entire practice of oncology.  The second piece is you need enough data to be able to train these models. And so, we needed to be practicing with checkpoint inhibitors long enough to see patients that had toxicities, to see patients that had benefit, and then to jump into the data science of actually trying to learn from them. And so this really was the culmination of systems put in place by a lot of people before us and then really the right time [when] we started to have now enough data to really start to learn from.   Dr. Shaalan Beg: The publication discusses the steps of how you validated your tool. Talk me through how you see this being applied to the point of care for the next time you are about to start an immune checkpoint inhibitor for your lung cancer patient?   Dr. Travis Osterman: I think there are two different primary lanes that these types of models can be applied. In the drug development space, I think many of us are familiar that many assets, many drugs that are in the development pipeline are halted because of adverse events in toxicity profiles, but we also realize that not everyone gets those toxicities. And so we envision a future where before a drug that's in the drug development pipeline is taken out of the development pipeline, potentially, you could screen patients that are at lowest risks of actually having side effects from that immunotherapy and only screen those patients into the trial and that would potentially make more drugs available to more patients going forward. So I think that that's 1 lane.  I think the other lane in clinical practice is, let's say that I'm treating a patient who we determine has an increased risk for colitis. Instead of only seeing that patient back in 3 weeks, potentially, now, what if I had one of our nurse navigators, call the patient at weekly check-ins between visits to check in and see whether or not they were having any episodes of diarrhea and trying to intervene earlier. That might allow us to keep patients both out of the hospital, out of the emergency department to treat their symptoms more quickly to decrease the severity of their toxicity and keep them on treatments, especially if they're receiving benefit from it. So, I think there's an opportunity to improve both drug development and making more drugs available to patients and then also to identify patients that are at risk for toxicity, and then to do interventions to help mitigate those risks. Really, the idea of precision risk mitigation.   Dr. Shaalan Beg: One of the problems with electronic medical record-based tools in the past has been that they don’t evolve with time. We develop it, we set it, we deploy it, and it almost feels, to the users at least, that it stops evolving after that. With novel therapeutic agents coming into the clinic, we're seeing new ADCs, new novel checkpoint inhibitors entering the market. How do you envision tools such as yours to be refreshed so they can stay relevant with the modern armamentarium of medications which are being used?   Dr. Travis Osterman: So, if you ask any data scientist, the most requested item they will ask for is more data. And so, this initial set of models that we've described in this publication were trained exclusively on a single institution's data at Vanderbilt University Medical Center as we continue both to see more patients here, and then ideally look forward to collaborations with other centers. We expect that these models will continue to be refined and that the performance will improve as we increase the amount of training data, and we hope that that will do 2 things. One, it will counteract the kind of model drift that you described. But then two, it will allow us to ask some more specific questions that honestly, we weren't really powered to answer in our study here. For instance, we didn't look at cardiac toxicity, which is a concern if you're giving a CTLA-4 along with a PD-1 or PD-L1 inhibitor more so than single agent immunotherapy. We just don't have enough events to be able to train models on that. But with future collaborations, that would be a question we would love to tackle as well.  One of the things that's interesting about the implementation of these models is that we found many of the features that I would have expected to find as a practicing oncologist. For instance, when we're trying to predict the toxicity of pneumonitis inflammation of the lung, I as an oncologist would think that many of my patients that have COPD or interstitial lung disease at baseline seem to be at a higher risk. And so that's one of the features that I was looking to come out in the model. And that's exactly what we found. That was one of the contributing features that helps us predict a higher risk of pneumonitis. But what's interesting is that's certainly not the only feature; there end up being about a dozen features that are in that space that help predict that toxicity.   Similarly, for colitis, we found that the combination of receiving a CTLA-4 inhibitor in addition to a PD-1 or PD-L1 inhibitor, that combination together, which would increase risk for colitis, which is well-documented in our literature. So these models are not entirely black boxes. We've published the top features of these models that contribute to our predictions. And I think clinically the challenge for me has always been if I have a patient who has COPD, but it's pretty well-controlled and their O2 sat is normal, how does that patient's risk bring pneumonitis compared to someone who has poorly controlled COPD with low O2 sat at baseline, etc.? And so these models are really designed to help tease out some of those nuances.   Dr. Shaalan Beg: There are so many wonderful applications to use preexisting data that can improve the lives of our patients and frankly that can improve the work experience for clinicians. They can be used for risk stratification using these preexisting data. Can you talk a little bit about what are the barriers that people face or that your team faced in developing these tools, and what has changed or what's expected to change in the coming years to allow people to continue developing tools such as what was described?   Dr. Travis Osterman: I think it's important to realize that we are not unique in addressing this problem. This is a problem that I think has been a focal point of our cancer informatics community for the better part of the last, probably, decade. I think one of the things that distinguishes the work that we've done here is really this idea of clinical utility. And what I mean is we focused on data that would be collected at any routine oncology visit in the U.S., and I would argue worldwide, to use as features in our model. So, we're not running complex genetic testing that may or may not be paid for. We're not asking for new laboratory values to be sent or for extensive questionnaires that aren’t already in clinical practice. We're using pieces that are already being connected into the pipeline of oncology practices, and I think that's one of the differentiators of this project versus many others in this space.  Right now, these are only EHR data. We have a part of our project that's looking at imaging data and whether that adds value. But one of the pieces that I always advocate for, if we're going to ask practices for instance to upload these imaging files or to send a CD to a central location to improve the outcome, that's harder to work into an oncologist workflow than if all the data are already there in the health record and you can click a button and calculate this person's risk profile. And so, we've really tried to be pragmatic about our approach as we've entered this realm and that's been a real focus of our team.   Dr. Shaalan Beg: Many of the listeners of today’s podcast are busy clinicians, and you talked about how the idea for this project came from the problem you witnessed in your clinic. How can clinicians continue to be involved in such initiatives or drive these initiatives at their own institutions, in office situations where they may not have the resources that your team has? Can you speak to national efforts or collaborations in this regard?   Dr. Travis Osterman: Yeah. So, first of all, I would invite really anyone to reach out to our team, if they're in a position where they'll be interested in validating our models at their local institutions. We would be happy to work with them to provide the models to see how they perform on their data sets. I think that that's an important part of the academic review and informatics is to see how these models translate into other health care settings. And we also are interested to make sure that what I said in the prior discussion is correct, that we're only incorporating things that other institutions already have. So I think that that's certainly one.  The second is a part of a large National Cancer Data standard project called mCODE, the Minimal Common Oncology Data Elements, I chair that executive committee. And one of the pieces of that is trying to find a way to make all of these kinds of structured data interoperable between health records. And so I would just encourage all of my colleagues to always advocate for interoperability and, when there's an option, to store data in a way that makes that data more easily shared in the same formats between institutions. I think that that will pay many dividends for our field going forward. And I just want to plug all the team at mCODE for their work in this and maybe there'll be an integration and connection between mCODE and our project in the future.   Dr. Shaalan Beg: Thank you very much Dr. Osterman for sharing your insights with us today on the ASCO Daily News Podcast.   Dr. Travis Osterman: Thanks, Shaalan. Have a great day.   Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find a link to Dr. Osterman’s article in the transcript of this episode. And if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Travis Osterman @TravisOsterman   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Travis Osterman: Stock and Other Ownership Interests: Faculty Coaching Honoraria: Amazon Web Services Consulting or Advisory Role: eHealth, AstraZeneca, Outcomes Insights, Biodesix, MD Outlook, GenomOncology, Cota Healthcare, Flagship Biosciences, Microsoft, Dedham Group, Oncollege Research Funding: GE Healthcare, Microsoft, IBM Watson Health Travel, Accommodations, Expenses: GE Healthcare, Amazon Web Services
3/21/202415 minutes, 44 seconds
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Innovations in CAR T-Cell Therapy for Multiple Myeloma

Drs. John Sweetenham and Shaji Kumar discuss the emergence of CAR T-cell therapy for multiple myeloma, its benefits and challenges for patients, and its potential role earlier in the treatment of disease. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast.  Multiple myeloma is the second most common hematologic malignancy, and the American Cancer Society estimates that there will be more than 35,000 new cases of the disease diagnosed in the United States this year. The emergence of several novel therapies over the last decade has transformed the therapeutic landscape for multiple myeloma, and chimeric antigen receptor – or CAR T-cell therapy – is one of the newest treatments for this disease, which has created a great deal of buzz.  Dr. Shaji Kumar is an internationally renowned investigator of novel therapeutics and next-generation treatment options for patients with multiple myeloma, and I'm delighted to welcome him to the podcast today to discuss innovations in CAR T-cell therapy in this space. Dr. Kumar is a professor of medicine and chair of the Myeloma Group, as well as chair of research in the Division of Hematology at the Mayo Clinic in Rochester, Minnesota. He is also the editor-in-chief of The Hematologist.  You'll find our full disclosures available in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.  Shaji, it's great to have you on the podcast today. Dr. Shaji Kumar: Thanks, John. Dr. John Sweetenham: Shaji, to begin with, maybe we could ask you for an overview of where CAR T-cell therapy sits in multiple myeloma right now. We know that CAR T-cell therapy has improved the survival for some patients with myeloma in recent years. But of course, relapse still remains a problem. Can you tell us a little about the therapies that are currently approved for multiple myeloma in the CAR T-cell space, and what are the potential benefits and challenges of these products? Dr. Shaji Kumar: Absolutely. It has been a revolution, I think, in terms of therapies for multiple myeloma during the past decade. We have seen so many new treatments approved for myeloma, and consequently, the survival of patients with myeloma has significantly improved. Two decades ago, we used to tell patients a median survival of 3 years, and today we tell patients a median survival of 8 to 10 years, a number that is continuing to go up. And it is all because of the new treatments that have become available for patients, especially over the past decade, and CAR T-cell therapy has been a game changer.   Now, the main treatments that we were relying on for the past 2 decades have been the immunomodulatory drugs, the proteasome inhibitors, and more recently, the anti-CD38 monoclonal antibodies. Unfortunately, what we see in the clinic is that patients go through these therapies and various combinations of these agents, and often over the 6 to 10 years after the diagnosis, they often become refractory to these drugs. And then we are left with very few choices, if any, for controlling the disease. And that's where the CAR T cells have really made an impact.  Over the past several years, clinical trials have shown that CAR T-cell therapy is highly effective. In fact, when we look at the initial trials that have been done in this space, the majority of these CAR T cells have been targeted towards what we call BCMA, or a B-cell maturation antigen that is present on both normal and abnormal plasma cells. Now, the concept of CAR T cells has been around for a while, and we have already seen success in other hematological malignancies, but it has been a little late compared to the other diseases in terms of its arrival in the myeloma field. But over the past few years, we have seen some dramatic progress. We currently have two different CAR T cells that are approved and available in the clinic. We have idecabtagene vicleucel (ide-cel) and also ciltacabtagene which is also called cilta-cel. Both of these CAR T cells are targeted towards BCMA.   In the early trials conducted with both of these CAR T cells, we’ve seen patients who have become refractory to all the available therapies, and now upwards of 90% of these patients are responding to these CAR T cells. We are now seeing responses that we had typically not seen previously in any of the other therapies – not only the high response rates but also the depth of response. What we are seeing is a significant number of these patients – nearly half – of these patients can actually be minimal residual disease (MRD)-negative in the bone marrow after the CAR T-cell therapy. And this is clearly unprecedented in this myeloma space. Now, the approval for both these CAR T cells has been based on the experience in patients who have become refractory to the currently available therapies. And the ‘line in the sand’ that the FDA has drawn for approval for these drugs has been at least 4 prior therapies. In those patients, when you look at the studies that have been done both for the ide-cel and the cilta-cel, it clearly demonstrates the advantages. And we can look at the data that's available in 3 groups. So we have the single-arm studies, the early phase I and phase 2 trials that have been done with both these CAR T cells. For ide-cel, we have the KarMMa trial, and for the cilta-cel, we have the CARTITUDE trials. In the initial studies, as I previously mentioned, we are seeing responses upwards of 90%, and we are seeing disease control that is lasting at least a year or more with these CAR T cells.   Now, of course, the question is, we do need randomized phase 3 trials to demonstrate that this is indeed true. Even before the phase 3 trials came along, there have been multiple case-control studies that have been done where the outcomes of patients getting these CAR T cells were compared to real-world controls or cohorts of patients who did not get these therapies. And these studies demonstrated that the outcomes of patients getting CAR T cells were significantly better than what has been shown in the real-world controlled population. And then finally, we have, of course, the phase 3 trials that have read out in patients with relapsed myeloma, in fact, in a group of patients in an earlier stage of the disease than who were studied in those single-arm studies. Now, based on the results from the single-arm studies, we got the approval from the FDA for the use of CAR T cells in this late stage of the disease. And with the phase 3 trials that have read out, both the KarMMa-3 trial and the CARTITUDE-4 trial again clearly demonstrate that these CAR T cells are much more effective than what we would have seen with the conventional therapies if those patients were assigned to those treatments. Now, clearly, it's not only a question of efficacy. We also know that they do come with some toxicities, and we have a good sense of the toxicities from those initial phase I and phase 2 trials. Now, as we have seen with the other diseases, the 2 major categories of toxicities that we see are the cytokine release syndrome and the neurological toxicity associated with CAR T-cell therapy.  In terms of the clinical features and the presentations, they are not different than what we have seen with the CAR T cells used in other hematological malignancies, but we do see different frequencies of these in the myeloma patient population. The cytokine release syndrome is something that is seen in a majority of the patients, at least in the lower grades. And over the time since we have been using CAR T-cell therapy, I think we have all become a lot more familiar with the management of the cytokine release syndrome, and we have very effective therapies to manage, and to some extent, maybe even prevent the onset of the cytokine release syndrome in patients undergoing CAR T-cell therapy.  The neurological toxicity is another toxicity that is unique to these immunological therapies, known as the ICANS, or the immune cell effector-associated neurological syndromes. And these, again, thankfully, are much less frequent than what we see with the cytokine release syndrome. But even with the ICANS and other neurological toxicities associated with CAR T-cell therapy, we have a better understanding of the biology behind it, and we also have better modalities to monitor the patients for these toxicities and intervene in an appropriate and timely manner to take care of them.  In addition to the ICANS and the cytokine release syndrome, we certainly do see other toxicities as well. We do see hematological toxicities, which are common for many of the treatments we use for hematological malignancies. Thankfully, these other toxicities can be easily managed. They often reverse themselves over time and haven't really posed any major hurdles in terms of the utilization of these modalities of therapy for patients with myeloma. Dr. John Sweetenham: Okay, that's great. Thank you very much, Shaji. I'll return to some of the potential late effects of CAR T-cell therapy in a moment. But before we get to that, as you know, in other hematologic malignancies, there has been a trend in recent years to moving CAR T-cell therapy further up the therapeutic algorithm, as it were. So there is consideration being given to using this as a first-line or second-line therapy. Do you think there is a potential role for CAR T cell earlier in the treatment of multiple myeloma? For example, could you see a time when it may be used as second-line treatment for this disease? Dr. Shaji Kumar: Absolutely. I think that's a very good point. And I think, just as with other cancers and as with myeloma, too, with many of the therapies we use for myeloma in the newly diagnosed setting or the time of first relapse, were all initially tested in these later relapses. We are following the same script even for the CAR T cells. In fact, the 2 phase 3 trials, the KarMMa-3 trial and the CARTITUDE-4 trial, enrolled patients in the earlier lines of therapy, either 1 prior line or 2 prior lines for these trials. And what we have seen with both phase 3 trials is that the outcomes, both the progression-free survival outcomes and the response rates, are significantly better compared to the standard-of-care therapies that these patients would have otherwise received.  Now, what is unclear at this point is, does every patient at the time of the first relapse need a CAR T-cell therapy, or can we be more selective in terms of deciding which particular subgroup of patients can benefit more from this CAR T-cell therapy in different lines or different relapses? The bottom line is, I think the data that we have right now clearly points towards the utility of CAR T-cell therapy at earlier lines of treatment. The question now is, which patients do we need to do at which stage? In fact, when you look at the newly diagnosed setting, there are ongoing clinical trials that are looking at replacing autologous stem cell transplant with CAR T-cell therapy. Those phase 3 trials are currently enrolling where patients are being randomized to either the autologous stem cell transplant, which is considered a standard of care for eligible patients, or giving them a CAR T-cell therapy. Similarly, even in transplant-ineligible patients, trials are exploring the possibility of using CAR T-cell therapy instead of giving patients a prolonged course of maintenance and consolidation.  One of the beauties with the CAR T-cell therapy right now is that it's a one-time treatment. You get the treatment and you do not get any additional therapies after that. It’s a protocol that is being debated – whether we will need maintenance therapies after CAR T-cell therapy, but I think that is something that will have to be explored in the context of clinical trials. But certainly, I think over the next 5 years, we will see the CAR T-cell therapy moving to earlier and earlier lines of therapy. My guess is in 5 years, there will be a subset of patients where we would offer them CAR T-cell as part of the first-line therapy, some others, maybe based on disease and patient characteristics, we might use it at the time of first or second relapse.   Dr. John Sweetenham: Great, thank you. Just to return to toxicities and some of the potential late effects. As you know, last November, the FDA launched an investigation to determine whether CAR T-cell therapy can, in rare cases, cause secondary cancers. You may remember that this was in response to reports of T-cell malignancies in patients who had received various types of CAR T-cell immunotherapies. The FDA determined that the risk of T-cell malignancies is applicable to all of the currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T-cell immunotherapies. Could you care to comment on this whether you have seen any evidence of this in your own work, and whether the events and the FDA investigation have impacted your clinical research or your clinical practice in any way in terms of patient monitoring or maybe in terms of trial approval? Dr. Shaji Kumar: This has been an important observation. As with all new therapies, whenever the question of long-term toxicities is brought up, especially second malignancies, it is something that needs to be looked into very carefully, and I think the FDA is doing exactly that. There have been reports of second cancers, particularly T-cell cancers. In fact, there were some statements that came out recently from the FDA where they commented on the fact that they had seen 22 cases of T-cell cancers by the end of 2023. And, in fact, in 3 of those cases where genetic sequencing was performed, they did notice that the genetic material or the chimeric antigen receptor was inserted into these cancer cells as part of the process. So I think there is a lot more work that needs to be done in terms of understanding the mechanism and probably also understanding how prevalent these instances are.  But I think, based on what we know as of now, these cases form a very tiny fraction of the total number of CAR T-cell therapies that have been used in patients with lymphoma and myeloma. In our own day-to-day practice, this has not really affected how we view this therapy. It clearly has made a significant impact for patients with no other treatment options. So in our daily practice, we continue to use CAR T-cell therapy as we have done before these reports came out. But we do inform patients about the risk and what we know about the risk of these T-cell malignancies.   In addition to T-cell malignancies, there have also been reports of myelodysplastic syndromes in patients undergoing CAR T-cell therapy. Again, it is important to remember that, at least in the myeloma setting, many of these patients have had multiple lines of therapy, often with drugs that can cause second malignancies, particularly myelodysplastic syndrome. So I think a lot more work needs to be done in terms of understanding what is the direct impact of CAR T-cell therapy versus what was lurking underneath because of the treatments that these patients had previously received. So I think it is important for us to continue to be very diligent, as with any new therapies that we introduce for the treatment of our patients. But at the same time, understand that, in the context of the benefits that these therapies bring to our patients, especially when they have no other treatment options.  Dr. John Sweetenham: Absolutely. So, at least for now, and probably in the longer term, the benefits of the therapy certainly appear to outweigh the risks, although it is important not to underestimate or minimize those risks.   I wanted to change direction a little bit and talk a little bit in the final question about care disparities and CAR T cell. Of course, CAR T-cell therapy is typically offered at large cancer centers and is very expensive. This means that there are issues of access to treatment. In addition, the literature shows us that non-Hispanic Black individuals are twice as likely to develop multiple myeloma compared to their White counterparts. Furthermore, at least right now, Black patients are less likely to receive these novel CAR T-cell therapies and continue to be underrepresented in clinical trials. So, this is a big, complex question, but can you talk a little bit about how outcomes differ between racial and ethnic groups who actually receive CAR T-cell therapy for multiple myeloma? And could you address what you think are the most appropriate strategies for minimizing the disparities in access? Dr. Shaji Kumar: That's a very, very important question, particularly in the context of multiple myeloma, where African American individuals are at a higher risk of getting plasma cell malignancies. I think we need to think about this in the context of what we know about disparities even before the CAR T cell came along. There has been a good amount of literature that has looked at the outcomes based on the types of therapies that could be impacted by this. There have been studies that have looked at cooperative group trials, which often have a good representation of minorities and have shown that if patients have equal access to advanced therapies that we have, their outcomes are comparable or sometimes even better for African American patients compared to Caucasian patients. So I think it’s very important that the treatment strategies that we develop are equally accessible to everyone.  In terms of CAR T-cell therapy or immunotherapies, I don’t think we have any concrete evidence to suggest that there is any difference in outcomes. And I think it's reasonable to assume that if patients are exposed to similar therapies, they will have similar outcomes, even in the context of immunotherapies. But at the same time, I think we must continue to study this diligently, and the only way to do that is to ensure that clinical trials include patients reflective of society in general. This will allow us to understand if any differences exist. In addition, I think there is a serious risk that with these expensive therapies, this gap can only widen. And I think that is one reason that we must be proactive, particularly with therapies like CAR T-cell therapy, which not only are expensive but also require quite a bit of logistical support for patients to go to larger centers to get these therapies, stay around these larger centers for upwards of a couple of months, which means they are living outside of their usual societal structure, and ensure there is access to the resources that are needed to enable them to do that. So I think there is a lot that is still unknown, but I think we really need to be proactive in ensuring equal access to these therapies. Dr. John Sweetenham: Yes. Thanks for a very thoughtful response to that question, also for the work that you are obviously doing to help address this extremely important issue.  I’d like to thank you for sharing your insights with us today and for the extraordinary work that you’re doing and your team are doing to advance care for patients with multiple myeloma. Dr. Shaji Kumar: Thank you, John. Dr. John Sweetenham: And thank you also to our listeners for joining us today. If you value the insights you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. The guests on this podcast express their own opinions, experience, and conclusions. Guest statements do not necessarily reflect the opinions of ASCO. Mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s guest:    Dr. Shaji Kumar @myelomaMD   Follow ASCO on social media:       @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn       Disclosures:      Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness     Dr. Shaji Kumar: Consulting or Advisory Role: Takeda, Janssen Oncology, Genentech/Roche, Abbvie, Bristol-Myers Squibb/Celgene, Pfizer, Regeneron, Sanofi, K36 Research Funding (Inst.): Takeda, Abbvie, Novartis, Sanofi, Janssen Oncology, MedImmune, Roche/Genentech, Carsgen Therapeutics Ltd., Allogene Therapeutics, GlaxoSmithKline, Regeneron, Bristol-Myers Squibb/Celgene Travel, Accommodations, Expenses: Abbvie, Pfizer
3/7/202420 minutes, 55 seconds
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ADCs in Breast Cancer: Sequencing, Resistance, and Managing Toxicity

Drs. Hope Rugo and Sara Tolaney discuss the promise of antibody-drug conjugates (ADCs) in the treatment of breast cancer, highlighting key trials that shed light on matching the right ADC to the right patient in the right setting. They also explore how combinations and sequencing of ADCs can augment their efficacy, the mechanisms of resistance, and the future potential of biomarkers to predict patient response. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco's Comprehensive Cancer Center. Antibody-drug conjugates, or ADCs, are rapidly changing the treatment landscape for patients with breast cancer. ADCs consist of antibodies that target tumor-specific antigens on the cell surface, chemical linkers, and cytotoxic payloads that can act powerfully to kill cancer cells. On today's episode, we'll be discussing advances in research to match the right ADC to the right patients and in the right setting. We'll also talk about the next steps, assessing how combinations and sequencing of ADCs can augment their efficacy, improve options for patients, and identify biomarkers in the future to predict how patients will respond so that we can match the right treatment to the right patient and their tumor. We need to gain a better understanding of the mechanisms of resistance that occur upfront as well as under the pressure of treatment.  Joining me for this important discussion is Dr. Sara Tolaney. Dr. Tolaney is an associate professor of medicine at Harvard Medical School, associate director of the Susan Smith Center for Women's Cancer, and chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute in Boston.  You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast are available at asco.org/DNpod. Dr. Tolaney, we're delighted to have you on the podcast today. Thanks for being here. Dr. Sara Tolaney: Thank you so much for having me. I'm looking forward to the discussion. Dr. Hope Rugo: Great! So, we'll move forward, and because we're friends and colleagues, I'm going to refer to you as Sara, and I'm Hope, since we’ll dispense with formalities in our discussion.  A lot of the talks that we give about ADCs start out with “a revolution in breast cancer therapy.” And indeed, this is a really exciting time with ADCs as treatment for breast cancer, and we're rapidly moving these agents into earlier disease settings. Can you tell us a little bit about the possibilities and challenges of using ADCs for the treatment of breast cancer today? Dr. Sara Tolaney: It's interesting that you say antibody-drug conjugates as revolutionizing outcomes of breast cancer, which I think is true. But on the flip side, I think it's also bringing up a lot of questions about how to use them, when to use them, and how to manage side effects. So there are a lot of good strengths for these antibody-drug conjugates, but a lot of unknowns that we're still trying to figure out. We had an older antibody-drug conjugate T-DM1 that we were all very familiar with that for years had been a treatment that we used very commonly in metastatic disease and now even use in early breast cancer, and I think has changed outcomes for patients. But over time, we've been able to develop newer antibody-drug conjugates as the technology has really evolved so that these agents now are able to deliver a lot of chemotherapy into a cancer cell. We're seeing very high drug-to-antibody ratios, and we're also seeing that these drugs can function via bystander effect, whereas T-DM1, for example, was not able to do that. But our newer ADCs, like sacituzumab govitecan or trastuzumab deruxtecan, are agents that do allow chemotherapy to get into that cancer cell, but also to get into neighboring cells.  And I think the technology evolution in being able to build these so-called next-generation ADCs has allowed for really unprecedented efficacy that we've not seen before. And it's also allowed us to develop these drugs in a way that's been different. Originally, we were developing T-DM1 to turn off HER2 signaling and to deliver chemotherapy into a HER2 cell. At least that's what we thought originally. And now we're really evolving so that we can just find a tiny bit of protein on a cancer cell and use it as a target, really in a subtype-agnostic way. And I think it's just a different way of thinking about how to use these agents to really deliver a lot of chemotherapy into cancer cells and have very robust efficacy. Dr. Hope Rugo: Yes, it is fascinating that some of the suppositions that we made with the first ADC don't seem to really hold true as well. And maybe they hold true in varying levels for the different ADCs. For example, this bystander effect is thought to allow us to target cells that have very low expression of the receptor that can be internalized even lower than our ability to detect these receptors by immunohistochemistry. And maybe we'll talk about that in a little bit.   But first, you mentioned already sacituzumab and trastuzumab deruxtecan, the ADCs that are currently approved for breast cancer. But can you tell us a little more about those ADCs and the key trials that have led to approval of these targeted agents? Dr. Sara Tolaney: Yes, I think when we first saw the data that came out with T-DXd and DESTINY-Breast01, I think my jaw dropped because I had never seen a waterfall plot like that. This was a single-arm study that looked at T-DXd in patients with very heavily pretreated metastatic HER2-positive breast cancer and saw very high response rates of over 60% and a clinical benefit rate of almost 98%, meaning that almost every single patient who got the drug and had a median of six prior lines of therapy had reduction in tumor size. And that’s unreal. I think it was revolutionary in the sense that we had never seen that kind of activity in such a pretreated population. The agent was studied in other registration trials, DESTINY-Breast03, which looked at T-DXd and compared it head to head with T-DM1 in a predominantly second-line metastatic HER2-positive population, and here, again, unprecedented results. I’ve never seen a p value like that or a hazard ratio of, again unreal, of a little under 0.3 and seeing a 28-month PFS with T-DXd relative to just a little under 7 months PFS with T-DM1. We have never seen patients with metastatic HER2-positive breast cancer have a PFS that long. Even in CLEOPATRA, it’s a little under 19 months in the first-line setting, where people were predominantly naïve to HER2-directed therapies. This, again, is really changing outcomes for patients.   But then, I think, when we go to the next step, we studied T-DXd in patients with HER2-positive breast cancer and it had again these unprecedented results. But there was some early data suggesting that it could even work in tumors that weren't truly HER2-positive but what we call HER2-low, meaning that they weren’t HER2/3+, they weren’t HER2-0 but they were 1+ to 2+ and not FISH amplified. And so even with a little bit of protein there, they were seeing activity in the early phase studies and so it led to DESTINY-Breast04, which compared T-DXd to chemotherapy of physician's choice in people who had had one or two prior lines of chemotherapy in the metastatic setting. It was predominantly geared to look at outcomes in hormone receptor-positive breast cancer. But there was a small group of 58 patients with triple-negative disease that were also included in that trial. And here again, a very unprecedented outcome seeing a response rate of about 50%, which, again, we never see in pretreated hormone receptor-positive disease. And a PFS of 10 months, and again, these are people who already had one or two prior lines of chemotherapy. So it’s, again, really changing outcomes. And so now I think it leads us to a lot of other questions that we are addressing in trials - can this drug work even if the tumor has maybe no HER2 expression, what about HER2-0, what about HER2-ultra low, meaning a little bit of staining but not quite 1+. And so these are questions that I think we will need to address and there are studies that will help us address that. On the flip side, we saw sacituzumab govitecan get developed in breast cancer. Initially, we saw very impressive results from a single arm study of sacituzumab in metastatic triple-negative disease where we saw response rates of a little over 30%. These are patients who were very heavily pretreated with metastatic triple negative breast cancer where, unfortunately, response rates end up being in a 5% range so it was a home run in that setting. So that led to the ASCENT trial, which compared sacituzumab govitecan to treatment of physician's choice therapy and that study really enrolled people who were, in essence, second line and beyond in the metastatic triple-negative setting and showed almost triple progression free survival, in essence, doubled overall survival. So again, very robust efficacy leading to confirming its approval. And then we saw data from TROPiCS-02, which looked at sacituzumab in metastatic hormone receptor-positive disease and also showed improvements in both progression free and overall survival. And this was in pre-treated populations of 2 to 4 prior lines of chemotherapy. These agents, again, have established robust efficacy, and so now the idea is can we move these drugs earlier in development into earlier line settings and can we even move these agents into the early disease setting and potentially cure more patients? So hopefully, we’ll figure out ways to make that happen. Dr. Hope Rugo: Yeah, that was a great summary of this exciting data. And I think we really got an idea of what waterfall plots could tell us from DESTINY-Breast01 where you could count the number of patients whose cancers grew with therapy on one hand. It's been a huge advance. I think it’s where we get this “revolution” even in patients with a median of 4 lines of prior chemo, and, in the ASCENT trial, we were able to see this improvement and survival in the hardest-treated subset of metastatic breast cancer triple negative disease. And then the remarkable data in HER2-positive and HER2-low breast cancer hormone receptor positive disease. We’re really covering all of the subset of breast cancers.   When we introduce new therapies though, and of course, our interest is moving them earlier as lines of therapy in the metastatic setting, we really have to think about the adverse events and how those are going to affect their patients, and balancing the risk benefit ratio. Obviously when the benefit is so huge, we’re more thinking about how do we proactively manage these side effects, educate our patients, use prophylaxis when possible. Can you share with us some of your insights on management strategies for toxicities?  Dr. Sara Tolaney: You bring up a very good point, and I will say the ADCs were designed with the idea being that we could deliver a ton of chemotherapy into a cancer cell. So obviously, my hope had been that we weren't going to see a lot of chemotherapy-like side effects because the goal was to try to spare normal cells of these side effects. But unfortunately, we do see that these agents do have real toxicities, and I think that is an important message. So, for example, with sacituzumab, for people who have hair going into it, they will lose their hair during the course of treatment, and so that's important to make patients aware of. It can lower blood counts, and about 50% of patients who are on sacituzumab will end up needing growth factor support while they're on treatment. So, that is again something that needs to be monitored and managed. But usually, we're pretty good at managing neutropenia, and with the growth factor support, I find that it actually works really well.  Another thing with sacituzumab is the potential risk of diarrhea, but most of the diarrhea is low-grade diarrhea. It’s rare that you get someone who has high-grade diarrhea with sacituzumab. Usually, I find it works to just instruct patients to use loperamide as needed. And again, usually that works well. And certainly when needed, dose modification can also help with these side effects and so it is important to keep in mind that this is another option. With T-DXd, one thing that we do have to keep in mind as an unusual side effect is the potential risk of interstitial lung disease. We see that in about 10% to 15% of patients getting T-DXd. That is something that we do have to be very mindful of. For the most part it is low-grade ILD. But there are rare occasions where there have been deaths from ILD. And we're seeing with some of the newer trials, the death rate is usually under 1%, but it is a real potential risk. And so it is really important to counsel patients when getting T-DXd about this potential side effect, that way they are good about communicating with you if they get any new symptoms, such as shortness of breath or dry cough, to get you aware of it and can work it up and get imaging certainly if that occurs.  And then I think the management for ILD is a little unique and a little different truthfully than the way we manage pneumonitis from other drugs. Normally, when I am treating patients who develop pneumonitis, even if it is mildly symptomatic, we often will hold treatment, give steroids, and rechallenge them when it gets better. But with T-DXd, if anyone develops symptomatic pneumonitis, you actually have to permanently discontinue the T-DXd per the guidelines because we just don't know the safety of being able to rechallenge that patient once that pneumonitis resolves. For grade 1 ILD, meaning someone who has, for example, ground glass changes seen on imaging but doesn't have any symptoms, you have to hold the drug and wait until those imaging findings resolve and then you can restart. I usually do treat grade 1 ILD patients with steroids with the hope being that maybe it will allow for the pneumonitis to resolve more quickly, although in truth I don't know if that's the case. I have just taken that approach because I don't like leaving patients off the drug for too long if not needed. Again, I typically treat them with steroids, reimage in three to four weeks, and see if I’m able to restart. If they resolve within 28 days, you can restart at the same dose. If it takes longer to resolve, you need to dose modify.  And then I think the other big thing with T-DXd is to know that it is categorized as a highly emetogenic agent. Most of us are using three-drug prophylaxis, which I think works really well. It is also important to realize that there can be some delayed nausea, which is a little unusual with some of our other agents. And so to warn patients about that and I find that use of olanzapine or ondansetron for the delayed nausea tends to work pretty well.  Hope, do you have any pearls for us? Obviously, you are very experienced in using these agents; are there any things you would recommend for the management of ADCs?  Dr. Hope Rugo: Yes, it's such a great question and an important area because, particularly as we are using these agents earlier, we really need to have strategies for both how long to continue as well as manage the toxicities. I agree with the nausea, olanzapine has been really a great addition, and using a triplet as initial premedication makes a big difference for T-DXd and other deruxtecan ADCs that are in the pipeline. And then I think that the ILD issue, we’re really learning more about the risk factors as well as retreatment. And hopefully, we’ll have more data this year at ESMO Breast and maybe ASCO on retreatment for grade 1. We certainly now do not have any data on the safety of retreatment for grade 2, so that is really not accepted now. For sacituzumab, I think the interesting area is the metabolism and the impact. So with neutropenia, as we move the drug earlier, it's easier and easier to manage, we see less severe neutropenia. We can give growth factors, which we are all good at in oncology. But I think the question about managing diarrhea and who is at risk still exists. Understanding pharmacogenomics and UGT1A1 is an interesting area where patients who have diarrhea could be tested to see if they are poor metabolizers which affects a little under 10% of the overall population. Because in that group, you could give less drug and get the same benefit with less toxicity. So I think this is all very interesting. It is important for providers and patients to be educated so that we can manage this appropriately. And I think you gave an excellent overview.   We have new agents in the pipeline also and maybe we’ll talk about those next, and then we’ll talk a little bit about sequencing and resistance, as well as the unmet need for brain metastases. So lots of areas to talk about. There are a number of TROP-2 ADCs that are in the pipeline, and one that has presented phase III data, datopotamab deruxtecan. But other studies are being developed with new TROP-2 ADCs as well. But then there are a huge number of ADCs there with new targets, for example, immune effector targets, and new payloads, even immunotherapy and two different payloads or bispecific antibodies. And then there is interest in combining ADCs with immunotherapy and PARP inhibitors. We saw data in bladder cancer, I think it was bladder cancer, with combined 2 different ADCs at ESMO in 2023. So a lot of new approaches. How are we going to manage this moving forward? And where do you think we are going to position some of these next sort of "me-too" drugs?  Dr. Sara Tolaney: It's an excellent question, and you're right, the field is exploding with new antibody- drug conjugates. So, it's going to leave us with this conundrum of what to do. And you brought up the really interesting example of the fact that we have an approved TROP-2 ADC, we have as sacituzumab govitecan, and for example, we've recently seen some really exciting data come out from TROPION-Breast01 looking at another TROP-2 ADC, datopotamab deruxtecan or Dato-DXd where that ADC performed better than chemotherapy in a head-to-head trial in terms of progression-free survival in a hormone receptor-positive population. Then there's another TROP-2 ADC, moving forward in development moving to phase III that Merck is developing MK-2870. All three of these ADCs are targeting TROP-2 and have a TOPO 1 payload. So, it leaves you with the question of how do you think about that? Is there going to be a role for using serial TROP-2 ADCs? Could one work after the other, even when they have very similar payloads? How are we going to incorporate them? How do you pick one over the other? So, it is going to be tricky for us as we get more and more of these agents. I think we're all excited about seeing ADCs that may have different targets and different payloads, where maybe we will see that sequential utilization will have robust efficacy if we swap things out. Again, we don't have data here yet, but I think there are other agents in development. For example, you could think of like, disitamab vedotin targets HER2 and has an MMAE payload. So, could it be that someone progresses on T-DXd for HER2-low, but then could go on to disitamab vedotin? How will that work? So, we have a lot to learn, but it's really nice to have so many options.  Dr. Hope Rugo: Yeah, it'll be interesting to see whether or not we select the ADC based on a rational understanding of the tumor and the patient, or whether it's simply what's easier to give and has the right toxicity for that patient.  So, that sort of brings us to our next topic, which is how are we going to sequence these agents? How are we going to understand the mechanisms of ADC resistance? At San Antonio in 2023, we saw a presentation where there was a top-alteration, and the patient had a really long response to a top-directed ADC, or an agent that carried a topoisomerase inhibitor. And that really struck me that we're going to see these alterations. There was a fresh autopsy study that suggested that the alterations may be different in different organ sites of disease. How are we going to figure this out? Dr. Sara Tolaney: Yeah, I also was really puzzled to see those data from San Antonio where we've sort of simplified ADC resistance in our heads to say, well, maybe someone becomes resistant because they lose target expression, or maybe someone becomes resistant because they've developed resistance to the payload, kind of like the way we think of someone developing resistance to getting chemotherapy. But obviously, it's probably far more complex than that. With these ADCs, they need to be able to internalize the ADC and could there be mechanisms of resistance related to the internalization process? So, I think there are lots of potential areas where resistance could be occurring. I think, we don't understand it very well. We've seen patients, for example, who have responded. This is just anecdotal, but we have data, for example looking at, Dato-DXd in the phase 1 triple-negative study where there were some patients who responded despite having progressed on sacituzumab. Well, why is that? You would think if it's target resistance or payload resistance, it would be the same target and a very similar payload. So, why would those drugs work one after the other? And that's why I think we just don't understand this well enough at this point in time.   So, it's clearly an area where more research is needed because it does have significant implications on how we think about using these drugs sequentially. We will need to understand these resistance mechanisms because there do seem to be some rare patients who benefit from these sequencing strategies and then others who don't. So, it would be nice to be able to figure this out and hopefully in the future, we'll be able to test patients and know what drugs to give them. But I think we're far off from that, unfortunately, right now. Dr. Hope Rugo: Yeah, it does seem to be a relatively elusive approach, and I think, in part, it's due to the heterogeneity of cancer. And maybe, as we're better and better at analyzing tumor cells in the blood, which are a rare group, and ctDNA, which, of course, we do now to look for mutations, maybe that'll be an approach that we'll be able to take. And also, of course, moving the drugs earlier into the disease setting with less heterogeneity and mechanisms of resistance might help as well.  I was fascinated by the fact that although the PFS to the first ADC seems to be overall much greater than the PFS to the second ADC, when you sequence them, there are a few patients who have a longer PFS with the second, even if these are just sacituzumab T-DXd sequencing in various directions. So, it's clearly very complex. And right now, I think we're just sequencing and we don't really know how to do it. We just choose what we think is best for that patient first and go on to the next one later, which is interesting. And one of the choices might be treating brain metastases, which of course remains a huge unmet need. And if we could find effective treatment for brain metastases, maybe we could also prevent them in some patients more. What do we know about the central nervous system (CNS) penetration of ADCs and the clinical results? Dr. Sara Tolaney: At first, we were not optimistic that these drugs would have activity in the brain because we thought that these were very large agents that probably couldn't penetrate into the blood-brain barrier. But in fact, I think we were all very excited to see that there is actually data suggesting that these drugs can actually have robust efficacy in the CNS in patients who have active brain metastases. And so what we've seen so far is data with trastuzumab deruxtecan or T-DXd, there have been some trials that have been done, including studies like DEBRA and TUXEDO, which have looked at T-DXd in patients who have active brain metastases and are showing very robust response rates within the CNS. So, we're seeing intracranial response rates on the order of 40% to 50%. And clinically, this is what we're seeing as well. These are smaller studies and there's a larger trial, DESTINY-Breast12, which will hopefully validate the robust efficacy in the CNS with T-DXd. So, again, it's really nice to see this.  To your point, though, one area that I'm curious about, as you were alluding to, is will these drugs be able to prevent CNS disease? And I think that is a very different question because here the blood-brain barrier is not intact when patients have progressive brain metastases, and so these ADCs are causing robust activity. But if you look, for example, and I'll be curious to see what happens, DESTINY-Breast05 is looking at T-DXd in the post preoperative setting for patients who have residual disease and comparing it to T-DM1. And unfortunately, we saw that T-DM1 was not able to prevent brain metastases when looking at data from KATHERINE, where in fact, rates of CNS as the first site of recurrence were similar with T-DM1 and trastuzumab. So, now we'll be interested to see, will it be any different with T-DXd? Will T-DXd be able to have any role in prevention? I think we haven't seen anything like that with ADCs to date, so that would be a paradigm shift in our way of thinking.  Right now, there are strategies being taken from a prevention standpoint of trying to add a tyrosine kinase inhibitor in that early-stage setting, such as what is being done in the COMPASS-RD trying to add tucatinib to T-DM1 to see if that would do it. But again, we really need to understand, again, how these drugs work, particularly when the blood-brain barrier may not be intact. But again, very exciting data with T-DXd in an ongoing trial, actually through SWOG looking at sacituzumab for patients with CNS disease. And we've seen some preliminary data with sacituzumab showing that it actually does penetrate into the brain when they've looked at drug levels in the tumor in the brain, comparing it to plasma, it actually looks similar. So, we know it's getting in there and we'll have more robust efficacy data, hopefully coming soon. Dr. Hope Rugo: Yeah, that was a great summary of that data. It's been exciting also to see some responses in patients with leptomeningeal disease as well, where we've really been struggling with anything that works for more than a few weeks or months at the most. So I'm holding out great hope that we're going to see a big difference because even though TDM-1 had some efficacy, it was nothing like what we're seeing with T-DXd. So we'll see. And the same with sacituzumab with triple negative disease, where sometimes brain metastases can be an isolated site of recurrence, even in patients who have a pathologic complete response. So it has been a big challenge.  So I think that what we've learned from you is a lot about the mechanisms and the data about these new ADCs, the tremendous hope that these are bringing to our patients, but also the really exciting new approaches with new payloads, new targets of drugs that are in development, as well as potentially some different ADCs that have the same target and similar mechanisms of action of this payload. Really fascinating to hear about this, the future work on sequencing, on mechanisms of resistance, and on brain metastases. We have, of course, 2 prospective trials that we'll be looking at sequencing, one with T-DXd and Dato-DXd, and one registry trial with T-DXd and sacituzumab govitecan in the US. So that's also going to, I think, provide us with some important information.  We could talk for a long time about this, but I just wonder if you have any closing comments to sum up your thoughts.  Dr. Sara Tolaney: I think you did a great job leading us through thinking about ADCs, and I think it'll be really interesting to see what happens in the future. While again, these agents have become a standard for us for patients with metastatic disease, I'm going to be curious to see how everything evolves and to see if we'll be able to substitute chemotherapy with ADCs in early disease settings and change outcomes. Will we be able to have novel combinations? Will we be able to sequence these drugs one after another? Will we actually have biomarker predictors to help us sort out which drug to give when? So, still a lot to learn, but clearly a very exciting field right now. Dr. Hope Rugo: Indeed. Sara, thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast on your great work to develop novel therapies for breast cancer. It's always a pleasure to talk to you, and even greater to work with you on the future progress of treatment for breast cancer. Dr. Sara Tolaney: Thank you so much, Hope. Again, really nice to always discuss these data with you. I always learn a lot, so thank you. Dr. Hope Rugo: Thank you. And thank you to our listeners for joining us today. You'll find a link to all of the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of a product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:   Dr. Hope Rugo  @hoperugo  Dr. Sara Tolaney @stolaney1     Follow ASCO on social media:   @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Hope Rugo:  Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc, Stemline Therapeutics Travel, Accommodations, Expenses: Merck, AstraZeneca   Dr. Sara Tolaney: Consulting or Advisory Role: Novartis, Pfizer, Merck, AstraZeneca, Genentech, Eisai, Sanofi, Bristol-Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Immunomedics/Gilead, BeyondSpring Pharmaceuticals, OncXerna Therapeutics, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Umoja Biopharma, Menarini/Stemline, Aadi Bio, Artio Biopharmaceuticals, Incyte Corp, Zetagen, Bayer, Infinity Therapeutics, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR Therapeutics, Hengrui Pharmaceutical (USA), Sumitovant Biopharma Research Funding (Inst.): Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol-Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Seattle Genetics, OncoPep, Gilead Travel, Accommodations, Expenses: Eli Lilly, Sanofi, Gilead Sciences
2/15/202430 minutes, 14 seconds
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Advances in Precision Oncology for GI Cancers at GI24

Drs. Shaalan Beg and Rachna Shroff discuss key abstracts on GI cancers that were featured at the 2024 ASCO Gastrointestinal Cancers Symposium, including SKYSCRAPER-08, EMERALD-1, and NEST-1 in esophageal squamous cell carcinoma, hepatocellular carcinoma, and colorectal cancer, respectively. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I’m an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of oncology at Science 37. Today, we'll be discussing key abstracts and other exciting highlights from the 2024 ASCO Gastrointestinal Cancers Symposium. Joining me to discuss some key takeaways from the meeting is the chair of this year's Symposium, Dr. Rachna Shroff. Dr. Shroff is the division chief of Hematology Oncology and chief of GI Medical Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for clinical and translational research at the University of Arizona College of Medicine – Tucson. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod.  Dr. Shroff, welcome back to the ASCO Daily News Podcast, and congratulations on a great Symposium. The scientific advances and innovative, multidisciplinary approaches that were featured throughout the meeting were really inspiring and reflect the incredible strides we’re making in GI cancer research. Dr. Rachna Shroff: Thank you so much for having me back. I am delighted to be here.  Dr. Shaalan Beg: Dr. Shroff, the theme of this year's symposium was "Taking Personalized Care to the Next Level." I’d love to hear your reflections on the sessions that you found most exciting and really resonated with the attendees.  Dr. Rachna Shroff: Yes, thank you. We were really excited about this theme because we really felt that “Taking Personalized Care to the Next Level” translated to thinking through personalized approaches to patient care, not just in the traditional ways that we think of with precision oncology and genomics driving our care, but also how we can think through multidisciplinary approaches and an individualized care plan. Thinking through how artificial intelligence and novel clinical trial designs can and should be implemented to meet the needs of our individual patients. And so we really highlighted that in what was a somewhat new reboot of a session called “Intersections,” which were every day and were really more cross-tumor; they were tumor agnostic but were thematic focused. As I mentioned, those themes were really based on feedback that we had from prior attendees, as well as from the program committee’s feeling on what are really the questions that we are dealing with and that are burning in the clinic today and that includes the emerging role of artificial intelligence and machine learning and how we integrate that into our clinical care, approaches to oligometastatic disease, and it’s not really just something that we think of in colorectal cancer but haven’t fully used that paradigm to really apply it to other GI malignancies. And then the art and science of clinical trial design where, again, traditional randomized phase 3 trials might not be the best and most innovative and most expedient way of bringing novel therapeutics to our patients. And so, I thought that all of those sessions were really highlighting different important topics that we deal with day to day. Additionally, we had a really fantastic keynote lecture from Dr. Kimmie Ng of the Dana-Farber Cancer Institute. She is a world-renowned expert in the early-onset colorectal cancer space, and the timing of her keynote was perfect with the new cancer statistics that came out literally days before GI ASCO that demonstrated this just dramatic rise in early onset GI malignancies as a whole, not just colorectal. And she spoke really in a comprehensive manner not just on clinical approaches, screening approaches, and how to find these patients at an earlier stage, but also kind of gave us a call to action, if you will, in terms of public health initiatives, as well as like I said, clinical care and really thinking outside of the box for how to reach these patients.  And then, of course, we always have what I think is one of my favorite aspects of the meeting, which are the networking opportunities that include the Trainee and Early Career Networking Luncheon, the Women's Networking Reception, and the Meet the Experts Luncheon where, especially as junior career investigators, you have an opportunity to meet what we think of as the “big names” in GI cancer. Dr. Shaalan Beg: Absolutely, I remember my first couple of GI ASCO meetings and those were probably the most memorable sessions that I attended as junior faculty as well.   So let's take a deeper dive into some key abstracts from the meeting. I'd like to begin with Abstract 245. This is the SKYSCRAPER-08 study. It's first-line tiragolumab and atezolizumab with chemotherapy in an Asian patient population with esophageal squamous cell carcinoma. What are your key takeaways from this study?  Dr. Rachna Shroff: Yeah. This was an exciting study in my opinion in the sense that thinking through how we can build on immunotherapy backbones is obviously a pressing question across the GI cancer space. So this was a phase 3 randomized, double-blinded, placebo-controlled trial that looked specifically at patients with esophageal squamous cell carcinomas. And the study was enrolled fully with an Asian population. It looked at taking the traditional chemotherapy backbone and adding to it an anti-PD-L1 with atezolizumab and an anti-TIGIT with tiragolumab. Again, that proof of principle of using anti-TIGIT and PD-L1 has been looked at across a lot of different GI cancer spaces and we know that the esophageal squamous cell cancers tend to be very immunotherapy responsive. So this was a really important question.  This involved a number of patients, a little over 460 patients, who were randomized one-to-one to receive the tiragolumab with atezolizumab with the standard paclitaxel and cisplatin, that's used for esophageal squamous versus chemotherapy alone with placebo. And the primary endpoint was independent review of progression-free survival, and overall survival. And so, out of the 461 patients randomized, there was at the primary analysis, a median improvement in progression free survival, from 5.4 months in the control arm to 6.2 months with a tira-paclitaxel plus chemo arm with a hazard ratio of 0.56, highly statistically significant. Similarly the median overall survival was also improved from 11.1 months to 15.7 months again with a hazard ratio of 0.7 and some of the other key efficacy endpoints were also improved with the addition of the anti-TIGIT PD-L1 approach. And importantly, there was not really safety signals that jumped out at us.  And so, to me, what this means is that, in our patients with esophageal squamous cell carcinoma, we really should be thinking about chemotherapy with immunotherapy as a backbone and how we can build on it. And, you know, I would imagine that it's hard to argue with both the PFS and OS endpoint that adding anti-TIGIT won't necessarily be kind of the new approach to these patients. And importantly, I'll point out that it seems to be a benefit across the subgroups, including PD-1 status, which is always our big question here. I think the only thing to keep in mind is this was an all-Asian population and whether or not that kind of immune profile of the immune responsiveness is different in those patients, but regardless, a positive phase 3 trial. Dr. Shaalan Beg: It's really exciting to see immune checkpoint inhibitors or immunotherapy beyond PD-1 targeted, CTLA-4 targeted treatments making their way into GI Cancers.  Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: Sticking with the immunotherapy theme, let's focus on hepatocellular carcinoma. So LBA432, the EMERALD-1 study of transarterial chemoembolization combined with durva with or without bevacizumab looked at people with unresectable hepatocellular carcinoma eligible for embolization. So really a highly anticipated study, I'm wondering what your thoughts are and whether it'll be practice-changing for this field.  Dr. Rachna Shroff: I was excited to see the press release when it showed that the study was positive, and I think it's because now that we're using immunotherapy in the advanced HCC space, our obvious question is, can we integrate it into multimodality approaches? There are a lot of smaller studies looking at neoadjuvant IO approaches, and in this intermediate stage, unresectable hepatocellular carcinoma patients. We wanted to know if there was a utility to liver directed therapy with immunotherapy.  So, this was a large study. It was a global study looking at unresectable HCC with preserved Child-Pugh function. But it was Child-Pugh A and up to B7, importantly. And there were 616 patients randomized in a 1:1:1 fashion, with the control arm being just TACE alone. But then, there was also an opportunity for durvalumab with TACE, as well as durvalumab plus bevacizumab with TACE. The patients would receive durvalumab during their TACE treatments and could receive up to four TACE treatments and then subsequently were either continued on durvalumab alone, durvalumab plus bevacizumab, or the placebo. The primary endpoint was progression-free survival, powered specifically to look at TACE versus durvalumab plus TACE. In this study, the primary endpoint was met with a significant improvement in PFS. Median PFS was 15 months versus 8.2 months, with a hazard ratio of 0.77. Most prespecified subgroups demonstrated this benefit.  Importantly, there was a secondary endpoint looking at durvalumab plus TACE versus TACE alone, and that actually did not show a statistically significant improvement in median PFS from 8.2 months in the control arm to 10.0 months. The overall response rates were slightly higher with the durvalumab plus bevacizumab approach at 43.6%. And importantly in these patients, who oftentimes have a higher burden of disease in the liver, median time to progression is a really important and clinically meaningful endpoint. That was 22 months with the durvalumab plus bevacizumab and TACE versus 10 months for TACE alone. I would just point out that the overall concern we always have with bevacizumab is the increased risk of bleeding and the treatment-related adverse event profile. Overall, there were no safety signals that emerged from this, with nothing that really, especially in that bleeding risk category, jumped out at us. Of course, we haven't seen the overall survival data yet because we have not seen enough follow-up to really see that number.  I do think that this is potentially practice-changing, and I think it just demonstrates that there's probably some synergy between anti-VEGF with anti-PD-1, and then the liver-directed treatments. The obvious question for us in the United States is that the vast majority of people are moving away from TACE and towards more radioembolization and what can we extrapolate from this? Does this really tell us much if people are using more of a Y90-based approach? I think those are a lot of the burning questions that most of us have.  Dr. Shaalan Beg: Yeah, and it's a very interesting direction that the HCC space is taking because we heard in previous meetings, the role of PD-1 inhibition as adjuvant therapy after resection. Now, we have data for local-regionally advanced disease over local-regional treatments. And of course, you already mentioned the data for more advanced disease. So it sounds like immunotherapy may be impacting the management of anyone diagnosed with hepatocellular carcinoma.  Let's talk about the MONET trial, Abstract 249, which compared thoracoscopic esophagectomy and open esophagectomy for thoracic esophageal cancer. Do you think this is a study which may influence the treatment of patients with thoracic esophageal cancer? Dr. Rachna Shroff: So, this was, again, I think, a really important question. It was a randomized, controlled phase 3 trial comparing a more minimally invasive approach with TE — thoracoscopic esophagectomy — versus an open approach. This had patients with clinical stage 1-3, excluding T4 thoracic esophageal squamous cell carcinomas. They were randomized 1:1 to the open versus the TE approach, with a primary endpoint of overall survival and an important secondary endpoint of relapse-free survival. 300 patients were randomized, and at the second planned interim analysis, the median follow-up was a little over two and a half years. The 3-year overall survival was 82% in the TE group versus 70.9% in the open group. The DSMC of this trial actually recommended early termination based on the non-inferiority, which is what they were specifically looking at. There was a very statistically significant one-sided p-value for non-inferiority.  Importantly, the 3-year recurrence-free survival was also markedly better in the TE group versus the open group, with no real notable differences in R0 resection, or a large percentage of patients who needed to be converted from a TE to an open approach, and really not any significant difference in overall postoperative morbidity. I think this just supports the concept that minimally invasive approaches for our patients with GI malignancies can and should be considered. Again, esophageal squamous because they tend to be seen a lot more in Asia, this study was conducted in Japan, but I think that being said, a lot of our surgeons in Europe and in the U.S. are also very amenable to minimally invasive approaches. And I think this just supports the fact that an open approach is not necessary. So, I would think again, that this is something that is implementable and I think will affect the field.  Dr. Shaalan Beg: Moving on to metastatic cholangiocarcinoma, there have been many FGFR inhibitors that have shown activity and promise and are approved for the management of cholangiocarcinoma with FGFR alteration. But at this ASCO GI, we heard the results of the safety and efficacy of an FGFR1, 2, and 3 inhibitor, tinengotinib, as monotherapy for advanced metastatic cholangiocarcinoma (Abstract 434). How do you see this fitting into the broad picture? Dr. Rachna Shroff: Yeah, so this was highly anticipated data, primarily because at this point, the FGFR space in cholangiocarcinoma is quite crowded. And so a lot of us were getting sick of the "me-too" drugs. What is really unique about tinengotinib is that, not only is it a selective multikinase inhibitor, but it also, in preclinical models as well as in early phase one trials, demonstrated potent inhibition of patients with FGFR2 fusions and rearrangements who had acquired resistance mutations. So, as we better understand the first generation of FGFR inhibitors and note the resistance mechanisms, these drugs are now being developed to try to circumvent or overcome those.  This study looked at 4 different cohorts: 1 cohort with FGFR2 fusion patients who had primary progression who never responded to FGFR inhibitors, a second cohort with FGFR2 fusion patients who had progression after primary response, so those with acquired resistance, and then there was non-fusion FGFR alterations because we do know that a number of cholangiocarcinoma patients have other FGFR alterations that are not fusions, and then those with FGFR wild-type. The primary endpoint was objective response rate, with a total of 48 patients enrolled across the four cohorts. And so the 40 patients who were evaluable in the group that had primary resistance, which was the first cohort, there was a response rate was 9.1% and that was partial response, and 31% had tumor reduction with tinengotinib. And similarly in those with acquired resistance, 37.5%, 3 out of 8 patients had a partial response and tumor reductions were noted with an overall disease control rate between those patients with FGFR2 fusions of 94.7%, between those with primary and secondary resistance.  In the patients who had FGFR alterations, there was 3 out of 9 patients with a partial response and again, tumor reductions were notable across the board and the disease control rate was 88.9%. The FGFR wild-type group, not surprisingly, did not see any partial responses, but interestingly, 75% of these patients had at least disease control, and the median progression-free survival was 5.26 months, again, kind of most notably impressive in the 2 cohorts that included FGFR2 fusions. The toxicity profiles are what we come to expect for FGFR inhibitors and we’ve gotten better at managing those and mitigating some of those so there was really nothing to jump out there. So there is now an ongoing randomized phase III trial specifically looking at tinengotinib versus physician's choice in patients with FGFR2-altered cholangiocarcinoma after having received prior FGFR inhibitors. So that’s where I think it’s in is for those of us who know that there are multiple drugs in the space, our big question is can we sequence through that? Can we offer multiple FGFR inhibitors in these patients? And I think we are all eagerly anticipating this data as well as the subsequent data to really justify the use of these novel second generation FGFR inhibitors.  Dr. Shaalan Beg: It's been fantastic to see the evolution of these compounds in precision medicine, or precision oncology at its finest, in terms of understanding mechanisms of resistance and treating refractory disease.   Let's focus on colorectal cancer. I’ll tell you, there has been a lot of discussion, Dr. Shroff, on social media, on insurance companies sometimes rejecting one biologic or the other based on tumor sidedness. We have talked about tumor sidedness predicting response on this podcast based on data from previous studies. But this year in GI ASCO, Abstract 207 explored the role of tumor genomics and tumor sidedness and they said that it’s tumor genomics, that tumor genomics better explains the differences on outcomes, and it explains it better than sidedness. What does this mean to the field? Because a lot of professional organizations have guidelines that are asking people to now incorporate sidedness. So how does that change based on these results? Dr. Rachna Shroff: I really commend these authors on leveraging real-world data, and I think we’re getting better and better at recognizing that real world data actually informs our clinical decision making, possibly better than sometimes some of these studies that lead to the guidelines and algorithms that we develop. So this is a perfect example of a little bit cart before horse in trying to understand the way that sidedness and genomics may interplay.   So this was a study that basically leveraged both the Foundation Medicine and Flatiron Health clinical genomic database and looked at patients with microsatellite stable metastatic colorectal cancer. There were a total of 3,845 patients included in a kind of two-thirds one-third split between left sided and right-sided colorectal cancer. And they found the typical genomic alterations that historically have been thought of more with left-sided colorectal cancer like APC and then more of the RAS BRAF alterations in the right-sided patients. But I think what they really thought and what I think was remarkable is they really looked at the patients and how they received chemotherapy with anti-EGFR or bevacizumab therapies, and they did a multivariate analysis to really see what is driving outcomes. And like you mentioned, what they found was patients in the RAS pathway, those classified as having alterations in the RAS pathway, had less favorable outcomes, while those with APC altered group had more favorable outcomes. And that was regardless of treatment received and sidedness.  And so when they did an analysis of what was called a “likelihood ratio test,” they found that when genomics was added to the sidedness evaluation, there was an improvement in outcome prediction, but not when sidedness was added to genomics. Like you said, it kind of demonstrates, at least in this mining of real-world data from Flatiron that tumor genomics is probably a better driver and a more important driver in determining outcomes than sidedness.  I totally agree with you. I would push for us to really kind of bring a little bit of noise to this and to make insurance companies and other companies that are looking at this to think through this a little bit more and make sure that we’re putting all of the data together in a comprehensive passion before making the treatment plans and determinations. Dr. Shaalan Beg: The last abstract I'd like to ask you about is Abstract 117, the NEST-1 trial. This study looked at neoadjuvant botensilimab and balstilimab for resectable mismatch repair proficient and deficient colorectal cancer, both MSS and MSI. What are your key takeaways from this study?  Dr. Rachna Shroff: This is another study that is demonstrating that there may potentially be a role for immunotherapy in microsatellite stable patients. I will make the caveat that this was a single-arm study that really was looking at feasibility safety, with efficacy as a secondary endpoint. The combination of bot-bal in the neoadjuvant space for colorectal cancer patients, they received one dose of boten and two fixed doses of bal two weeks apart and then were taken to surgery. They limited the number of patients and out of the 12 patients that were enrolled, they limited the number of mismatch repair deficient patients. So to your point, they allowed both, but they wanted to make sure it was not just MSI-high patients. What they basically found is that it was safe and did not delay surgery or increase risks of adverse events. But importantly, there was significant regression of tumor noted. And some interesting spatial biology analyses demonstrated potentially novel mechanisms of action, especially in the MSS population, and that ctDNA reductions correlated with pathologic response. There were a lot of different things that they were looking at, basically suggesting that bot-bal is safe and can be used in both mismatch repair–deficient and proficient patients with colorectal cancer. And now importantly, they’ve added some additional cohorts and expanding the study. As I mentioned, this is right now just 12 patients, but does definitely have a provocative result.  Dr. Shaalan Beg: Thanks so much, Dr. Shroff.  Finally, the role of cell-free DNA (cfDNA) in GI cancers has been an exciting and important development in our field. There's tremendous data that emerged at the GI meeting, and we have decided to do a separate ASCO Daily News Podcast dedicated to ctDNA. So listeners, please look out for our coverage of key studies on ctDNA in GI cancers very soon here on the ASCO Daily News Podcast.  Many thanks, Dr. Shroff, for sharing your insights with us today and for your great work in building a robust GI meeting this year. Thank you very much. Dr. Rachna Shroff: Thank you so much. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Our guests on this podcast express their own opinions, experiences, and conclusions. These statements do not necessarily reflect the views of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO.   Find out more about today’s speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics
2/8/202422 minutes, 45 seconds
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Key Advances in Prostate, Kidney, and Bladder Cancers at GU24

Drs. Neeraj Agarwal and Todd Morgan discuss CONTACT-02, KEYNOTE-564, CheckMate-67T, and other notable studies featured at the 2024 ASCO Genitourinary Cancers Symposium, as well as additional key abstracts in prostate, kidney, and bladder cancers that will significantly influence clinical practice. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program and professor of medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of ASCO Daily News. Today, we'll be discussing practice-changing abstracts and other key advances in GU oncology featured at the 2024 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Todd Morgan, the chair of this year's ASCO GU. Dr. Morgan is a urologic surgeon, chief of urologic oncology at Michigan Medicine, and a professor of urology at the University of Michigan. Our full disclosures are available in the transcript of this episode, and the disclosures of all guests on the podcast can be found at asco.org/DNpod. Todd, thank you for joining us today. Dr. Todd Morgan: Thanks so much, Neeraj. It's an honor to be here and I'm just thrilled to be able to do this with you. Dr. Neeraj Agarwal: Thank you. So, the GU meeting showcased significant advancements across the spectrum of GU malignancies. Can you tell us about the hot topics that captured the headlines this year? What did you find exciting this year at the ASCO GU Symposium? Dr. Todd Morgan: The theme of this year's meeting was "20 Years of Advancing Science and Transforming Patient Care," and this reflected ASCO GU's incredible milestone in GU cancer research over the last 2 decades. We were thrilled to welcome over 5,200 attendees from over 70 countries, and, believe it or not, there were more than 875 abstract submissions, compared to more than 300 in the meeting's first year. Most of the participants were present in person and that was fantastic. It enabled great networking opportunities and opportunities for experts, trainees, and mentees to exchange knowledge and ideas. Without a doubt, ASCO GU remains the annual meeting in our field, and it's amazing to hear the breadth and depth of the state-of-the-art science that's presented at this meeting, and so much of it impacts patient care the second that you return home. Additionally, the meeting's focus on diversity and interactivity, networking, multidisciplinary collaboration, and evidence-based care were absolutely phenomenal from my standpoint. We had a lunch session for women's networking that was a huge success—the first time we've done that. The keynote lecture by Dr. Cheryl Lee that talked about ensuring adequate representation in clinical trials was a huge hit, and we had tremendous positive feedback from that lecture. There were also multiple featured sessions on different diagnostic and therapeutic challenges in localized, recurrent, and advanced GU cancers. And, Neeraj, my personal favorite during the symposium is always the Trainee and Early-Career Networking Luncheon on the first day and then the additional networking luncheons on the 2 following days. I had great conversations with a ton of trainees and junior faculty, and I feel so fortunate for the opportunity to get to know the future superstars in our field. So I’d like to kick it back to you for a second because the first day started with a focus on prostate cancer and some of the key clinical trials. A great example is Abstract 17, which was the second oral presentation delivered, and really congratulations to you, Neeraj, on sharing the exciting data from the CONTACT-02 trial which we were eagerly awaiting. And I'd love to get your thoughts on the data that you presented. Could you tell us more about that trial? Dr. Neeraj Agarwal: Yes, Todd, I agree with you. It was such an exciting conference overall, and thank you for your leadership of this conference. So let's talk about the CONTACT-02 trial. It was a phase 3 randomized trial assessing the combination of cabozantinib and atezolizumab versus a second NHT in patients with metastatic castration-resistant prostate cancer after progression on one NHT. This patient population had to have extrapelvic soft tissue metastases, which could be liver metastases, lung metastases, or lymph nodal metastases, and about up to a quarter of patients had liver metastases. And overall, this was a high-risk patient population which was randomized to, as I said, cabozantinib plus atezolizumab versus a second line NHT. And these patients had received a prior NHT, mostly in the mCRPC setting.  The co- or dual primary endpoints were overall survival and progression-free survival (PFS). And a unique thing was that PFS was assessed only by RECIST 1.1 because, as per our discussions with regulatory authorities, the trial was focused on soft tissue metastases because of questions in the past that cabozantinib can affect bone lesions in an artifactual fashion, possibly concerns. That’s why the PCWG 3 criteria were not used as the primary endpoint, but, of course, indeed used as another key endpoint, so we have information on both. Anyway, coming back to the endpoint 1:1 randomization. The randomization was stratified by presence or absence of liver metastases, prior docetaxel chemotherapy, and the setting in which NHT was given (mCSPC or CRPC). The PFS or primary endpoint was significantly improved with a 35% reduction in risk of progression or death with the cabozantinib-atezolizumab combination versus second NHT. And there was a trend for overall survival, with a hazard ratio of 0.79 favoring the cabozantinib-atezolizumab combination. Interestingly, all subgroups benefitted, regardless of age, region, site of metastases, but we decided to choose three clinical subgroups of interest such as patients with liver metastases, patients with prior docetaxel chemotherapy in the castration-sensitive setting, and bone metastases, and all these subgroups seemed to be benefitting with the strongest signal in the liver metastasis subgroup, with a 57% reduction in risk of progression or death, which I would argue we have never seen with any combination or any regimen in the metastatic prostate cancer setting yet, barring some targeted therapies in very selected patients. But overall, across the non-biomarker-selected patients, we have never seen this kind of signal. Toxicity — no discussion is complete without discussing toxicity, so I would like to highlight that. Safety signal — there were no new safety signals. The most common grade 3-4 adverse events were hypertension in 7%, anemia in 6%, which were similar in both arms, and, of course, diarrhea and fatigue in 4% each. And if we look at the secondary endpoints, such as time to chemotherapy and time to symptomatic skeletal events, they tended to favor the cabozantinib-atezolizumab. To sum it up, cabozantinib-atezolizumab showed a significant PFS benefit, with a 35% reduction in risk of progression or death, with a trend for overall survival in this patient population with an unmet need. So thank you so much, Todd, for allowing me to summarize the results of this trial. Dr. Todd Morgan: Yeah, wow. That's so impressive, and not surprising that you could so fluidly go right through all that data. Amazing. We heard some discussion of the NHT control arm in this trial. Could you discuss that for a bit? Because it obviously has implications on the similar control arm of other ongoing trials in this setting. Dr. Neeraj Agarwal: Absolutely. Pretty much all trials, every trial which has recently been reported or started in metastatic castrate-resistant prostate cancer have a similar second NHT arm. Whether there were multiple immunotherapy trials which we have just reported, or new trials which are starting or just started enrolling patients. And the reason for that is no randomized trial has ever shown superiority of docetaxel chemotherapy over a second NHT after failure of prior NHT in the mCRPC setting. That's number one. If you look at NHT as a control, it is accepted by health authorities globally with multiple recent trials which are just starting also having NHDR and it would not have been possible without the approval of global regulatory authorities across the world.  Then, if you look at the recently reported trial in the mCRPC setting with prior treatment with an NHT, there is an indication that chemotherapy may not be superior to NHT. For example, in the KEYNOTE-641 trial in patients with mCRPC with prior NHT, randomizing patients to enzalutamide plus pembrolizumab versus enzalutamide, the median PFS with enzalutamide was 9 months. This is very similar with docetaxel in patients randomized to docetaxel plus pembrolizumab versus docetaxel; the median PFS with docetaxel is 8 months or 8.3 months. And lastly, if you really want to have a comparison of chemotherapy with NHT which has been done after progression on NHT and docetaxel chemotherapy, so later line of mCRPC setting, that is the CARD trial, as you can imagine, cabazitaxel versus NHT, especially in patients with visceral metastasis, which was the point of discussion. For example, people may not feel comfortable randomizing patients to NHT compared to taxane. The hazard ratio for PFS supporting cabazitaxel was 0.79, so almost a 0.80 PFS hazard ratio, which we have never seen turning out to be a clinically significant benefit. So, if you combine all these data together, I think it was absolutely acceptable to us as investigators to have a second NHT as the control arm. And of course, when we are consenting the patient, we have to keep alternatives in mind, and we do talk about those alternatives with the patients. And if alternatives seem more applicable, we should not be talking to patients about those clinical trials or a given clinical trial in the clinic. I'm glad you brought this up, Todd, because this control NHT arm is not an issue with this trial, but all trials which should be presented in GU ASCO in the future meetings in the coming years. So, thank you. Dr. Todd Morgan: Yeah, thank you. It's such an important topic and controversy at some level, but it's a difficult problem to think about and obviously highly relevant to all the trials that we're looking at. Congrats again on that trial, that's tremendous. There was another important randomized phase 3 trial and it covers radiotherapy in patients with high-risk localized prostate cancer. Can you give us your insights on that one? Dr. Neeraj Agarwal: Yeah, Todd, I think you are referring to LBA259, titled "Long-term Results of Dose Escalation of Radiation Therapy from 70 Gy to 80 Gy Combined with Long-term Androgen Deprivation Therapy in High-risk Prostate Cancer: The GETUG-AFU 18 Randomized Trial." As you mentioned, in this randomized phase 3 trial, Dr. Christophe Hennequin and colleagues randomized patients with high-risk prostate cancer, which means they had to have either clinical stage T3 or T4 disease, or PSA ≥20 nanograms per milliliter, or a Gleason score between 8 and 10. These patients were randomized to receive ADT for 3 years combined with either dose-escalated intensity-modulated radiotherapy. So, I’d like to highlight, this was in the context of IMRT in the dose of 80 Gy or a conventional dose of 70 Gy. Now, you can argue that more people are using more than 70 Gy nowadays, but across the world, the conventional dose is still considered 70 Gy. So, 80 Gy versus 70 Gy were tested. Patients also had to have negative lymph node status on CT scans and MRI. The primary endpoint was biochemical progression-free survival or clinical progression-free survival at 5 years following the ASTRO Phoenix definition. Secondary endpoints – and these are quite important secondary endpoints – include overall survival, acute and late toxicity, and quality of life. The best part is that this trial met its primary endpoint with a 44% reduction in risk of biochemical or clinical progression or death in the dose-escalation radiotherapy arm compared with the conventional radiotherapy arm. Interestingly, a significant 52% improvement in prostate cancer-specific survival and a 39% improvement in overall survival was observed in the dose-escalated arm. So, 80 Gy continued to be superior to 70 Gy IMRT across the primary and secondary endpoints. Now, the best part is, regarding the toxicity profile, there was no significant difference between the 2 arms, with 78% of patients in the higher dose arm and 76% of patients in the conventional arm experiencing grade 2 or more toxicities. Dr. Todd Morgan: Great summary and really important, great news for our patients. Of course, it's a slightly different setting as it's high-risk localized prostate cancer. I checked in with our radiation oncologists at the University of Michigan after that [presentation] because I couldn't remember exactly where we are in terms of dose on these patients. And they were like, “Yeah, we've been doing 80 to 90 Gy for several years,” so it's great having this data to support that. And I think, as you said, the field at many centers has already moved that way. And again, the key takeaway from this abstract would be that IMRT, in combination with long-term androgen deprivation therapy, is effective and safe and increases not only the biochemical or clinical PFS rate, but also the cancer-specific survival and overall survival, again, in high-risk localized prostate cancer patients. And it does not appear to increase long-term toxicity. So really important. It'd be great to switch gears and discuss kidney cancer, if that's okay, and talk about some key abstracts in that field. What do you think? Dr. Neeraj Agarwal: There were so many exciting data in all cancers, which is amazing. So, Todd, could tell us about the LBA359, which I thought was one of the most impactful abstract presentations in the ASCO GU this year. It was titled, “Overall Survival Results from the Phase 3 KEYNOTE-564 Study of Adjuvant Pembrolizumab Versus Placebo for Treatment of Clear Cell Renal Cell Carcinoma (ccRCC)."   Dr. Todd Morgan: Yeah, this was a really big moment in our field, complete with a mid-presentation round of applause that was well deserved. And so this abstract was presented by Dr. Toni Choueiri from Dana-Farber Cancer Institute, and it included patients with clear cell renal cell carcinoma at intermediate high or high risk of recurrence, meaning that they had positive nodal disease or negative nodal disease with PT 2 and grade 4, or sarcomatoid features, or stage PT 3 or 4. These patients underwent nephrectomy with or without metastasectomy less than 12 weeks before randomization and had not received prior systemic therapy for clear cell RCC. Patients were randomized to receive either pembrolizumab 200 milligrams or placebo IV every three weeks for at least 17 cycles, or until disease recurrence, intolerable toxicity, or withdrawal of consent. Disease-free survival by investigator assessment was the primary endpoint, and overall survival was a key secondary endpoint. In this abstract, Dr. Choueiri and colleagues report results of the third prespecified interim analysis with a median follow-up of around 57 months in 496 patients receiving pembrolizumab and 498 patients receiving placebo. So, just as a reminder to the audience here, the first interim analysis reported at a median follow-up of 24 months and showed a significant reduction of 32% in the risk to recurrence or death in patients in the pembrolizumab arm. Then subsequently in November of 2021, the FDA approved pembrolizumab for the adjuvant treatment of patients with RCC who are at intermediate high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. At that time, though, overall survival data were still immature. So, at the third prespecified interim analysis with a median follow-up of around 57 months, pembrolizumab showed, for the first time in an adjuvant RCC setting, improved overall survival with a 38% reduction in the risk of death. The estimated OS rate at 48 months was 91.2% with pembrolizumab and 86% with placebo. Furthermore, the OS benefit was observed across key subgroups, including patients with non-metastatic disease, patients with metastatic but no evidence of disease, patients with PDL-1 combined positive score less than or greater than or equal to one, and patients with presence or absence of sarcomatoid features. In each of these subgroups, the forest plot looks really impressive. And the DFS benefit was similar to previously reported interim analyses with a hazard ratio of 0.72. Also, no new safety signals with pembrolizumab were observed so just tremendous data. Dr. Neeraj Agarwal: Thank you, Todd, for such a great summary of these very important results. So the key message from this abstract, as you said, is that after a median follow-up of around 57 months, which is a long follow-up, adjuvant pembrolizumab demonstrates a statistically significant and clinically meaningful improvement in overall survival versus placebo in patients with RCC at high risk of disease recurrence after surgery. And this is, by the way, the first phase 3 study to show improved overall survival with any adjuvant therapy in RCC. Basically, this means we should continue to use adjuvant pembrolizumab or at least bring it up in our discussion with our patients who are in a similar situation with high-risk RCC after surgery. So this is great news overall. Todd, there was another kidney cancer abstract, LBA360, which compared, interestingly, subcutaneous nivolumab with intravenous nivolumab in patients with metastatic renal cell carcinoma. Could you please give us your insight about this abstract?   Dr. Todd Morgan: Sure. Really interesting study. Really interesting data that were presented. So as you mentioned, CheckMate 67T was a multicenter, randomized, open-label phase three study led by Dr. Saby George and colleagues that evaluated pharmacokinetics and objective response rate non-inferiority of subcutaneous nivolumab versus IV nivolumab in patients with locally advanced or metastatic clear cell RCC. So patients with measurable disease that progressed during or after 1 to 2 prior systemic regimens and who did not receive a prior immuno-oncology treatment were randomized 1-1 to receive either subcutaneous nivolumab 1200 milligrams every 4 weeks or IV nivolumab 3 milligrams per kilogram every two weeks until disease progression, unacceptable toxicity, withdrawal of consent, completion of two years of treatment, or death. The coprimary pharmacokinetics endpoints for non-inferiority testing were time-average serum concentration over the first 28 days and minimum serum concentration at steady state determined by a population pharmacokinetics analysis. A key secondary endpoint was objective response rate by independent review. So in 248 patients receiving subcutaneous nivolumab and 247 patients receiving IV nivolumab, non-inferiority for the coprimary pharmacokinetics and key-powered secondary objective response rate endpoints were met. The relative risk ratio for objective response rate was 1.33. The median PFS by independent review was 7.23 months in the subcutaneous group and 5.65 months in the IV group. Treatment-related serious adverse events occurred in 6.5% of patients in each group, and study drug toxicity led to 3 deaths in the subcutaneous group and 1 death in the IV group. These results could support using subcutaneous nivolumab as a new option to improve healthcare efficiency, especially since the average injection time with subcutaneous nivolumab was less than 5 minutes. I think we all know what issues are going on in infusion beds across the country, including, I'm sure, your center and mine. Dr. Neeraj Agarwal: Yes, absolutely. I think this is great news for our patients, Todd. Thank you. This shows that we are not only improving therapeutic options and diagnostic tools, but maybe we're also on the right track towards more practical administration routes, assisting in addressing the treatment burden and improving the efficiencies of healthcare systems. We love to have this option available for our patients, especially those who are pressed for time. So, Todd, would you like to move on to bladder cancer now?  Dr. Todd Morgan: Yeah, Neeraj, that'll be fantastic. I'm sure listeners would love to hear more about LBA530. Could you tell us more about this one, Neeraj? Dr. Neeraj Agarwal: Of course. I think this abstract is titled "Enfortumab Vedotin in Combination with Pembrolizumab Versus Chemotherapy in Previously Untreated, Locally Advanced or Metastatic Urothelial Carcinoma: Subgroup Analysis Results from EV-302," which was a global phase three study and was presented by Dr. Michiel Van Der Heijden. As our audience may recall, the EV-302 trial was presented at the ESMO 2023 meeting by Dr Tom Powles and the results were very exciting where, for the first time, a combination outperformed traditional gemcitabine-cisplatin chemotherapy. In this trial, patients with previously untreated with metastatic advanced urothelial carcinoma were randomized 1-1 to receive a 3-week cycle of a combination of enfortumab vedotin, which, as we know, is an antibody-drug conjugate targeting nectin-4 expressed on the cancer cells and pembrolizumab, which is a PD-1 inhibitor, versus gemcitabine and cisplatin or carboplatin, which were, until recently, the standard of care in this setting, and continue to be so in many countries in the world. The combination of enfortumab and pembrolizumab reduced the risk of progression or death by 55% and reduced the risk of death by 53% in the overall population. So consistent decrease in the hazard ratios for PFS and OS, and consistent improvement in overall survival and PFS in that previously reported presentation in the ESMO 2023. Now, based on these results, this combination was recently approved by the FDA in December 2023 for patients with advanced or metastatic urothelial carcinoma. So now the abstract, which was presented at the ASCO GU 2024 meeting, reported the results of a prespecified subgroup analysis. Select secondary endpoints included objective responses, duration of response, and safety. In 442 patients receiving the combination of enfortumab vedotin plus pembrolizumab, and a similar number of patients receiving chemotherapy both PFS and OS were higher for the combination of EV and pembro among prespecified subgroups such as race, platinum eligibility, PDL-1 expression, metastatic site, involvement of the liver or kidney function. Interestingly, the combination of EV and pembro reduced the risk of death by 53% in patients with visceral metastasis and 54% in patients with node-only metastasis. The improvement in PFS seems to be consistent regardless of the site of metastasis. In patients with moderate to severe renal function, the risk of death was reduced by 50% in patients receiving combination therapy. This is one of the best findings of these results because we always face challenges in treating patients with suboptimal kidney function and we cannot use cisplatin. Overall, EV plus pembro continues to show superior efficacy compared to platinum-based regimens across subgroups across the subgroups across the site of metastasis regardless of kidney function and so on. Dr. Todd Morgan: Yeah, just amazing data. I love hearing you spell it out like that. So, thank you again for the opportunity for me to sit here with you and listen to you talk about these data. It's impressive that we have been able to expand our therapeutic arsenal for urothelial carcinoma with an immune-targeting regimen that can spare our patients potential side effects of chemotherapy. What would your final takeaway on this abstract be? Dr. Neeraj Agarwal: I agree with you, Todd. I would add that the OS benefit was consistently observed across these select prespecified subgroups, including those historically associated with poor prognosis. The results of this new analysis support the finding of primary results, which indicate that EV plus pembro is a potentially new standard of care for patients with newly diagnosed, locally advanced, or metastatic urothelial carcinoma. Before we wrap up the bladder cancer session and the podcast, Todd, could you please give us insights about LBA531? Dr. Todd Morgan: Yeah, absolutely. I loved getting to hear this abstract presented. This one is titled “Ambassador,” known as the AMBASSADOR trial aligns A031501, a phase 3 randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma versus observation, that was presented by Dr. Andrea Apolo. It's an open-label, randomized, phase 3 trial that included patients with muscle-invasive urothelial carcinoma of the bladder, upper tract, or urethra. Eligible patients had pathologic tumor stage T2 or greater and/or positive pathologic nodal disease or positive margins at surgery following neoadjuvant chemotherapy, or patients with pathologic tumor stage T3 or greater and/or positive pathologic nodal disease or positive margins at surgery without prior neoadjuvant chemotherapy, and who were cisplatin ineligible or declined adjuvant cisplatin-based therapy. These patients were randomized one to one to either receive pembrolizumab 200 milligrams every 3 weeks for 1 year or observation. The dual primary endpoints were disease-free survival and overall survival. Secondary objectives included evaluation of DFS and OS in PDL-1 positive and negative patients and assessing safety. A total of 354 patients were enrolled to receive pembrolizumab and 348 to the observation arm, and 21% of the patients in the observation arm received a subsequent immune checkpoint inhibitor. At a median follow-up of 22.3 months for DFS, the median disease-free survival in the pembrolizumab arm was 29 months, while it was only 14 months in the observation arm with a hazard ratio of 0.69. At the interim analysis, OS data showed only a trend toward better outcomes in the pembrolizumab arm, which did not, however, reach statistical significance, with a median of 50.9 months in the pembrolizumab arm and 55.8 months in the observation arm with a hazard ratio of 0.98. These results could nevertheless have been impacted by the subsequent treatment of patients in the observation arm with an immune checkpoint inhibitor, especially after the FDA approval of nivolumab in 2021 for patients with muscle-invasive urothelial carcinoma, based on results of the CheckMate 274 trial. In terms of the safety profile, grade three or more adverse events occurred in 48.4% of patients in the pembrolizumab arm and 31.8% of patients in the observation arm. Dr. Neeraj Agarwal: That's great, Todd. This is such a great summary of this trial, and this is exciting news for our patients with muscle-invasive urothelial carcinoma. I'm hoping that pembrolizumab will be another option for our patients when we are discussing adjuvant immunotherapy in the clinic, moving forward very soon. With that, we have covered several abstracts addressing prostate, bladder, and kidney cancer, significantly influencing our medical practices, at least at the current moment or in the near future. Todd, thank you for sharing your insights today. These are undoubtedly exciting updates for all members of the GU oncology community, and we are grateful for your valuable contribution to the discussion. Many thanks. Dr. Todd Morgan: Thanks, for having me, Neeraj; this was really fun. I'm just really proud and excited to still be part of this field, to be part of the GU oncology field, and it continues to be exciting for all the folks who are coming up. Dr. Neeraj Agarwal: Indeed. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.   Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers:   Dr. Neeraj Agarwal @neerajaiims   Dr. Todd Morgan @wandering_gu   Follow ASCO on social media:   @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:    Dr. Neeraj Agarwal:    Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas   Dr. Todd Morgan: Consulting or Advisory Role: Myriad Genetics, MDxHealth, TerumoBCT Research Funding (Institution): Prostate Cancer Foundation, National Institutes of Health, Department of Defence, GenomeDX Biosciences, Myriad Genetics, MDxHealth  
2/6/202430 minutes, 6 seconds
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What’s New in Prostate Cancer, RCC, and mUC at GU24

Drs. Neeraj Agarwal and Jeanny Aragon-Ching discuss several key abstracts to be presented at the 2024 ASCO GU Cancers Symposium, including sequencing versus upfront combination therapies for mCRPC in the BRCAAway study, updates on the CheckMate-9ER and CheckMate-214 trials in ccRCC, and a compelling real-world retrospective study in mUC of patients with FGFR2 and FGFR3 mutations. TRANSCRIPT Dr. Neeraj Agarwal: Hello, everyone, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah’s Huntsman Cancer Institute, and editor-in-chief of ASCO Daily News. I am delighted to welcome Dr. Jeanny Aragon-Ching, a genitourinary oncologist and the clinical program director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing key posters and oral abstracts that will be featured at the 2024 ASCO Genitourinary Cancer Symposium, which is celebrating 20 years of evolution in GU oncology this year.  You will find our full disclosures in the transcript of this podcast, and disclosures of all guests on the podcast at asco.org/DNpod.  Jeanny, it’s great to have you on the podcast today to highlight some key abstracts for our listeners ahead of the GU meeting. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. It’s an honor to be here. Dr. Neeraj Agarwal: Jeanny, as you know, this year we are celebrating the 20th anniversary of the ASCO GU Cancers Symposium, and judging from this year's abstracts, it’s clear that this meeting continues to play a major role in advancing GU cancer research. Dr. Jeanny Aragon-Ching: Indeed, Neeraj. This year's abstracts reflect the important strides we have made in GU cancers. So, let's start with the prostate cancer abstracts. What is your takeaway from Abstract 19 on BRCAAway, which will be presented by Dr. Maha Hussein, and of which you are a co-author? As our listeners know, several PARP inhibitor combinations with second-generation androgen receptor pathway inhibitors, or ARPIs, have recently been approved as first-line treatment for patients with metastatic castrate-resistant prostate cancer, or metastatic CRPC, and the question of sequencing PARP inhibitors and ARPIs instead of combining them has emerged. From that perspective, the results of the BRCAAway trial are very important. Can you tell us a little bit more about this abstract, Neeraj?  Dr. Neeraj Agarwal: I totally agree with you, Jeanny. The BRCAAway study attempts to answer the crucial questions regarding sequencing versus upfront combination of therapies in the mCRPC setting. It is a phase 2 trial of abiraterone versus olaparib versus abiraterone with olaparib in patients with mCRPC harboring homologous recombination repair mutations. Enrolled patients had mCRPC disease and no prior exposure to PARP inhibitors or ARPIs or chemotherapy in the mCRPC setting and had BRCA1 or BRCA2 or ATM mutations. As previously mentioned, these patients were randomized to 3 arms: abiraterone monotherapy at 1000 milligrams once daily, or olaparib monotherapy at 300 milligrams twice daily, or the combination of abiraterone and olaparib. The primary endpoint was progression-free survival per RECIST 1.1 or Prostate Cancer Working Group 3-based criteria or clinical assessment or death, so, whichever occurred first was deemed to be progression.   Secondary endpoints included measurable disease response rates, PSA response rate, and toxicity. This was a relatively small trial with 21 patients in the combination arm, 19 patients in the abiraterone monotherapy arm, and 21 patients in the olaparib monotherapy arm. It should be noted that 26% of patients had received docetaxel chemotherapy in the hormone-sensitive setting, and only 3% of patients had any prior exposure to an ARPI, and these were darolutamide or enzalutamide or in the non-metastatic CRPC setting.  The results are very interesting. The median progression-free survival was 39 months in the combination arm, while it was 8.4 months in the abiraterone arm and 14 months in the olaparib arm. An important finding that I would like to highlight is that crossover was also allowed in the monotherapy arms. Of the 19 patients receiving abiraterone, 8 crossed over to receive olaparib, and of the 21 patients receiving olaparib, 8 crossed over to the abiraterone arm. The median PFS from randomization was 16 months in both groups of patients who received abiraterone followed by olaparib or those who received olaparib followed by abiraterone. This is striking when compared to 39 months in patients who started therapy with the combination therapy of abiraterone with olaparib. Dr. Jeanny Aragon-Ching: Thank you so much for that wonderful summary, Neeraj. So the key message from this abstract is that combining olaparib and abiraterone upfront seems to be associated with improvement in PFS compared to just sequencing those agents. Dr. Neeraj Agarwal: Exactly, Jeanny. I would like to add that these results are even more important given that in real-world practice, only half of the patients with mCRPC receive a second-line treatment. Based on these results, upfront intensification with a combination of an ARPI plus a PARP inhibitor in the first-line mCRPC setting seems to have superior efficacy compared to sequencing of these agents. Dr. Jeanny Aragon-Ching: Thank you so much. Now, moving on to a different setting in prostate cancer, there were a couple of abstracts assessing transperineal biopsy compared to the conventional transrectal biopsy for the detection of prostate cancer. So let's start with Abstract 261. Neeraj, can you tell us a little bit more about this abstract? Dr. Neeraj Agarwal: Sure, Jeanny. So, in Abstract 261 titled "Randomized Trial of Transperineal versus Transrectal Prostate Biopsy to Prevent Infection Complications," Dr. Jim Hugh and colleagues led a multicenter randomized trial comparing these 2 approaches, so, transperineal biopsy without antibiotic prophylaxis with transrectal biopsy with targeted prophylaxis in patients with suspected prostate cancer. The primary outcome was post-biopsy infection. Among the 567 participants included in the intention-to-treat analysis, no infection was reported with the transperineal approach, while 4 were detected with the transrectal approach, with a p-value of 0.059. The rates of other complications, such as urinary retention and significant bleeding, were very low and similar in both groups. The investigators also found that detection of clinically significant cancer was similar between the 2 techniques and concluded that the transperineal approach is more likely to reduce the risk of infection without antibiotic prophylaxis. Dr. Jeanny Aragon-Ching: So the key takeaway from this abstract sounds like office-based transperineal biopsy is well-tolerated and does not compromise cancer detection, along with better antibiotic stewardship and health care cost benefits.  Moving on to Abstract 273, also comparing these two approaches, what would be your key takeaway message, Neeraj?  Dr. Neeraj Agarwal: In this Abstract 273, titled "Difference in High-Risk Prostate Cancer Detection between Transrectal and Transperineal Approaches," Dr. Semko and colleagues found that the transperineal biopsy based on MRI fusion techniques was also characterized by a higher possibility of detecting high-risk prostate cancer and other risk factors as well, such as perineural and lymphovascular invasion or the presence of cribriform pattern, compared to the conventional transrectal method. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So we can see that the transperineal approach is gaining more importance and could be associated with more benefits compared to the conventional methods.   Let's now switch gears to kidney cancer, Neeraj. Dr. Neeraj Agarwal: Sure, Jeanny. Let's start by highlighting Abstract 361, which discusses patient-reported outcomes of the LITESPARK-005 study. So what can you tell us about this abstract, Jeanny?  Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So as a reminder to our listeners, based on the LITESPARK-005 trial, it was a Phase 3 trial looking at belzutifan, which is an inhibitor of hypoxia inducible factor 2 alpha or I’ll just call HIF-2 alpha for short, was very recently approved by the FDA as a second-line treatment option for patients with advanced or metastatic clear cell renal cell carcinoma after prior progression on immune checkpoint and antiangiogenic therapies. The title of Abstract 361 is "Belzutifan versus Everolimus in Patients with Previously Treated Advanced RCC: Patient-Reported Outcomes in the Phase 3 LITESPARK-005 Study," and this will be presented by Dr. Tom Pells at the meeting. At a median follow-up of 25.7 months, the median duration of treatment with belzutifan was 7.6 months, while it was only 3.9 months with everolimus. At the time of data cutoff date for the second interim analysis, 22.6% of patients remained on belzutifan while only 5% remained on everolimus. In the quality of life questionnaires, the time of deterioration to various quality of life scores, as assessed by standardized scales, was significantly longer in patients randomized to the belzutifan arm compared to those in the everolimus arm. Also, patients in the everolimus arm had worse physical functioning scores. Dr. Neeraj Agarwal: Yes, Jeanny. In addition to the improved outcomes associated with belzutifan, patient-reported outcomes indicate better disease-specific symptoms and better quality of life among patients treated with belzutifan compared to everolimus. This is great news for patients with advanced renal cell carcinoma.  Now, Jeanny, can you please tell us about the two abstracts that reported longer follow-up of CheckMate 9ER and CheckMate 214 trials in untreated patients with advanced or metastatic renal cell carcinoma? Dr. Jeanny Aragon-Ching: Yes, Neeraj. So you are referring to Abstracts 362 and 363. Let's start with Abstract 362. This abstract reports the results after a median follow-up of 55 months in the CheckMate 9ER trial, comparing the combination of nivolumab and cabozantinib to sunitinib in patients with advanced RCC without any prior treatment, so first-line therapy. The primary endpoint was PFS per RECIST 1.1 as assessed by an independent central review. So there were key secondary outcomes including overall survival (OS), objective response rates, and safety. Consistent with prior analysis at a median follow-up time of 18.1 and 44 months, the combination of nivolumab and cabozantinib at a median follow up of 55.6 months continues to show a significant reduction in the risk of progression or death by 42% and in the risk of death by 23% compared to sunitinib.  Dr. Neeraj Agarwal: And Jeanny, what can you tell us about the efficacy results of this combination by IMDC risk categories? Dr. Jeanny Aragon-Ching: Similar to prior results in patients with intermediate to poor risk IMDC risk category, the combination treatment maintained significant efficacy and reduced the risk of progression or death by 44% and the risk of death by 27%. To put it simply, the update now shows a 15-month improvement in overall survival with the cabozantinib-nivolumab combination compared to sunitinib, which is amazing. Also, in patients with favorable IMDC risk group, which represented truly a small number of patients in the trial, there was a strong trend for improvement of outcomes as well. I would like to point out that no new safety concerns were identified. Dr. Neeraj Agarwal: So, it looks like the key message from this abstract is that with longer follow-up, the combination of nivolumab and cabozantinib maintains a meaningful long-term efficacy benefit over sunitinib, supporting its use for newly diagnosed patients with advanced or metastatic renal cell carcinoma.   Let's move on to Abstract 363, which compares nivolumab with ipilimumab to sunitinib in first-line advanced renal cell carcinoma. What would you like to tell us about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Yes, Neeraj. The title of this abstract is "Nivolumab plus Ipilimumab versus Sunitinib for the First-Line Treatment of Advanced RCC: Long-Term Follow-Up Data from the Phase 3 CheckMate 214 Trial." In this abstract, Dr. Tannir and colleagues report outcomes with the longest median follow-up in first-line advanced RCC setting for any clinical trial. So the median follow-up now is about 18 months. The primary endpoints were OS, PFS, and objective response rates, as assessed by an independent review according to RECIST 1.1 criteria in the intermediate to poor risk IMDC risk group, which is the intent-to-treat (ITT) analysis, while secondary outcomes included the same outcomes in the ITT population of patients. Although the progression-free survival was similar in both arms, the combination of nivolumab-ipilimumab reduced the risk of death by 28% compared to sunitinib in the ITT population of patients. When stratifying the results by IMDC risk groups, the combination arm of nivolumab-ipilimumab showed significant improvement in the intermediate to poor risk group, but there was no difference in the favorable risk group. But in the study, no new safety signals were identified. Dr. Neeraj Agarwal: Thank you, Jeanny, for such a comprehensive description of the results of these two studies. I'd like to add that the median overall survival of patients with metastatic renal cell carcinoma in the ITT population in the CheckMate 214 trial has now reached 53 months, which would have been unimaginable just a decade ago. This is wonderful news for our patients. So the key takeaway from these two abstracts would be that immune checkpoint inhibitor-based combinations remain the backbone of first-line advanced renal cell carcinoma treatment.  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. This is wonderful news for all of our patients, especially for those who are being treated for first-line therapy.  Now, let's move on to the bladder cancer abstracts. We have two exciting abstracts from the UNITE database. What are your insights on Abstract 537, titled "Outcomes in Patients with Advanced Urethral Carcinoma Treated with Enfortumab Vedotin After Switch-Maintenance of Avelumab in the UNITE Study"? Dr. Neeraj Agarwal: As our listeners know, enfortumab vedotin is an antibody-drug conjugate that binds to a protein called Nectin 4 expressed on bladder cancer cells. In this abstract, Dr. Amanda Nizam and colleagues describe outcomes in 49 patients receiving third-line enfortumab vedotin after prior progression on platinum-based therapy and maintenance avelumab. At a median follow-up of 8.5 months, the median progression-free survival was 7 months and the median overall survival was 13.3 months with enfortumab vedotin in this treatment-refractory setting, the objective response rates were 54%. The message of this study is that enfortumab vedotin is an effective salvage therapy regimen for those patients who have already progressed on earlier lines of therapies, including platinum-based and immunotherapy regimens. Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for that comprehensive review.  I want to focus on another patient population in the UNITE database, which is the use of fibroblast growth factor receptor (FGFR) alterations. Can you tell us more about the sequencing now of erdafitinib and enfortumab vedotin in these patients with metastatic urothelial cancer, as discussed in Abstract 616? Dr. Neeraj Agarwal: Sure, Jeanny. As a reminder, erdafitinib is a fibroblast growth factor receptor kinase inhibitor approved for patients with locally advanced or metastatic urothelial carcinoma harboring FGFR2 or FGFR3 alterations after progression on platinum-based chemotherapy. However, the optimal sequencing of therapies in these patients is unclear, especially with enfortumab vedotin being approved in the salvage therapy setting and now in the frontline therapy setting.  So in this retrospective study, all patients with metastatic urothelial carcinoma had FGFR2 or FGFR3 alterations. Dr. Cindy Jiang and colleagues report outcomes in 24 patients receiving enfortumab vedotin after erdafitinib, 15 patients receiving erdafitinib after enfortumab vedotin, and 55 patients receiving enfortumab vedotin only. This is a multicenter national study. Interestingly, patients receiving both agents had a longer overall survival in a multivariate analysis, regardless of the treatment sequencing, than patients receiving enfortumab vedotin alone or only with a hazard ratio of 0.52. The objective response rate of enfortumab vedotin in the enfortumab vedotin monotherapy arm was 49%. When these agents were sequenced, the objective response with enfortumab vedotin was 32% after erdafitinib and 67% when used before erdafitinib. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. I think these are important real-world data results, but I would like to point out that larger and prospective studies are still needed to confirm these findings, especially regarding the outcome of erdafitinib after enfortumab vedotin, particularly when the latter is used in the first-line setting. Dr. Neeraj Agarwal: I totally agree, Jeanny. Now, let's discuss some abstracts related to disparities in the management of patients with genitourinary cancers.  Dr. Jeanny Aragon-Ching: Sure, actually, I would like to discuss 2 abstracts related to disparities in patients with prostate cancer. So the first one, Abstract 265, titled "Patient-Provider Rurality and Outcomes in Older Men with Prostate Cancer." In this study, Dr. Stabellini, Dr. Guha and the team used a SEER Medicare-linked database that included more than 75,000 patients with prostate cancer. The primary outcome was all-cause mortality, with secondary outcomes included prostate cancer-specific mortality. The investigators showed that the all-cause mortality risk was 44% higher in patients with prostate cancer from rural areas who had a provider from a non-metropolitan area compared to those who were in a metropolitan area and had a provider also from a metropolitan area. Dr. Neeraj Agarwal: Those are very important data and highlight the healthcare disparities among the rural population with prostate cancer that still exist.  So what is your key takeaway from Abstract 267, titled "Rural-Urban Disparities in Prostate Cancer Survival," which is a population-based study? Dr. Jeanny Aragon-Ching: Of course. This abstract discusses, actually, a very similar issue regarding access to healthcare among rural versus urban patients. In this study, Dr. Hu and Hashibe and colleagues and team at the Huntsman Cancer Institute assessed all-cause death and prostate cancer-related death risk in a retrospective study in which patients with prostate cancer based on rural versus urban residencies looked at 18,000 patients diagnosed with prostate cancer between 2004 and 2017. 15% lived in rural counties. Similar to the prior abstract we talked about, patients living in rural areas had about a 19% higher risk of all-cause mortality and a 21% higher risk of prostate cancer-specific mortality in comparison to patients living in urban areas. Dr. Neeraj Agarwal: So Jeanny, we can say that both of these abstracts, led by different groups of investigators, highlight that patients with prostate cancer living in rural areas have inferior survival outcomes compared to those living in urban areas, and it is time to focus on the disparities experienced by the rural population with prostate cancer.  Dr. Jeanny Aragon-Ching: Yeah, absolutely Neeraj. I concur with your thoughts.  So, any final thoughts before we wrap up the podcast today? Dr. Neeraj Agarwal: Yes, before concluding, Jeanny, I want to express my gratitude for your participation and the valuable insights you have shared today. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today.   As we bring this podcast to a close, I would like to highlight the significant advances happening in the treatment of patients with genitourinary cancers during our upcoming 2024 ASCO GU meeting. Many studies featuring practice-impacting data will be presented by investigators from around the globe. I encourage our listeners to not only participate at this event to celebrate these achievements, but to also play a role in disseminating these cutting-edge findings to practitioners worldwide. By doing so, we can collectively maximize the benefit for patients around the world.  And thank you to our listeners for joining us today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.  Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guest speakers express their own opinions, experience, and conclusions. Guest statements on the podcast do not necessarily reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today’s speakers:     Dr. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:      Dr. Neeraj Agarwal:       Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:    Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers’ Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 
1/22/202425 minutes, 10 seconds
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Celebrating 20 Years of Evolution in GU Oncology

Drs. Eric Small, Anthony Zietman, and Eric Klein share their reflections as founders of the ASCO Genitourinary Cancers Symposium and discuss key moments in the Meeting’s development, its role in advancing GU cancer research, and major challenges ahead for the field as the Symposium celebrates its 20-year anniversary. TRANSCRIPT Dr. Eric Small: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Eric Small, your guest host of this ASCO Daily News Podcast today. I'm the co-leader of the UCSF Prostate Cancer Program and deputy director and chief scientific officer at the UCSF Helen Diller Family Comprehensive Cancer Center. This year, quite amazingly, we're celebrating the 20th anniversary of the ASCO Genitourinary Cancers Symposium, which is hosted annually in San Francisco. The Symposium has heralded some of the biggest strides in GU oncology and has the largest multidisciplinary, global audience for GU cancer research. I was honored to have a role in the development of ASCO GU two decades ago, along with my friends and colleagues, Dr. Eric Klein, emeritus professor and chair of the Glickman Urological and Kidney Institute at the Cleveland Clinic. And Dr. Anthony Zietman, a professor of radiation oncology at Harvard Medical School and the Massachusetts General Hospital. On today's episode, we'll be reflecting on key moments in the meeting's development, its role in advancing GU cancers and GU cancer research, and major challenges that lay ahead for the field. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Eric and Anthony, I'm delighted to have this opportunity to catch up with you both to discuss ASCO GU, thank you for coming on the podcast today. Dr. Eric Klein: Thanks for having us. Dr. Anthony Zietman: Thanks for the invitation. Dr. Eric Small: Well, it's really exciting and it's wonderful to see the two of you. So, the ASCO GU Symposium has been a key annual event for all of us in the GU field. But to give our listeners some background, when the Symposium was first created, when we first met in San Francisco, starting on Thursday, February 17, 2005, it brought together 1,035 individuals interested in the prevention and treatment at that point of prostate cancer alone. At that time, the meeting was co-sponsored by ASCO, the American Society for Therapeutic Radiology and Oncology or ASTRO, the Society of Urologic Oncology (SUO), and the Prostate Cancer Foundation. It was actually the culmination of several years of planning. Clearly, it represented the first truly multidisciplinary scientific and educational meeting dedicated solely to prostate cancer, and we'll come back to talk about that. The meeting went back and forth between San Francisco and Florida for a few years before finally, settling permanently in San Francisco. In the last 20 years, ASCO and the Symposium's co-sponsors expanded the meeting to include all genitourinary specialties. This year, ASCO received more than 875 abstract submissions and anticipates that there will be even more attendees than last year. On a personal note, it's truly amazing to me that here we are, 20 years later, and the meeting is going stronger than we could ever have imagined. I must say that my motivation to help organize this meeting stem from two issues that were somewhat in tension with each other. First, the field of prostate cancer and prostate cancer research was just starting to take off at the time, and we really needed, as a community, a venue where across disciplines, we could talk and meet with each other. But that was in real tension, at least at ASCO, where we were relegated at the Annual Meeting to a tiny room at the far end of the convention center on the last day of ASCO, because really, that's all we could muster. And I do remember making a pitch, assuring folks that there was an unmet need, and that the field was going to take off, who knew? So, I'm wondering, and either of you can jump in (Dr. Klein, Dr. Zietman), tell us how you got involved in the first GU meeting, and what's the most salient feature of your involvement? Anthony, do you want to start? Dr. Anthony Zietman: I think it's really important to discuss the historical context at which this meeting was born. Back in the 1990s, we were incredibly polarized as specialties in GU oncology. PSA had been introduced in the late '80s, early '90s, screening was everywhere. There was a tidal wave of patients and an almost reckless race to treatment. All surgeons believed that all patients with localized early prostate cancer needed surgery and that they could do individually, a beautiful job. And all radiation oncologists believed that they could deliver morbidity-free treatment and could do it to everyone regardless of your age or stage. And there were a few, there were a few who thought maybe we didn't need to screen everyone, and maybe there was a little bit of overtreatment, maybe we've gone a little bit too far, but those voices were really suppressed in the '90s. Those voices didn't have a voice. Many of us also believed there was more morbidity to our treatment than we'd appreciated. And that was the media in which, us three, all young research physicians, probably all in our low forties were given the charge of this meeting. And the thing I most remember about it in the planning, is that we actually decided collectively to give voice to everyone, including maverick voices. It wasn't just about the party line, and it wasn't just about the North American line, there were Britts and there were Swedes, and there were Dutchmen who had very important things to say as well, and very, very different perspectives. And we also chose to give voice to young people as well as just our party elders, so to speak. I don't know which of us, if any of us, or maybe it was our society suggested but we do it all in a single room such that rad oncs and surgeons were all together, and it led to a kind of forced truthfulness, which started to break down this groupthink that we developed in our own silo. So, when I look back, I think that that context was very important and that what we sought as young program chairs was we sort of tapped in something that was latent in our field. Eric KIein, I don't know if you remember things as I did. Dr. Eric Klein: I do. And things were very siloed then. We had hired early in the mid-90s, I think, a young radiation oncologist named Pat Kupelian, who became a close collaborator and a good friend, and who really changed the narrative around treating prostate cancer at the Cleveland Clinic, which was all surgical prior to that time. And he did such high-quality work, it was hard not to pay attention. And he actually took it on himself in his early years when he wasn't very busy to sit down and go through all the patients that we had treated with prostate cancer at the Cleveland Clinic, radiation versus surgery, and had the temerity to write a manuscript that showed that there was no difference in survival, based on PSA biochemical recurrence and metastasis and that sort of thing. And that was sort of game changing. And it really clued me into the fact that for patient's sake, we needed to be talking to our colleagues. The second perspective was from the perspective of having attended a couple of Prostate Cancer Foundation meetings. And I think they really deserve credit for increasing the visibility of prostate cancer research, and funding it and recruiting really good scientists from other disciplines. When young scientists were told, and we heard this repeatedly, "Don't spend your career researching prostate cancer, it's a dead end." And PCF did a great job of having a multidisciplinary meeting, which was smaller and not so clinically focused, but also got me excited. Dr. Eric Small: I think you're right, Eric. And I think that the transdisciplinary nature, as Anthony pointed out was new, it was innovative. No one had really, really thought about it. It was at the margins in different meetings. Your comments about PCF, Prostate Cancer Foundation, resonate because we did take a page from their book in many ways although that meeting, as you point out, is much more basic research-focused. I don't know if you guys recall that first year, in fact, PCF was a co-sponsor. We actually had asked Mike Milken to give a talk and he did. And obviously, once we expanded to the broader GU cancers, it was less pertinent for PCF to be involved. But absolutely, I agree with you, Eric, they deserve credit. PCF, and the PCF involvement, was one of the things that changed. There's many things that are constant that haven't changed, even though the science clearly has evolved dramatically. And I'm wondering if you guys can comment on things that are the same. One thing that stands out for me: I had the opportunity to look through the agenda for the 2005 meeting. And right there, very prominently, was a special lunch session that we had designed for mentorship and career development for trainees and early career investigators, and that's still ongoing and others have modeled it. And I think that was one amazing feature of this. One of you, I think Anthony mentioned that we invited a lot of young people to speak and to be the path blazers, but we also did this career development piece, and it was a wonderful event. I wonder if either of you or both of you could comment on other things that you think are constants and you anticipate will always be there. Dr. Anthony Zietman: I think to me that constant is that every time I go, I hear speakers I've not heard before. Often very senior speakers, I've never heard them before. But it is the practice of GU ASCO to invite people that are outside your sphere of experience, which is very challenging. Dr. Eric Klein: Two things strike me. I think one is the international nature of the faculty. We tried very hard (and subsequent program directors have) to be very inclusive and to bring the work that was the most cutting-edge to the stage. There are lots of things that are done in Europe that started there sooner. PSMA treatment, for example, and many other ProtecT trial and many other things. And the debates on stage and how that gave the opportunity for every subspecialty to have the opportunity to share its perspective on particular case management issues and case management conferences, I think have been around forever. And maybe, the most valuable part of it all is to hear people's perspective on how to manage a particular patient. Dr. Eric Small: I think the other comment you made Anthony that resonated and still goes on, was it was a conscious decision to have a single session in one room where everyone attended. And not to do the usual small breakouts and concurrent sessions, but sort of the philosophy being, is we all need to hear the same thing, we all need to be in the same room at the same time. And it really fostered this transdisciplinary approach; it was truly educational for us. Now, it's sort of part of what we do, and part of what our patients expect of us. I think that bringing us all together into one room was really great. Dr. Anthony Zietman: But it's now so part of what we do, but it's difficult certainly for younger faculty and for residents to believe we ever did it any other way. But we did, and I don't know whether ASCO GU led that or reflected that, but that was the zeitgeist among young individuals like us. And it's really become the culture of contemporary practice. Dr. Eric Small: So, given that that's the culture now, which it is, and I think sure, we should take credit for it, at least in GU: why then is it important for people to continue to attend GU ASCO today if it's now our culture to do that? Dr. Anthony Zietman: For me, it's because we share information as equal partners in a multidisciplinary team. And our practice is so multidisciplinary and multi-modality these days that we can't exist alone, we no longer try to. Dr. Eric Klein: Nor can we. The amount of knowledge that's being generated in each subspecialty and it's spinoffs is so great. It's impossible for a busy surgeon to stay on top of that. And this is sort of one-stop shopping for everything that's really current and appropriate to know about. And again, I always look at these things from the patient perspective, and my ability to counsel patients about what their best treatment options might be, I thought more and more dependent, and I think today more and more depends on being knowledgeable about everything that's going on, and not just one narrow field that you happen to be an expert in. And that's why I think it's so important for youngsters to attend and even oldsters like us to attend to stay current. Dr. Anthony Zietman: Yeah, and also, multidisciplinary means so much more these days. It does mean oncologists and radiologists, information technologists. I mean, who knows what it'll mean in the future, but it's always expanding. Dr. Eric Small: And I think it's interesting, back when we did this, when we started it, we were worried about being able to fill one meeting with prostate cancer information - we did easily. It was not immediately clear that there was a role or room for additional GU cancers. And then there was an explosion both in kidney cancer work at first, and then bladder cancer. And now it's unbelievable how much is there. And perhaps, this meeting needs to be twice as long. So, I agree with you guys. I think that it's the best way to stay current. The other thing that I really appreciate about this meeting and others have a hard time doing it, is that it provides, as Eric indicated, for the busy clinician. It integrates sort of the important information that's coming in terms of more basic science and makes it readily available and digestible, which isn't always the case at pure science meetings and may or may not be apparent in other meetings. I, again, was looking at the preliminary agenda in 2005, we had asked Bill Nelson to talk about molecular targets or prevention, how forward-thinking. And that's continued to be the case that this is a meeting where you get that integration from the laboratory. Dr. Anthony Zietman: Well, and I would add to that, not just the integration of it, it's where now you get to hear things first. I mean, it used to be that, you went the AUA or ASTRO or ASCO to hear things. Now, everyone one wants to present it first at GU ASCO. Dr. Eric Klein: Yes, that's correct. Dr. Anthony Zietman: And I think we actually made it permissible in the early days that you could present at GU ASCO and at your specialty meeting. Dr. Eric Small: What are the challenges in the field that are going to likely shape the content of future meetings? And we've all alluded to the fact that the meeting is evolving and has done a really good job of staying current with the clinical science. But beyond that, what do you two feel are important areas that this meeting is likely to continue to address? Dr. Eric Klein: So, biomarker development has always been an important part of this meeting, and I think we need to broaden our view of what biomarkers are now, and in the AI era, digital pathology and AI-based models that predict treatment response and outcome. My hope is that they will be studied in a rigorous fashion, and that they will end up outperforming the kind of single biomarker approach that we've used in the past. And we need to understand that; we need to understand the science behind AI to a certain level, and we need to understand what questions AI can address, and how that might be useful. But I'm particularly excited about digital pathology where sampling error becomes less of an issue and the number of potential inputs you're looking at that are related to the output should increase exponentially. Dr. Anthony Zietman: And I would add on the AI side of things, as a former journal editor, when AI papers came into the journal, we actually didn't have enough people who could review them, who had the understanding to review these papers and tell us, "Is this a good paper or a bad paper?" So, we're going to need to increase our understanding of AI, Eric, as you said. So, I think that will be a push in the years to come. Also, on a very practical level, it is such a popular meeting, keeping us all under one roof and in one room, will become just difficult. But it's part of the culture of the meeting, and I think it's what people want. Dr. Eric Small: It's a good challenge to have. Dr. Eric Klein: Feeding everybody too. I recall one constant has always been really good breakfasts and lunches. Dr. Eric Small: Right, that has been a standard of ours. One of the interesting things that I think has changed, we saw glimmers of it back in 2005, but it was early on and it was, I think very early on in sort of a good understanding of social determinants of health and equitable access to healthcare and the challenges posed by incredible technology development and making sure that that doesn't increase disparities. And I think that that focus has increasingly been present in meetings and is not going to be lost. And it also speaks, one of you spoke to our international audience, that increasingly, I think this meeting is going to address urologic oncology and how we address it not only in developed countries, but in lower- and middle-income countries. And I think that will be a focus as well. I'm excited with what the future holds for ASCO GU. It has been an incredible run. I'm hoping that we'll be able to perhaps catalog some of the salient presentations that have been done at this meeting over the years, but there's no question as both of you have pointed out, this has become the venue. Well, thank you both for sharing your insights with us today on the ASCO Daily News Podcast. Really wonderful to see you both and talk with you. Dr. Eric Klein: Great to be here. Thanks. Dr. Anthony Zietman: Great to be here. Looking forward to the next 20 years. Dr. Eric Small: That's right. Dr. Anthony Zietman: If I'm still around. Dr. Eric Klein: Yeah, let's do this again in 20 years. That'd be great. Dr. Eric Small: We will. And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use and the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today’s speakers:   Dr. Eric Small Dr. Eric Klein @EricKleinMD Dr. Anthony Zietman   Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Eric Small: Stock and Other Ownership Interests: Fortis, Harpoon Therapeutics, Teon Therapeutics Honoraria: Janssen Consulting or Advisory Role: Janssen Oncology, Teon Therapeutics, Fortis   Dr. Anthony Zietman: Leadership: Elsevier   Dr. Eric Klein:No relationships to disclose
12/14/202320 minutes, 13 seconds
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What the FDA CAR T-Cell Therapy Investigation Means for Oncologists

Drs. John Sweetenham and Fred Locke discuss the FDA investigation on the risk of cancer from CAR T-cell therapy and share insights on the known number of cases and the potential implications on clinical research and patient care. TRANSCRIPT Dr. John Sweetenham: Hello, I’m Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. CAR T-cell therapies have been game changers for treating certain cancers including lymphomas and leukemias, as well as multiple myeloma, since the vast majority of patients who have received CAR-T do not have other curative options with conventional non-cellular, anti-cancer therapies. But on November 28, the U.S. Food and Drug Administration announced that it is investigating whether CAR T-cell therapy can, in rare cases, cause secondary cancers. The FDA launched the probe after receiving reports from clinical trials and other data sources of T-cell malignancies in patients who received CAR T-cell immunotherapies. Joining me to discuss the investigation and its implications for the field is Dr. Fred Locke, a medical oncologist and translational researcher and a senior member and chair in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Moffitt Cancer Center in Tampa, Florida. Dr. Locke is an internationally renowned clinical research leader in the field of CAR T-cell therapy. You'll find our disclosures in the transcript of this episode, and disclosures of all guests on podcasts are available at asco.org/DNpod. Fred, it’s great to have you on the podcast today. Dr. Fred Locke: Thanks, John, I’m really glad to be here. Dr. John Sweetenham: So, T-cells are the backbone of CAR T-cell therapies, and there are currently 6 CAR-T products approved by the FDA. As our listeners will know, CAR T-cell therapies manipulate a patient's T-cells, enabling them to recognize and attack antigens on cancer cells and induce potential long-standing changes in the immune system. In its statement on November 28, the FDA said it determined that the risk of T-cell malignancies is applicable to all of the currently approved BCMA- and CD19-directed, genetically modified, autologous CAR T-cell immunotherapies. Fred, could you comment for us on the investigation: How many patients are reported to have developed second malignancies from CAR T-cell therapy, and whether there are likely to be more secondary cancers reported? Dr. Fred Locke: Yes, so the FDA and the reports are coming out that there are 19 cases of T-cell malignancy that we're aware of that have occurred after the current FDA-approved CAR T-cell therapies were administered for the treatment of leukemia, lymphoma, or multiple myeloma. The majority of those cases were reported through the FDA Adverse Event Reporting System. And we don't know a lot of details of those 19 cases. We think that there's probably about 13,000 to 14,000 patients who've been treated with the commercial CAR T-cell therapies. So if you kind of do some crude math, you can come up with 19 out of say, 13,500; we're at about 0.1% of patients who could have developed T-cell lymphoma after treatment with these CAR T-cell therapies. It's not entirely out of the realm of possibility that T-cell lymphoma could develop from gene-modified T-cells, and these are all the patient's own T-cells that have been modified outside of the body. But I would still posit that this is a really low incidence of T-cell lymphomas in these patients who really are without other great treatment options. Dr. John Sweetenham: Yeah, and I think that's a point that we'll return to a little bit later on in the conversation around the fact that you know, clearly, there are major benefits that have been associated with CAR T-cell therapy and hematologic malignancies so far. And of course over the years, I think that many of us have become familiar with and learned a great deal about how to manage some of the more serious side effects of CAR T-cell therapy. And you, of course, have led several pivotal national trials of anti-CD19 CAR-Ts for lymphoma. Can you comment at all on whether you've seen previous data from your own practice or others on the risk of second malignancy from CAR T-cell therapy? And can you share your insights on the data and any new emerging data that warrants our attention for the concern or risk of second malignancy? And I guess to round up that series of questions, is there anything currently in yours or others research into CAR-T to explain what's happening and why this is going on? Dr. Fred Locke: I think what may have prompted the FDA’s announcement of this is that on the same date that they came out with announcing their investigation, there was the release of the abstracts for the American Society of Hematology Annual Meeting. And within those abstracts, and unfortunately it was not selected for poster or oral abstract presentation, but discovered within those abstracts was one on a CAR+ T-cell lymphoma after ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma. And what these investigators and the company were reporting is that a patient with refractory multiple myeloma received the cilta-cel BCMA-directed CAR T-cell therapy and developed a stringent complete response, and about 5 months later developed a nasal facial plaque and PET+ cervical lymph nodes. And both the lymph nodes and the plaque were biopsied and showed a T-cell lymphoma in which 90% to 100% of the cells were positive by qPCR for the CAR construct and immunohistochemistry for the CAR protein. So this was a T-cell lymphoma growth where the cells were expressing the inserted protein, the chimeric antigen receptor protein, which is obviously not natural. And when they looked a little bit deeper at these patients, 91% of the cells have the same T-cell receptor sequence. So this was really a clonal sort of process. They did CAR integration analysis to see how the insertion of the CAR, the chimeric antigen receptor gene, could have potentially disrupted a gene within the T-cells. And what they found is that there were some dominant sort of insertions within certain genes suggesting monoclonality, but it wasn't within any sort of obvious activating genes that would be expected to lead to the T-cell lymphoma. They went on and did some additional analysis, and they showed that there was some existing TET2 mutations in the T-cells of this patient, prior to probably prior to the CAR T-cell manufacturer, and they weren't associated with clonal insertion. And I think, you know, it's possible that this patient who had a pre-existing mutation may have been susceptible to the development of a T-cell lymphoma prior to the CAR T-cell treatment. And TET2 was previously shown a number of years ago in a CLL patient treated with CD19 CAR T-cell therapy; it was shown that there was insertional mutagenesis, silencing the TET2 gene, and that associated with clonal expansion of the CAR T-cells in that patient and corresponded with remission of the CLL. However, the difference here is that that patient's T-cell clone went back down and contracted, and the patient remained in remission 5 years later with their T-cells still in the blood, but the minority of those T-cells had that that TET2 mutational insertional mutagenesis. All this is something we thought was theoretically possible, that T-cell lymphoma could develop after car T-cell therapy. And in fact, a prior trial using a different method of delivery of a CAR gene; instead of using a virus to insert the car into the into the T-cells, a transposon system called piggyBac was used. And in that trial, again, CD19 CAR trial, but in this case, it was allogeneic donor cells for patients who had relapsed after an allogeneic transplant. So it's sort of an autologous, you know, analogy, but it's using the donor cells. And in that trial, 2 out of like 10 patients developed clonal T-cell lymphoma, which was CAR+, but they weren't able to identify a clear insertional mutagenesis event in those cases. So, we've known this is possible, and it would have been great if this poster or if this abstract at ASH was presented as an oral or a poster so we could get more detail, but it's possible that that's the likely reason for the FDA’s announcement. Dr. John Sweetenham: Thanks. The bottom line, I guess, is that for now, the jury's still out on exactly what's underlying these observations, but something which I'm sure is going to be the subject of a lot of discussion during the ASH meeting this year and moving forward. I'd like to inform our listeners that ASCO released a statement on the FDA investigation, stating that the risk of T-cell malignancies due to CAR T-cell therapy appears to be very low. And we've just heard from Dr. Locke that, of the several thousand patients who've received CAR Ts, there are 19 cases so far, it's been reported, which puts us into some type of proportion. The ASCO statement goes on to say that based on available data, and while such malignancies have occurred in patients who have received CAR T-cell therapy, the causal relationship, whether these cases are spontaneous or are caused by the therapy, needs to be investigated further, and we've just heard a little about the detail of that. ASCO added that by issuing a warning but not revoking approval of these therapies, the FDA clearly believes that the current available evidence suggests the overall benefits of these products, used within their approved label, continue to outweigh the potential risks. So Fred, the risk of secondary malignancies is already included as a class warning in the U.S. prescribing information for these CAR T-cell therapies. But do you think that the CAR-T products could eventually be taken off the market, and how would your research be impacted if this were to happen? And maybe finally, how long will patients on CAR T-cell therapy need to be monitored moving forward? Dr. Fred Locke: I don't believe that CAR T-cell therapy will be taken off the market. As we've already talked about, the incidence is extraordinarily low and the causality is unclear. It would certainly impact my research, as I'm doing clinical trials with CAR T-cell therapies, but it would more importantly impact the way we treat patients. We did over 300 CAR T-cell therapy treatments last year here at Moffitt Cancer Center. We're one of the busiest programs in the world giving CAR T-cell therapy, and it is truly a transformative therapy for all the diseases that we administer these FDA-approved therapies for. For example, in diffuse large B-cell lymphoma, we participated in the ZUMA-7 clinical trial and recently reported that patients randomized to CAR T-cell therapy had improved overall survival. They were living longer than patients randomized in the second-line setting to get conventional chemotherapy and autologous transplant. This is clearly a therapy that can work. I would also add that the risk of secondary malignancies is real, but that's a risk for all cancer patients, particularly patients with hematologic malignancies, and for example, lymphoma patients who've gotten an autologous stem cell transplant are at a relatively high lifetime risk of developing a secondary myeloid malignancy, most commonly, treatment-related MDS or AML. And that risk is also present after CAR T-cell therapy. The degree of attribution of CAR-T versus the condition of chemotherapy for CAR-T versus the previous chemotherapy is all unclear, and more analysis needs to be done. But the risk of developing treatment-related MDS or leukemia is certainly higher than the small number of T-cell lymphomas reported. The other thing I want to point out is that there was an analysis of the SEER database that patients with B-cell lymphomas are at about a 5-fold higher risk of developing a T-cell lymphoma than the otherwise healthy population; and vice versa, by the way, T-cell lymphoma patients are at risk for developing B cell lymphoma. And in fact, in that SEER database, it's not a wildly different percentage chance of developing a T-cell lymphoma after a B-cell lymphoma. And this data came out before the advent of CAR T-cell therapy. So I really think we need more science to be done to understand what's happening for these patients. Will this impact the field? Well, certainly, there are treatments that are not CAR T-cell therapy that compete with CAR T-cell therapy or could; I'm a strong believer that they don't offer the same outcomes for patients, but we will certainly see people talking about this for some time. Then the other place where this could be relevant, I think, is as we look at CAR T-cell therapy for autoimmune disorders, and we're starting to see studies of that for lupus and other diseases, the risk to benefit ratio could be different in those cases. So this is something we really need to consider as we move forward with CAR T- cell therapy. Dr. John Sweetenham: Yeah, thanks, Fred. And as a major clinical investigator in the field of CAR-T at the moment, do you see any potential concerns about difficulties in getting patients onto the trials of CAR T-cell in the light of this information? Dr. Fred Locke: No, I really don't. We're not seeing hesitancy, at least in the patients who are referred in for CAR T-cell therapy. Again, it may give ammunition for those who are already predisposed to not refer patients in for CAR T-cell therapy, but I don't think it should. I think that these are low risks, and these therapies clearly have benefits to patients. And we should give their patients an opportunity to get these therapies, and I don't see it impacting our clinical trials at this point. Dr. John Sweetenham: Yeah, and your comments address what was going to be my final question to you and that is, as a referring oncologist, how would you advise a referring oncologist to talk with their patients about these data and their implications moving forward? Dr. Fred Locke: If the patient brings it up, I think the response should be that these are very few cases of very low incidence and very low risk. There are other risks to CAR T-cell therapy that are greater, and really speaking with a cell therapist who administers the treatment is probably the best way to give the patient the option to get CAR T-cell therapy if they want to, knowing all the risks and benefits. So, I would leave it up to the CAR-T treatment center to discuss those risks with the patient.   Dr. John Sweetenham: Well, thanks, Fred, for sharing your insights with us on these concerning developments in CAR T-cell therapy, and I think also for putting them into context in terms of the sort of magnitude of this problem in the context of the overall number of patients who are benefiting from this therapy right now. We truly appreciate your time, and thanks for sharing your thoughts with our listeners. Dr. Fred Locke: Thanks, John, my pleasure. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers:      Dr. John Sweetenham Dr. Fred Locke @DrFredLocke     Follow ASCO on social media:         @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn         Disclosures:        Dr. John Sweetenham:    Consulting or Advisory Role: EMA Wellness     Dr. Fred Locke: Consulting or Advisory Role: Novartis, Celgene, Calibr, Allogene, Gerson Lehrman Group, EcoR1, Amgen, Bluebird Bio, Bristol Myers Squibb, Iovance Biotherapeutics, Legend Biotech, Cowen, Kite (Gilean), Umoja Biopharma, Takeda, Sana Biotechnology, Daiichi Sankyo/UCB Japan, Bristol-Myers Squibb/Celgene, Janssen, A2 Biotherapeutics, Mittenyi Biotec, Caribou Biosciences, Takeda, Umoja Biopharma Research Funding: Kite Pharma, Allogene, Novartis, Bluebird Bio, Bristol-Myers Squibb/Calgene Patients, Royalties, Other Intellectual Property: Double Mutant Survivin Vaccine. US010414810B2 CAR T Cells with Enhanced Metabolic Fitness; Serial Number: 62/939,727 Methods of Enhancing CAR T Cell Therapies. Serial Number: 62/892,292. Evolutionary Dynamics of Non-Hodgkin Lymphoma CAR-T cell therapy.  Serial Number: 62/879,534. Travel, Accommodations, Expenses: Kite Pharma, A2 Biotherapeutics
12/7/202317 minutes, 26 seconds
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Managing the Complexities of Oncology Practice in 2024

Drs. John Sweetenham and Lawrence Shulman discuss the challenges that oncologists will be confronting in 2024 and share insights on how to build clinician resilience and optimize the oncology workforce to provide better, safer care for patients with cancer. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. I'm thrilled to welcome my friend and colleague, Dr. Larry Shulman, to the podcast today. Dr. Shulman is a professor of medicine, associate director of special projects, and the director of the Center for Global Medicine at the University of Pennsylvania Abramson Cancer Center. Dr. Shulman is also the immediate past chair of the Commission on Cancer, and also serves on the National Cancer Policy Forum of the National Academies of Science, Engineering, and Medicine. His acclaimed research has led to the development of models of clinical care to improve the patient experience and quality of care in the United States and internationally. His activities have also included innovations in health information technology, cancer survivorship care, and some other related areas. Today, Dr. Shulman will be sharing his valuable insights on some of the growing complexities and challenges that we'll be grappling with in oncology in 2024 and beyond, and potential solutions to address these issues. You'll find our four disclosures in the transcript of this episode, and disclosures of all guests on the podcasts are available at asco.org/DNpod. Larry, it's great to have you on the podcast today. Dr. Lawrence Shulman: Thank you so much, John. Dr. John Sweetenham: To start with Larry, as you know, the growth in the number of patients with cancer and cancer survivors in the U.S. is greatly outpacing the number of clinicians available to care for them. The American Association for Cancer Research, for example, estimates that there will be nearly 2 million new cancer cases in the U.S. alone this year and that the number will increase significantly in the years to come. The number of cancer survivors in total in the U.S. is predicted to grow to around 20.3 million by 2026. So, the question our community has been grappling with for some time now is: “How do we confront these realities and provide optimal care for patients, while at the same time building the resilience of the clinicians who need to care for them?” This is an area I know that you've focused on for a long time and you've published several papers in recent years as well as the great work that you've done as co-chair of the National Cancer Policy Forum workshop on the oncology workforce. Can you share your insights into some of these challenges? Dr. Lawrence Shulman: Sure, John. Thank you very much. As you mentioned, the number of oncologists in this country is pretty stable. There's consistent but relatively low number entering the workforce and those of us who were really in the first wave of oncologists in the 1970s are beginning to retire. A number of years ago we thought, well, we need to figure out ways to recruit more medical students and trainees into the field of oncology, but that's clearly not going to happen. And as you also mentioned, the number of cancer patients is rapidly increasing in this country, partly because of the aging population and partly because frankly we're better at treating them. The cure rates are better, and the number of survivors is going up. So, the math is pretty straightforward. We have a relatively stable number of oncology providers trying to care for a rapidly increasing number of patients and that's just not going to change. So, we need to have plan B; we need to figure out how we can better meet the needs in this country. And I think all of us who practice are feeling the strain of trying to take care of these increasing number of patients. I think there are a few things that are contributing to this as well. One—the good news is we have lots of new therapies, we have lots of genomics, which are leading us to better tailor therapies for our patients. But this is all complicated and it's a lot for us all to learn and keep abreast of and to manage on a day-to-day basis in the middle of a busy clinic. But the other thing is that I believe our care has become progressively more inefficient, making it harder every day that we go to clinic to care for the number of patients we need to. And that really has to change. For those of us who've been doing this for a long time, and I know you have as well, this has been a trend really over decades. It's gone in the wrong direction. It was a lot easier to practice a number of decades ago. Now, the requirements for documentation and pre-authorization and many other administrative tasks has just grown progressively over these years. And we need to figure out how to change that. And in addition, our electronic health records, which is where we live in clinic, have been remarkable and wonderful in many ways, but are also inefficient to use and we need to do a better job in optimizing their functionality. Dr. John Sweetenham: Great, thanks Larry. I do agree with you there and I think that in addition to the challenges of running the electronic health record and using that at the point of care, of course the other thing that many of our clinicians face now is an increasingly complex treatment landscape and a greater need for clinical decision support tools, which of course are not always at the moment quite as facile as we would like them to be. And I think partly because of that, many oncologists are feeling overburdened partly with these various administrative tasks they have, partly with frankly keeping up with their own specialty areas or if they're community-based general oncologists, just keeping up in general with the new information that's coming at them. And then add on top of all of that the emotional toll of caring for patients with cancer. And not surprisingly, perhaps I think we have started to see, certainly we have experienced an exodus of some oncologists in recent years who've decided to pursue careers outside of direct patient care and oncology. And those included some moving into other areas of academia, some going into industry, some going into various tech companies and so on. Are you concerned that we all struggle in the effort of building and support a resilient oncology workforce to meet the needs of this growing population that you mentioned? Dr. Lawrence Shulman: Yeah, I'm very concerned about that, John. And I think one way to think about this is that as you say, the practice of oncology inherently is a stressful and difficult, though quite rewarding way to spend your professional career. But we layer on top of that a lot of frustration and difficulties that really don't need to exist. And when I think about this, I think about really two buckets. There's a bucket of factors that are within our control in an individual institution or an individual practice, and I'll come back to that in a minute. The other bucket are external forces, things that are required by the government regulators, by the payers that need to be done in routine practice. We have less direct influence over those, though I think it's a profession, we need to think hard about how to influence the external factors as well. At the practice level, there are a lot of things that we can do. One has to do with optimizing our electronic health record, which does have, in most cases, the ability to have it customized by institution in a way that would make it optimal. And some of that again, is external because we're dealing with a vendor product that has some limited ability to be customized, but we need to do a better job of the technology that underlies our practice every day when we go to clinic. The other major factor in support, whether it's advanced practice providers, nurses, medical assistants, navigators, and other personnel who can in fact help to support the patients, help to support their families, and help to support the clinicians who are on the front line trying to care for these patients. And we all use the term, practicing at the top of your license and aspire to that. But I think frankly we don't do a great job in that regard, and we need to really think harder about how we do have the appropriate team around us. In addition, I would say that there are a lot of other things at the practice level that we need to think about, including the facility of ordering radiologic studies and consultations and so on, all of which are often more cumbersome than they should be. We really need to not put these obstacles in the way of our clinicians. Externally, I think we need to get the payers and to get the government CMS to understand that the current state, it's just not going to be viable going forward and they need to make some big changes. And I think one of the ways to think about this is that rather than doing something differently, you want to do a different thing. I mean, they really need to make some paradigm changes and what's required day in and day out from our clinicians. Dr. John Sweetenham: Absolutely. So, I want to pick up on something that you mentioned there, which is the role of navigators and the benefits that navigation, patient navigation, can have in several domains, but certainly it can help to reduce the burden on oncologists and strain in the system in general. But to take that a little bit further, I wonder if we could talk a little bit about how navigation can help in reducing care disparities. You were saying before we came on the podcast today, the concept of using patient navigators to reduce disparities in care is not new. It's been around for many, many years, but it seems like we almost have to keep relearning that they really help in terms of reducing various disparities which may be rural disparities, racial and ethnic and so on. There are plenty of data out there, as you've mentioned, just to quote a couple of studies, there was the ACCURE trial published a couple of years ago now, which was really a multi-pronged intervention to help Black patients overcome obstacles to completion of treatment. And it included navigation along with a number of other interventions, electronic health record flags to alert caregivers to missed appointments, providers to missed appointments, I should say. It also included physician champions to help engage the health care teams and some educational interventions as well with a significant impact on the access to care from Black patients. The Levine Cancer Institute in the Carolinas conducted a study in my own world, in aggressive large B-cell lymphoma a number of years ago, where they showed that they were able to navigate all of their patients into guideline-concordant care, which essentially eliminated the disparity in outcome between Black and White patients in their population. And then more recently, a study from the University of Maryland looked at Black men with prostate cancer and demonstrated that with the intervention from a navigator, the number of those patients who had their appropriate genetic testing was increased enormously to levels which were comparable with the White patients in their community. No clear evidence yet that that's impacted outcome, although intuitively, I think it would, but nevertheless, as you've already pointed out, there is a ton of evidence that navigation can help us to eliminate disparities. Could you talk a little bit about your own insights into that area and the work that you've done? Dr. Lawrence Shulman: Sure. A few years ago, the National Cancer Policy Forum held a workshop on navigation in cancer and we spent a couple of days in Washington going over many of the studies you've mentioned. And one of our speakers was Harold Freeman, who was a surgeon in Harlem. About 60 years ago, he showed that patient navigation could reduce disparities in cancer care in his setting. And I think the surprising and somewhat disappointing aspect of this is, well, we have a new therapy, whether it's immunotherapy or whatever that is shown to improve overall survival and outcomes. We adopt that, and we start using it. And yet here something that's relatively straightforward, patient navigation, which has been shown as you say, to improve access to care, to improve guideline-concordant diagnostics, guideline-concordant treatment, patient satisfaction, and ultimately improve outcomes and reduce disparities, but has not been embraced in the same way that new therapies have been embraced. And from my point of view, these factors are equally important. They translate in the patient outcomes ultimately just like the therapies that we choose to. And we need to really buy into that. We need to understand that this really affects our patient outcomes as much as our therapies do. So, a couple of things. One is that you've already mentioned the different ways that navigation might improve outcomes, and that's clearly the case. But there are other aspects which are really critical to a lot of conversations we've been having, and that is that navigators fill vital roles that when they're not present are often filled by the treating physician, trying to make sure that the diagnostic tests, the genomics are all done, trying to make sure that the patient is getting their radiologic studies on time, trying to make sure that the appropriate appointments are being set up. Navigators are very, very good at doing this. They're very good at bonding to the patients and helping the patients feel secure through this cancer journey. But if they're not there, either those things don't get done or the clinician, the treating physician or the advanced practice provider is doing that. And so, it has the dual effect of both burdening clinicians who really have another role in the care of the patients doing these other scheduling and navigation functions as well as improving the overall care. I will say that in my own experience, it's important to have navigators who are skilled in their areas, that understand the diseases that we're treating, that understand the patient's needs in relation to those diseases and the treatments and diagnostics that we have to offer. So, there is a real skill to navigation, but a skilled navigator really makes a huge difference to the patient. And again, not only in the very tangible ways that you mentioned, but also frankly in the psychological security of the patient. And patients will tell you this and there are surveys out there that show this, that patients who are undergoing a new diagnosis of cancer are terrified, do much better psychologically when they have a navigator at their side through this journey. But it has tremendous benefit to the clinicians as well. And why haven't we embraced navigators? I can only speculate, but one of the comments that I get from health system administrators is, “Well, they cost a lot of money, and their work is not reimbursed as part of health care reimbursement.” But there is, again, overwhelming evidence to show that the return on investment for navigators is substantial. And it's substantial because it keeps patients in your practice, it provides more efficient care at all levels. And we published out of the National Cancer Policy Forum work, an article that basically shows from a variety of different centers, including mine at Penn, that there is a tremendous ROI for having navigators. So yeah, it's a little bit of money upfront to hire them, but ultimately, it's a good thing financially as well as clinically. Dr. John Sweetenham: Yeah. So often with these kind of wraparound services that are so important to our patients showing and being able to clearly demonstrate the kind of downstream revenue from those services is difficult, but is I think probably evident to those of us who are in the clinic and see what happens. So, maybe we need some more sophisticated financial models to be able to highlight that to our leaders in the health systems, I think that the evidence is really quite clear. So, Larry, one of the disparities that you've mentioned, and perhaps we haven't focused on quite so much in this discussion, has been the issue of cancer care for rural versus urban communities. And I think it's important that we highlight the challenges that oncologists are facing in rural communities across the country in caring for patients who live many miles away from a hospital or clinical practice and where the oncologists do not have the kind of support system that you'd find in an academic center in a major city. Can you comment a little on that? Lawrence Shulman: Sure, John. This is a real problem. I and others have published on cancer survival statistics in rural settings and in small community hospitals and they are in fact inferior to larger academic cancer centers, probably for a multitude of reasons. And one of our colleagues, Dr. Otis Brawley, made the comment a number of years ago and still repeats it, that your likelihood of surviving cancer in the U.S. is more tightly linked to your ZIP code than your genetic code. And there is some truth to that. Now, there are tremendous challenges for providing cancer care in a small, rural hospital. We practice in academic medical centers; I'm a breast cancer doctor and I spend all of my time trying to stay current in breast cancer. And it's a field that's changing rapidly. It's hard for me to imagine how my colleagues who are generalists in the community are keeping up with the advances in so many different diseases. And I think frankly, it's really, really hard to do that. In addition, all of us at academic centers have weekly tumor boards. We get to ask our colleagues what their thoughts are about our difficult cases. We get a lot of input from pathologists, radiologists, and other colleagues. And frequently clinicians, physicians, oncologists, practicing in rural hospitals don't have that constituency around them for them to bounce difficult patients off of to try to figure out what the best approach might be for a patient. So, the differences are terrific, and the support is just not there. This is something that our country has not really confronted. We have a very big country geographically. Some of the areas of the country are quite rural. A patient can't be expected to travel four hours in each direction to an academic cancer center. We need to figure out how to better partner between our academic cancer centers and our community colleagues to support their care in ways that we've not done routinely up to this point. I know that the National Cancer Institute is very interested in this and trying to figure it out. But again, I think we have to feel a collective responsibility to support our colleagues in the community. They try really hard, they're working really hard, they're doing the best they can, but they just don't have the support that we have in academic cancer centers. Dr. John Sweetenham: Yeah, sure. Before we wrap up the podcast today, I'd like to circle back a little to something that you said earlier and a topic that I know that you've published about quite extensively in the past and that's the issue of health care technology. And I think we probably all agree that health care's been a little bit slow to capitalize on technology to improve our care processes and outcomes. And your research has highlighted that technology can facilitate patient-clinician interactions in a number of ways through augmented intelligence, texting, chatbots, among other things. Can you tell us a little bit about this, how you think that AI might be able to help us in the future to streamline the management of some of these medical and administrative issues that we've been talking about today? Dr. Lawrence Shulman: Sure, John. It's hard to turn the TV on or read a newspaper without an article on artificial intelligence. But the word you used is the word that I use, which is augmented intelligence. I don't think we're looking to replace clinicians with technology, but we're looking to in fact make their jobs easier, to remove some of the tasks that they don't need to do themselves as really an assistant, if you will, another assistant. We have used technology extremely poorly in the medical profession overall. I'm not quite sure why that is. But if you look at the banking industry or other industries, they've used technology tremendously well with great benefit, benefit not only for the people who are using the services, in our case, the patients, but also those who are providing the services, in our case, the clinicians. So, I think we need to do a better job. We need to have electronic health records that are in fact helping rather than sometimes hindering or making frustrating the care of the patients. We need to use artificial intelligence or augmented intelligence to interact with patients and help to manage them. We're using augmented intelligence chatbots to manage patients who are on oral chemotherapy able to do a lot of the tasks that normally the clinicians would be doing without in any way jeopardizing the safety or the well-being of the patients. The patients actually tell us that they like this, that it's just another way to feel connected to their practice in a way that's efficient and easy for them through texting rather than sometimes trying to call the practice, which can be frustrating. But there are lots of other things as well in analyzing data, bringing data forward that will help us to make the appropriate decisions. And one of the things that I often use as an example is the airline industry. And they have a remarkable safety record as we all know, thank goodness. But if you sit in the cockpit of an airplane and you look at the instruments, all the critical data is right in front of them, unencumbered and very clearly presented because they need those data to fly the plane, and they need those data to be rapidly and easily accessible. They can get all the data they need; you look at the cockpit ceiling, it's got a thousand switches on, everything they need is there, but the critical data is never hidden and always presented. I don't think that that in fact is the way our electronic health records are set up. In fact, quite the contrary. And all of us spend a fair amount of time looking for data and so on because the records are complicated, and they're used by a lot of different specialists. But we can use augmented intelligence to bring all the critical data up, just like the cockpit in an airplane, to make sure that we have what we need rapidly accessible, and we don't miss anything. We don't go looking for the genomic test and can't find them and then assume they weren't done and make a decision without critical data when in fact they were done, but the data is hidden. So, I think we have a lot of options to use technology to improve our daily lives. I think it will take away some of the frustrations that lead to burnout, and we'll also make practice not only more efficient, but frankly also much safer. I think we have to work hard on this. We could partner with that technology colleagues. We at Penn are trying to do that. I know others are trying to do it as well. And I think the patients will benefit, will all benefit. Practice will be better, safer, less frustrating, and the outcomes of the patients will be better. Dr. John Sweetenham: Yeah, thanks Larry. I think your analogy with an aircraft cockpit is so perceptive and I think that that's something if we could unclutter our electronic health records and what we're seeing in front of us in at the points of care in the clinic, I agree 100% that will be such a step forward. So, thanks for sharing that. Thanks also, Larry, for discussing some of these challenges that we're going to be confronting in the next year and beyond, as well as the potential solutions. I think one thing that is really important to remember despite these challenges is something that I mentioned in the introduction to the podcast today. So, when we are all feeling a little bit disheartened because of the challenges ahead of us, it's important to remember that in 2026 there will be an estimated 20.3 million cancer survivors in the United States, which really does underline how far we've come, certainly in the time that you and I have been practicing oncology, and really important not to lose sight of that. We had a lot of challenges, but really the achievements of the last 50 years or so are pretty remarkable. It's been a real pleasure to have you on the podcast today, so thank you again for joining us and for sharing your thoughts with us. Dr. Lawrence Shulman: Thanks so much for having me, John. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. For more information on Dr. Shulman’s research discussed in this episode, please see the articles below: The Future of Cancer Care in the United States—Overcoming Workforce Capacity Limitations | Health Care Workforce | JAMA Oncology | JAMA Network Developing and Sustaining an Effective and Resilient Oncology Careforce: Opportunities for Action - PubMed (nih.gov) Re-envisioning the Paradigm for Oncology Electronic Health Record Documentation by Paying for What Matters for Patients, Quality, and Research | Health Care Reform | JAMA Oncology | JAMA Network Survival As a Quality Metric of Cancer Care: Use of the National Cancer Data Base to Assess Hospital Performance - PubMed (nih.gov) Establishing effective patient navigation programs in oncology - PubMed (nih.gov) Patient Navigation in Cancer: The Business Case to Support Clinical Needs Cancer Care and Cancer Survivorship Care in the United States: Will We Be Able to Care for These Patients in the Future? - PMC (nih.gov) Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:      Dr. John Sweetenham  Dr. Lawrence Shulman     Follow ASCO on social media:       @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn       Disclosures:      Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness     Dr. Lawrence Shulman: Consulting or Advisory Role: Genetech Research Funding (Inst.): Celgene, Independence Blue Cross
12/7/202326 minutes, 19 seconds
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Solutions and Key Research to Advance High-Quality Cancer Care

Drs. Cardinale Smith and Raymond Osarogiagbon discuss key research featured at the 2023 ASCO Quality Care Symposium, including the role of AI in quality measurement and solution-focused approaches addressing care delivery, financial toxicity, and clinician well-being. TRANSCRIPT Dr. Raymond Osarogiagbon: Hello. I'm Dr. Raymond Osarogiagbon, your guest host of the ASCO Daily News Podcast today. I'm the chief scientist at the Baptist Memorial Healthcare Corporation and director of the Multidisciplinary Thoracic Oncology Program and the Thoracic Oncology Research Group at the Baptist Cancer Center here in Memphis, Tennessee. I have the distinct delight of serving as co-chair of the 2023 ASCO Quality Care Symposium. And I am delighted to welcome my colleague, Dr. Cardinale Smith, who served as chair of the Symposium. Dr. Smith is a professor in the Department of Medicine and Geriatrics and Palliative Medicine at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York. Today, we'll be discussing solutions and key research to advance high-value, high-quality cancer care that were featured at the Symposium. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Dr. Smith, it's great to be speaking to you today. Dr. Cardinale Smith: Thank you. I'm excited to be speaking with you as well. Dr. Raymond Osarogiagbon: The Quality Care Symposium featured many novel approaches in care delivery, including innovative ways to advance health equity through supportive oncology. As a specialist in geriatrics and palliative medicine, your work has focused on supporting the needs of patients with cancer. What are the innovations in supportive oncology that you were excited about at the meeting? Dr. Cardinale Smith: I think we had several really fantastic sessions [on supportive oncology] at the meeting. One of the key things that came up around innovations in palliative care delivery was a roundtable discussion (“Innovations in Palliative Care Delivery for Structurally Marginalized Populations: A Roundtable Discussion”), and the speakers really focused on community-engaged approaches to the delivery of palliative and supportive care interventions. During the discussion, the speakers talked about utilizing the community voice and incorporating that into work to describe and enhance models of care delivery.  Dr. Manali Patel discussed her work on the transformative impact of patient navigators who focused on palliative care skills, in particular, communication, symptom discussions, and how that contributed to the improved outcomes of patients with advanced cancer. They saw reductions in mortality, lower acute care use, greater palliative care and hospice use, and lower total costs. Dr. Mao discussed a virtual mind-body fitness program to reduce unplanned hospitalizations among patients undergoing active cancer treatments. And Dr. Irwin presented her results of a randomized trial of patient-centered collaborative care for adults with serious mental illness who were newly diagnosed with cancer. I think these discussions just really centered on centering patients and focusing on supporting their care. And then finally, I was really excited to hear Dr. Deborah Mayer of UNC Lineberger Comprehensive Cancer Center, who received the Joseph Simone Quality Care Award, and she spoke about her distinguished career and how we can do better for our patients and ourselves (“Reflections on Improving Cancer Care: How Can We Do Better for Our Patients and Ourselves”). And what stood out for me was her recognition of the importance of “teaming,” and she really talked about acknowledging that before there was terminology for it. And it struck me because it remains so critically important in terms of how we advance the science and delivery of cancer. Dr. Raymond Osarogiagbon: Yeah, that Joseph Simone Award was amazing; I’ve got to tell you that Manali Patel's presentation blew me away. The video of the veterans talking about end-of-life care and the tough decisions, how they got to work, man, chills down my spine.  Dr. Cardinale Smith: Yeah, and I think what's even more incredible is that the folks who were helping to lead those conversations were not people who spent an incredible amount of time going to school to learn how to do this. They were folks from the community who were just engaging with people and conversations about their values. Dr. Raymond Osarogiagbon: What an original way to tackle the wicked problem. Just amazing. So improving clinician well-being was also a key topic at the meeting. Speakers addressed oncology workforce shortages and novel approaches for improving team-based care delivery. So, Cardi, what are your key takeaways from these sessions (“Building Clinician Well-Being Through Team-Based Care Delivery”) Dr. Cardinale Smith: Improving team-based care delivery is essential as the health care system can feel fragmented for patients, and, honestly, for us as clinicians as well. I think my takeaway [from this session] is that there has to be an organizational and systems-based approach to really improving this issue if we're going to make meaningful and impactful change. We were presented with data that shows that this really isn't a one size fits all approach, and what might work for physicians as a group does not work for APPs or nursing. And we really have to think about all of these different groups based on what they need.   Caroline Schenkel from the ASCO Center for Research and Analytics (CENTRA) presented impactful data on the state of the oncology workforce. And that data really assessed changes in the well-being of US-based ASCO physician members and compared the responses today in 2023 to a decade ago. And unfortunately, burnout and satisfaction with work life integration appears to have significantly worsened. And while that's not really surprising, it's disappointing. There were some factors that contributed to joy in work life, and that was speaking with and advising patients, as well as enhanced practice support inclusive of administrative patient care and staffing. So I do think that gives us some information that we can use to go forward to focus on strategies we should be really encouraging and leaning in towards. Dr. Raymond Osarogiagbon: I think it was Dr. Subbiah in this session who made the point – it's not just yoga, right? Don't tell people, “Go do yoga and get happy at work again.” You have to tackle the fundamental cause of the problem, which is this crazy workload and additional tangential obligations that we have that have taken over the core mission of patient care. Dr. Cardinale Smith: Absolutely. No one needs another pizza party. Dr. Raymond Osarogiagbon: Isn't that the truth? Dr. Cardinale Smith: I want to ask you some questions. I'm going to turn the tables on you now.  Dr. Raymond Osarogiagbon: Sure. Dr. Cardinale Smith: So let's talk about some emerging technologies. We had a session on artificial intelligence at the meeting that specifically focused on how AI will potentially impact quality care. Ray, tell me, what are some of your takeaways from these presentations? Dr. Raymond Osarogiagbon: Yeah, so AI, obviously, is a hot topic in this day and age. I had the privilege of chairing the session, “The Promise and the Perils of Artificial Intelligence (AI) in Oncology.” So we had a nice group of speakers. We had Danielle Bitterman from Dana-Farber telling us what AI is and what it promises to be for us. And then Andrew Hantel, who co-chaired the session with me, did a wonderful job describing for us the perils of AI. And then Julian Hong told us how AI promises to do all kinds of wonderful things in radiation oncology, so the huge promise of AI from back office to front office across this full spectrum of oncology, be it radiology, radiation oncology and so on and so forth, were covered.  And I would strongly urge that anybody who listens to this podcast should go to that session. Andrew Hantel talked about perils, for example, this AI black box. We don't really understand when [the AI black box] tells us this is the thing, this is the answer to your question, how does it arrive at that? How can we tell that the answers we're getting are correct or incorrect? And if we were wanting to validate, how do we go back, to do so is a real problem. And then one of the take-homes was, “You can call it all the things you want, but it's still fundamentally garbage in, garbage out.” So this machine learning, if the material fed into the machine is garbage, the answers you'll get back will still be garbage. And we had Dawn Hershman present a wonderful panorama of how AI is just another tool. It's not a panacea. We’ve still got the same problems. It's a new tool and we're still going to have to apply it using the same frameworks as we have always applied in all of science today.  And then there was an abstract that was presented from the UK as the young lady Bea Bakshi presented a paper, Abstract 74, “Accuracy of an AI Prediction Platform in Predicting Tumor Origin in a Real-World Study.” I would urge anybody who's interested in this to go back and watch that. Dr. Cardinale Smith: I was waiting a bit for them to talk to me about how the bots were going to take over, but I guess we're not quite there yet. And Dr. Lee Fleisher also added a lot of commentary. He was the former chief medical officer and director of the Center for Clinical Standards and Quality at the US Centers for Medicare and Medicaid Services (CMS). And he gave the keynote lecture, “Measuring and Driving Quality in the Future.” What did you think about some of what he had to add to this conversation? Dr. Raymond Osarogiagbon: Yeah, it was an interesting keynote. It was certainly one of the highlights of the program. He talked about measuring and driving quality of care in the future. And the thing that struck me was how he covered the full spectrum of the topics that we dealt with in the Symposium, including AI, which was quite remarkable.  Dr. Cardinale Smith: Yeah, I agree. I think he really did add an incredible amount to the conversation, and I think as much as we think CMS has control over so much of what we do, so much of it is controlled and regulated that in the end, they are just a body that oversees. And I think he really talked about that and hit that home.  Dr. Raymond Osarogiagbon: The one thing that struck me one of the throw away comments he made was how few physicians there were at CMS. What was it he said? Was it 30 something, 40 something on the regulatory side? Dr. Cardinale Smith: Yeah, it was less than 40, high 30s. Dr. Raymond Osarogiagbon: Surprising.   Dr. Cardinale Smith: Yeah. There aren't that many physicians that actually work there and yet they are driving so much of the decision-making.  Dr. Raymond Osarogiagbon: Yeah. Wow. So Cardi, let's talk about the session, the very beginning. I think you introduced that session on day one, “The Perfect Storm of High Cost Novel Therapeutics: Are We Leaving Patients Out? Dr. Cardinale Smith: It was an incredible way, in my opinion, to start the conference. I think that the speakers really came out strong, setting the stage on really the perfect storm. I think as we are developing more high-cost novel therapeutics, the first speaker, Haley Moss, talked about how all of these approvals are leading to these accelerated pricing of drugs and how really this is unsustainable. We continue to get new and new drugs that are working, right? I mean, we have longer life expectancies for patients with cancer.  Dr. Raymond Osarogiagbon: That's the good news, but somebody has to pay for it. Dr. Cardinale Smith: Correct. And the longer you live, the harder it is to be able to sustain this and people are going into bankruptcy for it. And then Arjun Gupta came in and talked about really thinking about these supportive care drugs and supportive care meds, and how we tend not to think about those medications, but they are medications that are not highly regulated and yet also are very costly. And I think what stood out for me most from the panel and this discussion was really the patient herself, Dr. Kelly Shanahan. She is a physician, an OBGYN who no longer practices and was diagnosed with metastatic breast cancer. And she really talked about how cancer put her into near bankruptcy and the cost implications to someone who we would consider in the top echelon of the financial spectrum.  Dr. Raymond Osarogiagbon: Yeah. You want to know what my favorite abstract was at this? It was Abstract 300, titled “Nationwide analysis of legal barriers impacting patients with cancer and caregivers.” Dr. Cardinale Smith: Okay, tell me about it. Dr. Raymond Osarogiagbon: Qasim Hussaini talked about how he had access to a unique data set of patients calling in for free legal assistance after diagnosis of their cancer. I was in awe of the uniqueness of his [and his co-authors’] approach. I don't think I've ever seen anybody tackle this problem in such an original way. I learned a lot from it, and I would definitely recommend that people go take a look at this Rapid Oral Abstract.  Dr. Cardinale Smith: Yeah. In fact, while we were sitting there in the conference, I was texting the director of oncology social work at my own institution and asking her if she heard of the organization that he worked with.   Dr. Osarogiagbon:  Yeah.  Dr. Smith: I'd like to highlight the last great session for our listeners. And it was really the last session of the conference, “Promises and Pitfalls of Liquid Biopsy Cancer Detection Tests in the Asymptomatic Population.” And I know sometimes folks don't always get to see or hear the last session. So, I would strongly encourage folks to check it out. I liked the session because it highlighted where we are in terms of thinking about diagnosing cancers among those who are asymptomatic. And it also highlighted a lot of questions that we have in terms of what we do with those results and who should be the responsible parties for that information? Does it fall to the primary care group? Does it fall to oncologists? And I think it was good to know that this is something that's top-of-mind for NCI and that they're really putting together a toolkit to think through this and to package that together for clinicians.  Dr. Raymond Osarogiagbon: I have to give you credit, Cardi. This was fabulous. The meeting was from end to end, just superb, and the attendance was record-breaking. Congratulations.  Dr. Cardinale Smith: Thank you. You are a fabulous partner. We had wonderful committee members, and the ASCO staff, as usual, is amazing. Dr. Raymond Osarogiagbon: Yes. We have to do this again in San Francisco next year.  Dr. Cardinale Smith: I'm looking forward to it.   Dr. Raymond Osarogiagbon: Thank you, Dr. Smith, for coming on the podcast to give us these highlights from the 2023 ASCO Quality Care Symposium. Our listeners will find the links to the sessions that we discussed on the transcript of this episode. Dr. Cardinale Smith: Thank you, Ray. It was my pleasure. Dr. Raymond Osarogiagbon: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you.   Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:  Dr. Cardinale Smith @cardismith Dr. Raymond Osarogiagbon @ROsarogiagbon   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Cardinale Smith: Honraria: AstraZeneca Speakers’ Bureau: Teva Dr. Raymond Osarogiagbon: Stock and Other Ownership Interests: Lilly, Pfizer, Gillead Honoraria: Medscape, Biodesix Consulting or Advisory Role: AstraZeneca, American Cancer Society, Triptych Health Partners, Genetech/Roche, National Cancer Institute, LUNGevity Patents, Royalties, Other Intellectual Property: 2 US and 1 China patents for lymph node specimen collection kit and metho of pathologic evaluation Other Relationship: Oncobox Device, Inc.
11/9/202317 minutes, 41 seconds
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How to Implement Universal Germline Testing for CRC

Drs. Shaalan Beg and Priyanka Kanth discuss the readiness, logistics, and barriers to implementing universal germline multigene panel testing for colorectal cancer (CRC) following new guidelines from the National Comprehensive Cancer Network that recommend genomic testing for all individuals with CRC younger than age 50. The experts also address other areas of unmet needs as new data emerge on moderate-risk genes and their association with CRC. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science 37 and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Last year, the National Comprehensive Cancer Network, or NCCN, updated its guidelines on colorectal cancer (CRC), recommending that all patients with colorectal cancer who receive a diagnosis before the age of 50 have multigene panel testing and that multigene testing should also be considered for patients 50 years of age and older with colorectal cancer, regardless of a personal or family history or other criteria. This represents a huge paradigm shift in the screening and care of patients with inherited cancers. And today, I'm joined by Dr. Priyanka Kanth, an associate professor of medicine and the director of the GI Cancer Prevention Program at MedStar Georgetown University Hospital in Washington, DC, to discuss new research that explores the readiness, logistics, and barriers associated with the implementation of universal germline testing in clinical practice.  You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Dr. Kanth, it's great to have you on the podcast today. Dr. Priyanka Kanth: Thank you, Dr. Beg. It's wonderful to be here today and discuss this very exciting topic. Dr. Shaalan Beg: As a gastroenterologist who sees patients and families with a high risk for GI cancer, including medically underserved populations, can you comment on the significance of the expanded NCCN guidelines for colorectal cancer? Dr. Priyanka Kanth: Yes, absolutely. So this is, I would say, a big change from NCCN recommending pretty much every colorectal cancer patient can undergo multigene panel testing or universal. So everyone who's younger than age 50 and has colon cancer should get multigene panel testing. But we are also expanding it to pretty much anyone who may have colorectal cancer, and we can offer multigene panel testing. So, we are broadening the pool of patients who can get tested, and this will bring in more patients from very different demographics. So I think it will expand to every arena of patients with different insurance profiles, underserved, and, as more insurance companies and Medicare/Medicaid picks up, I think this will help a lot more patients in not only following on their genetic testing, but also their family members.  Dr. Shaalan Beg: Medical oncologists are very familiar with the challenges of implementing somatic molecular testing for people who have cancer. I can only imagine that implementing universal germline testing also has significant logistical challenges and barriers. You recently published a study in JCO Precision Oncology along with your colleagues and captured some interesting perspectives from clinicians on their practice of implementing universal genomic testing for colorectal cancer. Can you tell us more about this? Dr. Priyanka Kanth: Absolutely. So I would first like to thank the lead authors and senior authors of this study. They are Linda Rodgers-Fouche and Sanjeevani Arora and Rachel Hodan, who literally wrote the study and created and did all the legwork. And as you know how hard it is to do these big survey studies, so really thank them.  The study is a cross-sectional survey of the members of this Community Collaborative Group of America, IGC, which I would say comprises a lot of genetic counselors, gastroenterologists, oncologists, and colorectal surgeons who take care of these patients. So these are highly specialized groups that work in the field of GI genetics. Roughly 300 plus members were sent the survey to get their take on how they think [multigene panel testing] can be implemented for all colorectal cancer patients.   So to give you a synopsis of the study, the majority of members who participated, 70% or more, they supported this universal germline testing for colorectal cancer patients. But interestingly, more than 50% also thought that it will require a change in their practice or how this will be delivered. So that's the major takeaway, I would say. We are all supportive but how to really deliver to the patient would be the biggest challenge or barrier for us in the future.  Dr. Shaalan Beg: So, your study reported concerns on knowledge among non-genetics providers. I would assume that includes a lot of clinicians who are the first people to be in contact with potential patients who would require testing. How can the field mitigate this problem? And what are some alternate delivery service models for increasing awareness and making the process of ordering and following up on the results more efficient for practices? Dr. Priyanka Kanth: We all know the biggest barrier I would say is resources like who's going to deliver the added pool of patients that get genetic testing. So most of the current scenario, they're all seen by genetic counselors, but we have a limited number of genetic counselors and they cannot truly deal with this big influx. So how to educate non-genetic providers would be the biggest barrier. But also implementing in the system itself, like can we do pretest counseling as the first contact with the patient to deliver to discuss like you should undergo genetic testing. So that contact, can that be done with a non-genetic provider or even by other modes like telemedicine? Or can we do something like an online chat box or something which could just not only go over all the types of testing but opens the door for the patient to ask questions. So if there are alternate modes of delivery where the pretest is taken care of, that would be one big change required.   The other part is like when the test is done, who returns the results? So where does it go and who explains the results? So at that point, we surely need more genetic and even non-genetic providers if they are comfortable. So how to educate them would be the biggest barrier. At that point, I think, we are still figuring out the biggest change is in the system and requiring a take from all the stakeholders who are part of taking care of these patients. So not only genetic counselors, but oncologists, gastroenterologists, pathologists who are taking care of this patient to be on board and have a really clear-cut flow of how these are delivered, how these results are returned, and how they are explained to family members. Dr. Shaalan Beg: The workflows and the resources that you have in a high-risk GI clinic at a center like Georgetown’s, I think it's safe to say, are much more than what typical resources a practicing provider will have in the clinic. How do you envision clinics resourcing for this type of test either through training or retraining their existing staff or by adding additional resources?  Dr. Shaalan Beg: At the community setting, it is really hard to educate essentially everyone as well. So, I feel like taking the load off the genetic counselor at the pretest level is the biggest implementation or change that can be done. And if we can remove that because not every patient is going to be positive for the gene mutation either; it does filter many patients who eventually will need returns. So at that place, how do you implement and where do you implement is the key and it is so system-based that I cannot even pinpoint. But I agree, bigger academic centers have better advantages and a knowledge base as compared to smaller community cancer centers or practices. Dr. Priyanka Kanth: Yeah, and I noticed that many of the respondents in your survey agreed with offering multigene panels, but there was variability by profession, and I was wondering if that resonated with you and that was an expected finding or not. Dr. Priyanka Kanth: Yes, and it was more so in terms of standardized multigene panel versus customized panel. So, this is fairly understandable because the genetic counselor is so well versed in offering which genes should be tested based on family history, but a non-genetic provider may not be fully equipped with the knowledge. So for example, myself, I do GI genetics, but if I have a patient with a lot of breast cancer in the family, I do defer them to a high-risk breast team. So there are nuances, too. The major difference here was also in standardized multigene panel, most of the gastroenterologists, oncologists were all for it compared to customized, which were more heavily leaned by the genetic counselor based on family history. And I can see why it's different because standardized, I would say, is much easier to implement and compared to customizing, which is based on family history or other cancer history and family. That's the major difference in the study. It comes down to education and experience and the follow-up based on what comes back from it.   Dr. Shaalan Beg: You've highlighted many factors, both from the pre-test, sort of preparing and selecting the right individuals, to ordering the right test based on the participant's risk factor profile and then optimal ways of following up on the results of these genomic tests. What are other areas of unmet needs when it comes to genomic testing for colorectal cancer? Dr. Priyanka Kanth: We know a lot about high-risk genes that are associated with colorectal cancer. We still are finding and learning about many genes, many moderate-risk genes, and their association with colorectal cancer. We don't have enough data or long-term cohort data to understand how they truly affect their lifetime risk for colorectal cancer and how do we truly surveil these patients. So that's one of the big barriers. Genetics still cannot explain all colorectal cancers. So as we get more data, we may discover more things and more genes that may be associated. But understanding these moderate-risk genes and their association with colorectal cancer would be, I think, one of the key areas to be looked into in the future. Dr. Shaalan Beg: And I would imagine as new biomarkers are identified, there will need to be a strategy to retest people who may have had genomic testing in the past. Dr. Priyanka Kanth: Absolutely. We are already encountering that in a practice. I have patients who have been tested maybe 10 years ago and just had Lynch mutation tested and were negative for that or so, and now we have so many other genes which are associated and also to understand family history changes. So, as family history changes, there might be clues to say that, “Okay, we should expand the panel or we should add these patients.” So it is a very dynamic situation. There could be a scenario in which we have a lot of patients who may need to be retested based on their current situation or even based on changing family history and the availability of genetic information. So, when I see a patient, I also tell them if we don't find anything or we are not doing anything major, we say, “Let's regroup in 3 to 5 years, let's see where we are,” or even with the risk mutation for some of the moderate-risk genes, we may change in a few years. So, revisiting that with these patients is highly useful. Dr. Shaalan Beg: So, is it safe to say that as of 2023, if we're seeing people in our clinic who have not had testing in the last 3 to 5 years, that they should have a discussion for repeat testing today? Dr. Priyanka Kanth: Yes, in terms of certain, I would say, newer polyposis genes in the GI world that have been included, some other moderate gene mutation which we have a little bit more sense of now and it has not been tested, I think that can be expanded. Five years is a safe bet. Last 2 to 3 years, maybe not so much, but you can revisit this. Also, some patients were tested for a smaller gene panel. So not 2 genes, but maybe 10 genes were included. That would probably still stand true. They may not need 70 gene panels, so it's still good to review that in the current scenario, and every few years, every 5 years, I would say.   Dr. Shaalan Beg: Whenever I think about any type of new test that has logistical challenges, has costs associated with it, and has operational demands of the clinic, I think about its disparate effect across different populations based on race, ethnicity, geography, demographics. Can you talk a little bit about how these guideline changes, what type of impact they may have, positive or not, for comprehensive genomic testing for colorectal cancer across different populations?  Dr. Priyanka Kanth: Yes, I think this is more positive than negative. This will include more patients and include more family members who were not being included, who were being missed. As we know that one of the reasons to do this multigene panel testing was the criteria, the family history criteria or the risk prediction models are not perfect. And the recent studies have shown that not every family member, every patient, is going to fit in these criteria. So we are getting more and more data in recent years that I think the much better, long-term option is to do a multi-chain panel and find it because we are missing patients. So it will increase the pool [of patients to be tested], and that will surely increase patients from all demographics. And as we do it more, there will be more buy-in from the payers and hopefully, this will decrease disparity. The problem, I think the negative part is how do we deliver it to everyone? If it is there but we are not able to deliver and that there is disparity on who gets the test and who does not, then that will create another disparity in a sense that it's there and we could have used it, but it's not being delivered. So the pros are we can include everyone, but how to include everyone is the big question. Dr. Shaalan Beg: So, Dr. Kanth, there are indeed challenges ahead in our pursuit for universal germline testing for colorectal cancer. I'd like to thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast.   Dr. Priyanka Kanth: Thank you very much for having me here. It was great to talk to you, Dr. Beg. Dr. Shaalan Beg: And thank you to our listeners for your time today. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:   Dr. Shaalan Beg @ShaalanBeg   Dr. Priyanka Kanth @priyanka_kanth   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook  ASCO on LinkedIn    Disclosures:   Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Priyanka Kanth:  Patents, Royalties, Other Intellectual Property: Methods and Compositions for Predicting a Colon Cancer Subtype
11/2/202315 minutes, 16 seconds
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Changing the Gut Microbiome to Improve the Efficacy of Immunotherapy

Drs. Diwakar Davar and Ben Boursi discuss the role of the gut microbiome in the outcome of cancer immunotherapy and the prevention of immunotherapy-related adverse events, as well as compelling research on nutritional interventions to improve response to immune checkpoint inhibitors. TRANSCRIPT   Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center.   Researchers have shown that microorganisms in the gut can impact the effectiveness of immunogenic chemotherapy for patients with cancer. Although microbial therapies for cancer are still at a very early stage of clinical development, compelling research in recent years has shown that changing the gut microbiome can help improve outcomes in patients receiving treatments for cancer enduring immune checkpoint inhibition.  My guest today is Dr. Ben Boursi, a GI medical oncologist at the Sheba Medical Center at Tel Aviv University in Israel. Dr. Boursi is also an adjunct professor at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania. He joins me today to discuss his pivotal research on the role of the gut microbiome in mediating its effects on immunotherapy. And again, I want to highlight that we're recording this on October 9th, and as you may well know, many recent events over the last couple of days have happened in Israel, and so Dr. Boursi has joined us at a very difficult time. So, we're very grateful for him taking time out of his suddenly very busy schedule to join us at a time that is fraught for all. You'll find our disclosures in the transcript of this episode. You'll also find the disclosures of all guests on the podcast at asco.org/DNpod. Ben, it's great to have you on the podcast today. Thank you for being here at such a difficult time, sharing what will, I think, be a great episode.  Dr. Ben Boursi: Thanks for having me, Diwakar. Dr. Diwakar Davar: Ben, the gut microbiome and its role in terms of mediating effects and side effects of cancer immunotherapy has gotten a lot of interest recently. You've done some fundamental work in this space. Why don't you briefly summarize for the audience, firstly, what is the gut microbiome and what are the major themes in relation to cancer immunotherapy?  Dr. Ben Boursi: Well, the microbiome is the ecosystem of microorganisms, bacteria, phages, fungi, that are crucial for immunologic, metabolic and hormonal homeostasis of the host. In the last decade, we began to understand the central role of the gut and tumor microbiome in tumorigenesis, metastasis, treatment efficacy and toxicities, and in 2022, polymorphic microbiomes became one of the hallmarks of cancer, in addition to previous hallmarks that focused mainly at the cellular/genetic levels. The initial studies in mice models showed that therapeutic efficacy of immunotherapy depends on both the presence and composition of the microbiota (In germ-free or antibiotic treated mice, immunotherapy is ineffective), and following these studies, three observational studies in human patients showed that the gut microbiome can predict response to immunotherapy and that response to immunotherapy could be transferred to germ-free mice by fecal microbiota transplantation (FMT) from responding patients.  These studies helped us to define three main research questions regarding the possible role of microbial modulation in cancer treatment. First, can microbial modulation overcome resistance to immunotherapy, both primary and secondary resistance? And this question was the focus of the initial proof of concept studies. Second, can microbial modulation improve response to immunotherapy in treatment-naive patients? And third, can microbial modulation prevent or treat immune related adverse events? The initial positive results of clinical trials also led to additional questions. For example, can microbial modulation induce anti-tumor immune response even in non-immunogenic tumors? And it is important to note that there are many ways to modulate the microbiota, but so far, the only reliable way that showed positive results is fecal microbiota transplantation that allows the transfer of the entire microbiota both in terms of composition and relative abundance. Dr. Diwakar Davar: That’s great. Essentially with the trials that I think the data sets that you're referencing of course, are papers by Jennifer Wargo, Thomas Gajewski, and Lawrence Zitvogel, looking at the role of gut microbiota in several different cancers, primarily immune checkpoint sensitive tumors such as melanoma, non-small cell lung cancer and kidney cancer. And then the work from several different groups showing that essentially proof of concept experiments can be done to try to change this, certainly preclinically, and now we know that that can be done clinically.   So, I guess the failure rates of immunotherapy in some patients are quite high. And we know that the microbial composition can change the likelihood to respond to immunotherapy based on all these trials. And actually, even going back to 2015, we had two seminal papers that looked at the role of CTLA-4 blockade as well. But subsequently, many years after that, 7 years after 2015, and certainly 3 years after 2018, when the three observational PD-1 papers were published, there were 2 pivotal trials in PD-1 advanced or refractory melanoma. They demonstrated that changing the gut microbiome can reprogram the immune system to attack tumors. So, there were 2 separate trials, both published the same issue of Science. One trial was led by your group at Sheba, and another one's led by us, the University of Pittsburgh. Why don't you summarize both studies for our audience. Dr. Ben Boursi: So, both studies were Phase I clinical trials of FMT in metastatic melanoma patients who failed immunotherapy. Recipients were metastatic melanoma patients that progressed on at least one line of anti PD-1 and in BRAF mutated patients, BRAF inhibitors as well. Donors in the Sheba study were metastatic melanoma patients with durable complete responses to immunotherapy for at least one year, and in the Pittsburgh study, you also included patients with durable partial responses of more than two years as donors. It is important to note that each fecal transplant in both studies was composed of a single donor. Prior to transplantation, we performed a microbiome depletion phase using a combination of two antibiotics, vancomycin and neomycin. The goal of this phase was to assist in engraftment (by avoiding colonization-resistance by recipient bacteria) and to “reset” the immune system, which may remind some people of the logic behind bone marrow transplantation. In the Pittsburgh study, there was no bacterial eradication with antibiotics, mainly because of studies showing that response to immunotherapy is lower following antibiotic treatment.  Both studies performed FMT through colonoscopy. At Sheba, we also performed maintenance FMT using capsules in order to keep the donor's microbial composition. After the initial FMT, both studies reintroduced the same immunotherapy in which the patient progressed in the past. Clinically, we have seen a 30% response rate with durable, complete and partial responses, and in the Pittsburgh study, there was a 20% response rate and 40% disease control rate. Both studies showed following FMT, immune response in the gut and in the tumor, and tumors that were immune deserts prior to FMT became infiltrated with lymphocytes. Interestingly, in our study, there were no moderate to severe immune related adverse events following FMT and reintroduction of immunotherapy. And this is despite the fact that five of the patients had significant side effects during previous rounds of the same immunotherapy.  Dr. Diwakar Davar: So essentially, in these very early proof of concept studies, what I think is pretty remarkable is that obviously the sample sizes were very small, but remarkably, patients that appeared to respond, responded in a setting in which they were not expected to respond. So, the probability of a patient responding to attempt at giving PD-1 in patients who were PD-1 relapse refractory is on the order of about 7%, based on an FDA analysis by Viva et al. And here, two separate studies, two independent studies, investigators had not known that each paper was being published, remarkably similar results clearly demonstrating that this is perhaps one of the best pieces of evidence to suggest that microbiome modulation may actually truly be effective in reversing PD-1 refractoriness.  More recently, our colleague Dr. Bertrand Routy at University of Montreal has done a proof of concept trial in evaluating the use of healthy donor fecal microbiota transplant in addition to anti PD-1 monotherapy in PD-1 naive metastatic melanoma. In this study, published in Nature Medicine a few weeks ago, his group reported an objective response rate of 65%. What are your thoughts about this study? And specifically, what are your thoughts about some of the pharmacodynamic and translational results that were demonstrated?  Dr. Ben Boursi: This is a very interesting question, because in both the Sheba and the University of Pittsburgh studies we chose responding patients as donors. We thought that by using these patients, we provide beneficial bacteria that enhance responses to immunotherapy through several mechanisms (molecular mimicry, immunomodulatory bacterial metabolites, modulation of immune checkpoint expression, and much more), and here in the Routy paper, the researchers used FMT from healthy donors without any selection for specific beneficial bacteria, and they demonstrated a similar effect on overall response rate. So maybe FMT works actually through reducing colonization by deleterious bacteria? Another question that we should ask is whether we need to choose donors differently when we use microbial modulation in treatment resistant patients compared to treatment-naive patients? Moreover, a previous meta-analysis of FMT studies across indications that was conducted by the group of Dr. Nicola Segata, demonstrated that recipients with better engraftment were more likely to experience clinical benefit, and that increased engraftment was mainly observed in individuals receiving FMTs through multiple routes, colonoscopy and capsules, as well as recipients that received antibiotics prior to FMT. But in Routy’s trial, they not only used healthy donors, they performed bacterial cleansing only prior to FMT instead of bacterial eradication with antibiotics, and used FMTs through colonoscopy only, and they didn't give maintenance FMT. Of course, such an approach is much more feasible in the clinical setting and is relevant for designing future clinical trials.  Dr. Diwakar Davar: So, many differences, relatively few similarities, but I guess one interesting point is that of engraftment, which is that in your paper, our paper, and certainly in Bertrand's paper, it is very interesting that engraftment appears to be a key pharmacodynamic biomarker of microbiome modulation. And certainly, the analogy that you used earlier, which is that it's very similar to what happens in a stem cell transplant, which is that if there's no take, there's probably not going to be any effect. So that's very interesting that engraftment is emerging as a key PD biomarker of essentially the success of any kind of microbiome modulation across multiple different settings.  Now, we've heard of certainly defined microbial consortia, of cultivated species, as an alternative gut microbiome modulation strategy that balances the benefits of the ecological complexity of FMT with the scalability and practicality of probiotics. Do you think we are ready to design consortia?  Dr. Ben Boursi: So to date there are several probiotics that use a single bacteria and several microbial consortia that were evaluated in clinical trials, and as you mentioned, they may offer more tractable solutions for widespread clinical use. If we begin with the single bacteria probiotics, two phase 2 clinical trials found that administration of the butyrate producing probiotic clostridium butyricum 588 (CBM588) to immunotherapy naive patients with metastatic renal cell carcinoma led to markedly better immunotherapy responses, although the probiotic had a minimal effect on the composition of the microbiota, and the control arm of the trial responded worse than expected. In addition, in preclinical studies, probiotic strains of lactobacillus and bifidobacterium have been shown to enhance immune control of transplanted tumors and to augment anti PD-1 activity. However, a clinical trial in patients with metastatic melanoma found that the use of lactobacillus or bifidobacterium probiotics was associated with reduced microbiota diversity and worse responses to anti PD-1.  So here the conclusion is that when we try to design probiotics, we should not focus only on the composition since other factors, such as the relative abundance also matter. Too much of a beneficial bacterial species may potentially be worse than having a balanced and diverse microbiota. For example, a recent study of patients with non-small cell lung cancer receiving immunotherapy found that patients with a detectable Akkermansia muciniphila in their gut microbiota (this is a beneficial bacteria) responded well to treatment, but those with relative abundance of Akkermansia muciniphila greater than 5% responded worse than patients lacking Akkermansia, and this is due to the mucolytic effect of the bacteria. So, the use of rationally designed consortia may be better than a single probiotic strain.  And there are currently 3 main microbial consortia that are being evaluated: the SER-401, a bacterial consortium enriched with clostridium, led in a randomized controlled trial to reduced response to immunotherapy compared to placebo control in first line metastatic melanoma patients, potentially due to a confounding effect of a vancomycin pretreatment; MET4 is a 30 bacteria consortium that was shown to be safe and to alter the gut microbiota and serum metabolome of immunotherapy naive patients. Here, the initial study was underpowered to determine the effect on treatment efficacy; And finally, VE800 is an immunotherapy enhancing 11-bacterial consortium that is currently being evaluated in phase 1 and 2 clinical trials, and we are looking forward to see the results with this agent. Dr. Diwakar Davar: So I guess where we are right now is that social design is clearly difficult because of all the reasons you've mentioned. The SER-401 data and the MET4-IO trials certainly give us pause for thought. Certainly, no pharmacodynamic changes that were seen with SER-401, MET4-IO did result in pharmacodynamic shifts metagenomically, but neither trial was positive. And certainly, the VE800 trial, which has been ongoing now for several years, and the lack of publicly reported data certainly doesn't suggest that there's a huge efficacy signal. So consortias, at least at this point, certainly do not appear to be having a significant effect, though we don't know what might happen in the future. Data from multiple groups has shown that gut microbial composition influences the development of immune related adverse events (irAEs) in both PD-1 and combination PD-1 and CTLA-4 treated patients. Unsurprisingly, as a result, there have been attempts made at evaluating the role of fecal microbiota transplants to treat refractory immune related adverse events and very specifically immune checkpoint associated colitis or IMC. So, Dr. Yinghong Wang, who is the chair of the Immunotherapy Toxicity Working Group at the University of Texas MD Anderson Cancer Center has been very prominent in this space, and in a recent paper published in Science Translational Medicine, which is a follow up paper to her early work in Nature Medicine, she reported that HDFMT, healthy donor fecal transplantation, was very efficacious in feeding early refractory immune checkpoint colitis. So, what are your thoughts on this approach and how important is this space and where else might it be efficacious?  Dr. Ben Boursi: When I talked about the Sheba clinical study, I mentioned the possible role for microbiota modulation in the prevention of immunotherapy related adverse events in general, not only colitis. But the study by Dr. Yinghong showed that FMT can actually treat immune-related colitis refractory to steroids and anti-TNF. Now, this approach is probably relevant not only for immune related colitis, but also to other immune related adverse events. We can define certain bacterial species that may be associated with different immune related events. For example, streptococci can be associated with immune related arthritis. And maybe in the future we won't need to use FMT, but we will rather be able to target these specific immunogenic strains by narrow spectrum antibiotics or phages. The main challenge would be to develop microbiotic targeting interventions that reduce immune related adverse events without compromising therapeutic efficacy.   Now, is microbial modulation relevant only for toxicity from immune checkpoint inhibitors? So, the answer is ‘no’. We know mainly from animal models of hematopoietic cell transplantation, CAR T, and immune agonist antibodies that antibiotic-treated or germ-free mice have markedly reduced immunotoxicity, such as graft versus host disease, cytokine release syndromes, and more. It is also worth mentioning that microbial modulation is relevant not only for reducing toxicity from immunotherapy, but also from chemotherapy and other anticancer modalities. And the best example is the gastrointestinal toxicity of irinotecan that is mediated by the bacterial beta-glucuronidase. And here the targeting may even be a bit less complex. Dr. Diwakar Davar: So, what we take away from that is that starting with actually your paper originally, and papers to be produced, immune-related adverse events can be prevented using microbiome modulation with FMT, and Dr. Wang's data suggesting that eventually FMT can be used to eradicate highly refractive colitis, again, this is important to keep in mind that this approach is not yet FDA-approved. It's being done under IND. It's not currently something that is a certain standard of care. One interesting area of drug development is that there's a French microbiome company named MaaT Pharma where they have an agent that is a very interestingly a pooled microbiome product from multiple different donors. Again, the trials in both Israel and Pittsburgh used individual donors. This is a pooled donor construct. The lead candidate is actually graft versus host disease. The trial is the ARES trial, A-R-E-S, as in the Roman god of war. This trial is actually ongoing in Europe, and I believe there's some effort to try to see whether or not it's going to be a trial that can be done in the United States as well. So, at this point in time, again, we don't know whether or not there are any developmental approaches from a pharmaceutical company in the United States, but certainly this is definitely an area of interest.  So microbial therapies are still relatively early. It's going to be interesting to see how the advanced field of nutritional interventions provide an appealing method for modulating the gut microbiome due to the excellent safety profile, cost effectiveness and noninvasiveness. And certainly, if you are what you eat and your bacteria are what they eat, which goes down to our diet, there's enough rationale to believe that certain nutritional interventions can have an effect via the intermedial gut microbiota modulation. Holistic dietary changes and or supplementation specific nutrients such as prebiotics could therefore be utilized to specifically shape the population of beneficial microbes and shift the immune microbiota landscape. Now, we have seen in data published by several of our colleagues that in patients with cancer, high fiber intake is associated with greater microbial diversity, greater abundance in fiber fermenting microbes such as members of the Ruminococcaceae family, and these are all associated with the response to checkpoint inhibitor therapy. So, what do you think about nutritional interventions? Do you want us to briefly summarize data regarding nutritional data and where it stands in cancer at his time? And can you speculate as to how effective this might be in the context of patients with cancer? Dr. Ben Boursi: So, let's begin with diet. A growing number of clinical and preclinical studies suggest that specific dietary interventions such as a high fiber diet can not only improve response to immune checkpoint blockers, but also reduce immunotoxicity such as graft versus host disease. And there are many other diets that are being tested such as ketogenic diets and intermittent fasting. And the effects of diet may be mediated by both microbiota-dependent and microbiota-independent mechanisms. The limitation of this approach is that changes to the microbiota induced by diet are generally quite variable between patients and can depend on an individual's microbiota prior to intervention. And patient compliance is also a concern, particularly in the very strict diets.  Now, regarding high fiber diets, several large cohorts of melanoma patients from the US, Australia, and the Netherlands demonstrated how a high fiber diet modulates the microbiome and results in a better response to immunotherapy, better progression-free survival. Additional studies that were presented at AACR in 2023 showed that high fiber dietary interventions, in which patients received a fiber-enriched diet for six weeks, was feasible and that the high fiber diet resulted in a rapid shift in the gut microbiota toward fiber-responsive short chain fatty acid-producing taxa and a shift of the metabolome, with increase in the short chain fatty acid acetate, Omega-3, Omega-6, polyunsaturated fatty acid, and tryptophan metabolites. Prebiotics can also promote the growth of beneficial microbial species in the gut by providing targeted nutrition. And one example of a prebiotic that was shown to enhance immunotherapy efficacy in mouse models is castalagin, which is isolated from the camu-camu berry. Castalagin directly binds the outer membrane of ruminococci and promotes their growth, which has been shown to increase the CD8-positive T-cell activity and anti-PD-1 efficacy. Now, since prebiotics rely on the presence of beneficial taxa already in the host microbiota, symbiotics, which refers to the administration of the appropriate prebiotic and probiotic together, may prove in the future to be more effective than using either separately. Dr. Diwakar Davar: Certainly, these dietary interventions can be very exciting and certainly we do know of several colleagues who are doing these diet interventions, though compliance with any kind of dietary intervention may be a challenge that decides how effective such an approach is going to be. So microbial therapies in general are still at a relatively early stage of development. And it'll be exciting to see how they advance. What approaches are you excited about? What is on your radar?  Dr. Ben Boursi: There are many exciting works that are currently ongoing, and to emphasize just a few: there are many clinical trials in immunogenic tumors, in addition to melanoma, for example, renal cell carcinoma, and non-small cell lung cancer, that also evaluate different modulation protocols. We should remember that one size does not fit all, and different tumors have different microbiomes. We have a project in collaboration with MD Anderson in MSI-high patients with exciting initial results. Another study that was initiated at Sheba is using microbial modulation in order to improve TIL therapy (to overcome resistance to TIL and T-cell exhaustion). There are also studies that try to change the pharmaco-microbiome, for example, to eradicate bacteria that inactivates the chemotherapy agent, gemcitabine, in pancreatic cancer patients. And there are groups that try to identify recipients that will respond to microbial modulation and to generate better donor-recipient matching algorithms. There are already signatures like TOPOSCORE that was presented at ASCO 2023 that try to predict response to immunotherapies through the ratio between harmful and beneficial bacteria. Now, there’s also more basic science work, for example, bacterial engineering. There was a wonderful study from the Fischbach group in Stanford that demonstrated how Staphylococcus epidermidis engineered to express melanoma tumor antigens was able to generate a systemic tumor-specific response in mice models when applied topically; functional imaging of the microbiome, for example, FDG uptake in the colon can reflect microbial diversity and response to immunotherapy; works that characterizes other microbiomes such as the urinary and skin microbiomes, and their interaction with the gut microbiome; and studies of the nonbacterial component of the microbiome, mainly phages and fungi. But for me, the most important word should probably be collaboration, because without joining forces internationally, we won't be able to understand the human metaorganism, the variations according to geography, ethnicity, lifestyle, diets, and much more in the microbiome. And this is crucial in order to really understand the complex tumor ecological niche within the human host. Dr. Diwakar Davar: I think one of the key points that you just mentioned is collaboration. That's going to be very, very critical as we move this forward for many reasons, including the unexpected impact of geography upon the composition of the gut microbiome in work that has been published by many groups, but also including ours in a paper that we published about a year ago now.  So, Dr. Boursi, thank you for your great work in this area. Thank you for sharing your insights with us today on the ASCO Daily News Podcast. This is a very difficult time for all of you and your colleagues in Israel, and we thank you so much for taking such a great deal of time out of your busy workday to spend some time with us.  Dr. Ben Boursi: Thank you very much. Dr. Diwakar Davar: Thank you to all our listeners today. This is a very exciting area. This is an area where we are discovering more every day than we knew just up until the day prior. You will find the links to the studies that were discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take the time to rate, review, and subscribe wherever you get your podcast.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:   Dr. Diwakar Davar  Dr. Ben Boursi   Follow ASCO on social media:   @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Ben Boursi: No relationships to disclose.        
10/12/202328 minutes, 25 seconds
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Navigating the Complexities of Next-Generation Endocrine Therapy in HR+ Breast Cancer

Drs. Hope Rugo and Nancy Davidson discuss the next generation of endocrine therapy in hormone receptor-positive breast cancer – SERDs, SERMs, CERANs, and PROTACs – and challenges relating to the optimal sequence of therapeutic options. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. Hormone receptor-positive (HR+) breast cancer is the most common subset of this disease and breast cancer is the most common cancer diagnosed in women worldwide. Endocrine therapy (ET) is the cornerstone of management in hormone receptor-positive breast cancer and may involve suppressing estrogen production with aromatase inhibitors in the cancer cell itself, or directly blocking the estrogen receptor pathway through selective estrogen receptor modulators, such as tamoxifen, or the injectable selective estrogen receptor degrader, fulvestrant. However, despite the availability of these therapies, the largest unmet need lies in treatment of HR-positive HER-negative disease lies after progression on endocrine therapy. On today's episode, we'll be discussing the emerging generation of endocrine therapies in breast cancer, some of which were designed to overcome common mechanisms of endocrine resistance, and the challenges relating to the optimal sequence of therapeutic options. Today, I'm delighted to welcome the world-renowned breast cancer researcher, Dr. Nancy Davidson, to the podcast. She's a professor and the executive vice president for clinical affairs at the Fred Hutchinson Cancer Center and professor of medicine at the University of Washington as well as past president of ASCO and AACR. You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Nancy, it's great to have you on the podcast today. Thanks so much for being here. Dr. Nancy Davidson: Thank you so much, Hope, for the opportunity. Dr. Hope Rugo:  You've done incredible work in the area of treating HR+ disease, but also in understanding some of the agents and pathways that are most important to our understanding of how we treat and really think about developing new drugs for HR+ breast cancer. The first generation of anti-estrogen drugs really included selective estrogen receptor modulators, but now we have a new generation of these anti-estrogen drugs. And there's also orally administered selective estrogen receptor degraders, so-called SERDs, that we hope someday will be an alternative with already one approved for the injectable SERD, fulvestrant. But there's a whole additional class of drugs, complete estrogen receptor antagonists, referred to as CERANs, and proteolysis targeting chimerics, PROTACs. These agents are all at various stages of development in both early and metastatic settings and really represent, I think, a confusing array of different treatments that are being studied, some of which of course are approved. Nancy, it would be great if you could tell us some about these exciting new agents, starting with our approved drugs and moving on to the agents that we're studying in clinical trials. Dr. Nancy Davidson: Hope, this is a terrific example of how basic science has really begun to inform clinical practice. For us as breast cancer practitioners, it was really easy for a long time because we only had tamoxifen. And then things like the aromatase inhibitors as a means of decreasing the estrogen ligand came into practice, as did fulvestrant, as you mentioned, a selective estrogen receptor degrader. Thanks though to a lot of understanding about estrogen receptor biology, and specifically, the discovery about a decade ago of estrogen receptor mutations, something that we didn't think exist ed for a long time, but which we now know exists in maybe a third to a half of breast cancers after exposure to aromatase inhibitors, that's led to really an explosion, this alphabet soup of possibilities that you talked about. SERMs, selective estrogen receptor modulators, tamoxifen is the classic one—something that acts as an agonist and as an antagonist, depending on the tissue. The SERDs, the selective estrogen receptor degraders, lead to estrogen receptor destruction. Fulvestrant is the classic example of this right now. But we're very excited that a second one has been FDA approved. That's elacestrant that was approved earlier this year, and it has specifically been developed to try to target those estrogen receptor mutant breast cancers because those are the ones that are particularly resistant. So that's the first of this new generation of SERDs that's coming on the market, has come on the market. As you say, a key advantage there is that it's oral, unlike  fulvestrant, which requires 2 monthly injections and is very, very inconvenient and uncomfortable for patients. Other SERDs are coming along. I think another one that is well along in clinical development is giredestrant, which is in the same family and being tested in clinical trials of the classic varieties. It's been tested in a window trial, looking at its ability to down-regulate Ki67. It's being tested against standard of care in first-line metastatic breast cancer. And there are some studies that are going to begin looking at it in the adjuvant setting as well. There are other members of this particular family, but I think that elacestrant is the one that we have at our fingertips right now, and giredestrant is one that's certainly coming along in clinical trials, and we should look forward to those results. For those who are interested in the giredestrant, the trials in question right now that are going on are persevERA, which is in stage 4 breast cancer, and lidERA, which is in the adjuvant setting. Now that's one new category, or it's an old category with a new twist. A second is these agents that are called complete estrogen receptor antagonists, CERANs, as you talked about them. The key here is that what they do is, the estrogen receptor has a couple of domains, and in particular, it has 2 different activation domains, AFT1 and AFT2. And these CERANs are complete estrogen receptor antagonists, so they block both of those domains. And the hope would be that they might end up being more effective than the other agents that we have available to us right now. So those are also in clinical trial at the present time, and we're waiting to see whether or not there's going be any value in that particular area that's going to able to go forward for us.   Another area that I think we want to talk about is the PROTACs, as you mentioned. These are proteolysis targeting chimeric entities. So, this is a kind of a complicated situation where you have a kind of bivalent situation where you have something that binds both to the estrogen receptor and then also to E3 ubiquinase. So, it leads to degradation again of the agents; that's another area for us to be watching. And then finally the SERCAs. So those are the selective estrogen receptor covalent antagonists, and what they do is they bind very specifically to a cysteine 530 that exists in the estrogen receptor but not in other steroid receptors. So that's where the selective part of this comes along. Now these are all in various stages of clinical investigation. Some of them are pretty early at this point, but I think the ones that are well established are elacestrant, giredestrant is coming along as we just talked about. Camizestrant is also coming along through the SERENA series of trials, and imlunestrant is also coming on through the EMBER series of trials. Hope, I would also be remiss if I didn't go back to an old drug that's a new drug, and that's lasofoxifene, which is also in the SERM family. Those who have been in our field for a while will remember that lasofoxifene was actually originally kind of tested in the prevention setting, where it seemed to have some activity. It came back into our interest because it has really strong activity against estrogen receptor mutant breast cancer models in the laboratory. And as a consequence of that, it's coming back into the clinic through a series of trials that are called the ELAINE trials, where we're looking to see whether or not it might also be better than fulvestrant. It too is an oral agent, so that's a real plus for us, and the first set of ELAINE trials would suggest that there's some nice activity without a lot of toxicity. So, lots going on in this field. You know, I think for all of these things, obviously, we're also working very hard to think about the toxicities. All of these, as I recall, are oral agents. So that gets rid of  1 huge toxicity, which is you don't have the need for some sort of injection. But they all do have some side effects. Frequently, [the toxicities] are like GI side effects or fatigue. In a couple of cases, there might be some concern about cardiac arrhythmias, but I think GI turns out to be one of the most important things that we have seen in some of these trials. Generally, it’s very well tolerated, though. I think another important question, which I'm sure is in your head and is in mine, is that how are we going to integrate these into what we already have? And so, I think a lot of the work right now is looking at patients who have already received an aromatase inhibitor plus a CDK4/6 inhibitor and are now going on to one of these new agents. But you might wonder, if they turn out to be effective and well-tolerated, whether they too should be perhaps combined with CDK4/6 inhibitors in place of the aromatase inhibitors or the fulvestrant that we use now. So, I think that we can imagine that those clinical trials are either in progress in some cases or will be coming on as we try to think about how to integrate these new approaches into our existing standard of care, which is already quite complicated, right? We've gone far from tamoxifen, which was good for everybody, to now a really complex algorithm about how we think about hormone therapy, both in early breast cancer and in metastatic breast cancer.  Dr. Hope Rugo: Well, that was a fabulous discussion about the new agents and our existing agents and both the exciting aspects, as well as the challenges. One question that comes up, I think a lot, and this is of course a huge question in many ways, but for ER-positive metastatic breast cancer, where these drugs are first being tested, maybe we'll talk about that first. There's one trial at SERENA-6, looking at camizestrant in patients who have developed evidence of an ESR1 mutation in circulating tumor DNA, who are on first-line therapy with an AI and a CDK4/6 inhibitor. What do you think about that study and where do you think that progress might go? Of course, that's based on data from another trial, which wasn't definitive, but suggested, had sort of a suggestion, you know, without studying the sequencing in detail that maybe you would have improved progression-free survival with that approach. Dr. Nancy Davidson: Yeah, by which you mean the idea of monitoring pre-ESR1 mutations and circulating DNA and then making therapy changes based on that? Is that what you’re talking about? Dr. Hope Rugo:  The PADA-1 trial, yes, and that led to this huge SERENA-6 trial, which of course is now accruing. Dr. Nancy Davidson: So, you know, we would love that, right? I think that obviously breast cancer for many years has been interested in trying to have circulating markers that we could use to help to guide our therapy in a more meaningful way than we have in the past. And I think that the trial that you've talked about is certainly one that's trying to make that see whether that's a possibility for us based on information like the PADA trial. I'm hopeful it's going to work out. I would say, let's see what that looks like, whether it's going to be useful or not. It seems to me in some cases, some of these trials have not been quite what we hoped for, but I don't think we necessarily had the molecular techniques or the sensitivity, nor did we necessarily have other things to move to because, you know, those two approaches require both a really good test, but also the ability to use the test to define a new therapy that's going to lead to improved patient outcomes. And I think that these are ingredients that we now have available to us at our fingertips more than we did, say, a decade or 2 decades ago. Exciting approach. Dr. Hope Rugo:  I do think there's a lot of challenges inherent in this process, monitoring blood on a regular basis and following up and then randomizing based on results. But I think [SERENA-6] is an incredibly important trial, as you have mentioned, to try and think about moving past using circulating tumor cells, which didn't work, to just change blindly to the next therapy, but more have a rational reason to change to a drug that may be more effective before the disease itself progresses. And just for our listeners, the unique aspect of trials like this in SERENA-6 is that you change therapy before you have evidence of disease progression, but only this molecular evidence of a mutation that is associated with resistance to the therapy you're on. So, it's a really important question. We'll see what happens, as you mentioned, sometimes we're not clever enough to really get around the fact that there are multiple mutations driving resistance in this setting, so we'll see how straightforward this is. The question also comes up, and I think that's a question with many of these trials now, is they're randomizing patients after a progression on an AI and CDK4/6 inhibitor to receive the novel endocrine therapy or fulvestrant. One of, I think, the concerns of treating oncologists is that then you're sort of eliminating the possibility of a targeted agent in that setting. And of course, we have new targeted agents we're studying as well, AKT inhibitors and new inhibitors of the PI3 kinase pathway. So, the newer trials are now combining, as you mentioned. There's a lot of concerns about drug-drug interactions here and how you might really combine them. And then there are triplet studies looking at CDK4/6 inhibitors, oral SERDs primarily, and pi3-kinase and CDK4/6 inhibitors. What's your thought on these and will they really help to move the needle forward? Dr. Nancy Davidson: I think that's a really interesting question, Hope, is whether or not we're going to find that combination therapies from the get-go are the way to go, or whether we're going to end up having to use maybe more serial therapies. Because not only is it a question about whether or not you can tackle all of these different resistance mechanisms simultaneously, but I think the other question is, as you say, are there negative drug-drug interactions, and are there toxicities that are intolerable? Although these are targeted in all cases and they're relatively benign in terms of side effects from the breast cancer perspective, they're not devoid of toxicity. And so, I think that's going to be another issue for us – whether they're well tolerated during the time that patients are taking them. I guess the other thing I always think about, Hope,  is that it's hard to know about value of cancer care, but you know, we are talking about agents that are not inexpensive. You know, when you think about the financial toxicity, in addition to the side effect toxicity that you and I just talked about, trying to think about what that value is going to look like is going to be very important for us. Also, as somebody who worked for a long time in the lab and in the clinic, you know, there are an infinite number of combinations that you and I could think about that are rational. And so, the question is, how are we going to pick the ones that are the most rational, if you will, the ones that seem to be the most promising, and take them forward into clinical trials? Because patients are our most precious resource. And so, we want to make sure that we are bringing forward only those things that really seem to have a very strong foundation and the opportunity to improve outcomes over time. Tough, tough question for us to try to think about, as you've talked about. The other thing is that, you know, these trials are not only for postmenopausal women, who are the majority of patients, but we also want to target them to premenopausal women. So, in those women, we're also looking at using an LHRH agonist on top of this, right, because many of these things are really at least so far designed for the postmenopausal state. So stay tuned. Lots of work going on. I think one of the interesting things will be making the leap from using these in metastatic disease at time of progression to taking them forward into the early breast cancer space. And several of the agents are now beginning to do that because of very strong preclinical and clinical data to date. Dr. Hope Rugo: So, we have new agents that we're studying in the metastatic setting, and we've seen a trend to move fairly rapidly from phase 1B trials directly into phase 3 trials, because as you pointed out so clearly, there are a number of drugs in this setting, and we don't really know not only which agent is better, but even what class of agents is better. So, as we move more quickly from phase 1B to phase 3, the question comes up about how we're going to study these agents optimally in the early-stage setting. They, I think we all thought that maybe changing based on ctDNA evidence of a mutation might be an approach, but that's complicated. A big question for you is whether or not you think that's ready for prime time as it's being marketed as such. And then the second question is really, are we better changing our whole approach upfront in high-risk disease or should we wait until after patients are exposed to their endocrine therapy and then switch as we go along; the EMBER-4 trial is looking at that switching approach? Dr. Nancy Davidson: Yeah, I think that this is obviously the billion-dollar question for many companies and for many of us as investigators. I don't know that I have a crystal ball into what the best approach might be. We know that already some of these have been abandoned. For example, amcenestrant. So, I don't even have to learn how to say it because it has been abandoned. It did go to phase 3, as you pointed out, in the advanced setting, looking at it with palbo vs letrozole plus palbo, and it didn’t really show a whole lot that the company wanted to pursue.  So, I think that sometimes these things are going to be abandoned based on the metastatic setting, which is a large trial, and that’s a trial where obviously it might be a little easier to the circulating markers, as you talked about, than maybe in the early-stage breast cancer setting.  I think that probably these early-stage trials are going to end up being big; they’re going to have be clean. I’m guessing that most companies and most investigators will want to target them towards high-risk individuals, as you talked about, for 2 reasons. One is that ethically, I think we feel more comfortable with that. These are individuals where standard therapies are maybe not serving them as well as we would like and where we have information to think that we can at least have equipoise about a new approach. And the second is that from a trial design point of view, the event rate is likely to be higher, and therefore you might get answers earlier and with a smaller clinical trial. So that's where I suspect we're going to go. But it's a challenging question, and I think that many investigators and many companies are really trying to struggle with that right now because we do have so many options. And we're not quite sure how to, first, develop these new drugs, but then really importantly, put them in the context of our existing drugs. And as you say, we're also simultaneously trying to develop superior molecular or circulating markers to guide us. So, there's so many variables that are going on right now in this field that, from my point of view, itmakes it really exciting, but it also makes it pretty complicated, both for investigators and for pharma as we try to think about how to position these going forward. But what a great problem to have, Hope, because remember when you and I started in breast cancer, pretty much all you needed to know was tamoxifen. And I think you and I also probably started at the tail end of the time when we were using androgens and progestins and agents that now have basically completely fallen out of favor. Dr. Hope Rugo: Estrogen Dr. Nancy Davidson: Estrogen, yeah, and your side effect profiles were not as good. So, it's a good problem to have. It's a nice situation when science can inform our clinical investigation, our clinical practice. Dr. Hope Rugo: Yes, I think it'll be fascinating to see where we end up at the end, but of course, the complexities of this include the fact that sometimes just the clinical trial design leads to a less than positive result because of the way the trial itself has been designed, which I think is the nice part about moving these earlier into treatment of high-risk disease, but also brings up the question of all sorts of areas we’re not really a place to discuss today, like how the statistical design is made, et cetera, that can sometimes result in poor evaluation of excellent agents. One of the questions that comes up, and you brought this up earlier, which I think is really important, is that we are in the era of combining our endocrine agents with targeted agents, and, oral agents, in a fascinating way, really bring up drug-drug interactions in a way that the injectable fulvestrant hasn't, and aromatase inhibitors were kind of quiet on the impacting metabolism, unlike tamoxifen. But we are seeing some drug-drug interactions and certainly the discussions about using these agents may include the question about whether or not you're having more diarrhea or nausea or fatigue or one drug causes photopsia, flashing lights, things like that. Keratitis is becoming a new toxicity to follow.  How are we going to figure out how to sequence these drugs and are they only going to work better all of them as a class in patients with ESR1 mutations in their tumors? Dr. Nancy Davidson: I think we don't know the answer to the second question yet. That's something that really needs to be sorted out. Even if they do, that's still a really important subset of patients, assuming that we continue to start with the aromatase inhibitors, right? That's where those things really seem to emerge right now. I don't know how we're going to figure those things out. I guess that I'm hoping that maybe a couple of agents in these classes will become kind of the lead agents. And so, we'll be able to do this work with a handful of things as opposed to a whole array of things. But we'll see. I think that even within classes, obviously, these agents are going be slightly different, probably. And so it may be that one member of a class may be slightly better from a, maybe not from an efficacy point of view, but from a toxicity point of view. And we'll just have to see how it goes. I don't think I have any magic answers about that. Dr. Hope Rugo: Yes, it'll be interesting to see whether or not the agents work in sequence too. You know, could you use a PROTAC after an oral SERD, for example, or a CERAN? That'll be fascinating to see. Dr. Nancy Davidson:  I'm hoping that preclinical modeling may help with that a little bit, though of course we all know that there are plenty of things that do well in preclinical models, GEMS and rodent models and PDXs, and sometimes those things translate nicely into clinical practice, but sometimes they don't. Dr. Hope Rugo: You mentioned, Nancy, that when we started out, that it was a fairly simple decision about what endocrine therapies, and we ran out very quickly. We're seeing some of those old classes come up with new agents. And you mentioned lasofoxifene, the oral SERM that seems to have some benefits and works in the later-line setting and also can be combined with a CDK4/6 inhibitor; [and also] has data with abemaciclib. There's also a new androgen receptor agonist, enobosarm, that's being tested as well. Do you think that these older mechanisms have a future as well? Dr. Nancy Davidson: I do. I think that because we'll be able to understand the biology better than we did in the past. A lot of our hormone therapy was pretty empiric several decades ago. But I think with better understanding of mechanisms and better understanding of what the patterns of resistance might be for a particular tumor, that we might be able to think about those things. You're right that there's a whole parallel universe right now in androgen receptor targeted therapies that we're not talking about today, both in perhaps in hormone-responsive breast cancers, but also in triple-negative breast cancers in a certain subset. And so that's an area where we probably need to be watching what our prostate cancer colleagues are doing as they develop these agents and thinking about where they might mechanistically make sense to apply in the breast cancer field. It won't be the first time that we've received insights from them because remember, prostate cancer people knew about androgen receptor mutations a really long time before we figured out that they existed in estrogen receptor as well. So, there's a nice cross talk, I think, between the prostate cancer field and the breast cancer field in that regard. Dr. Hope Rugo:  That's an excellent point. And we learn a lot from our colleagues studying other malignancies, and prostate cancer has been a big area there for us and hopefully will help us with studying these agents because there's different toxicity profiles, of course, as well. And then you mentioned the approval of elacestrant, the first oral SERD to have regulatory approval, and it's approved in patients who have ESR1 mutations in their tumors. We're also studying it in the ELEVATE trial in combination with all of the different targeted agents, the CDK4/6 inhibitors, mTOR inhibitor, everolimus, and the PI3 kinase inhibitor, alpelisib, to really try and understand how these can be optimally combined. Would you check for ESR1 mutations at diagnosis of metastatic disease, or would you do this more after progression or start of progression of disease on an aromatase inhibitor? Dr. Nancy Davidson: I tend to be a conservative, Hope, and so unless there's a clinical trial that might be able to be considered, I would tend to check it only after progression on the aromatase inhibitor. But I think some people are earlier adopters, and I suppose it's possible that they might want to know from the get-go. Having said that, I do think elacestrant has an approval after aromatase inhibitor, as I recall. So, presumably the patient would have to have that exposure before you would be able to act on the ESR1 mutation by administering the oral SERD. This is also a new area that may well change with time, right? You know, as we develop different agents, as the agents have different requirements or different indications, and as we perhaps have better tests, it may be things that we don't do routinely now will become very routine in the future. And perhaps in series like you talked about in a serial fashion. Dr. Hope Rugo: Absolutely. I think that's a really important comment about how we're going to think about treating hormone receptor positive disease and potentially, you know, we have new chemo options, of course, not part of our talk discussion today and antibody drug conjugates. So, the future is certainly challenging in terms of understanding this appropriate sequencing. We need data, but it's exciting to have these options. As you pointed out, this is this is a great problem to have, you know, too many drugs with efficacy to try and understand how to use these in the most appropriate way. And as you also pointed out, the use in young women is particularly important. Whether or not you need to suppress the ovaries with all of these new agents is going to be important to understand as well as a next step. I don't know if you have specific thoughts on that area as well. I mean, that may reduce toxicity for younger women. Dr. Nancy Davidson: I guess our approach right now has been to suppress them, but I agree with you; you wonder if you look at some of the mechanisms of action, whether that's really a requirement biologically and medically, or whether it's something that's kind of a leftover from the approval process. You know, that for the drug approval, these women were suppressed. I think we need to work that out because that's another area where certainly women could have ovaries removed. That's pretty straightforward, although it requires a surgical procedure. But otherwise use of LHRH agonists continues to be injections, right? And so, if we're trying to minimize convenience or maximize convenience and minimize toxicity for women with any stage of breast cancer, anything we can do, it seems to me to eliminate an injection is going to be a good thing. So important for us to be able to work that out as well, even though numerically it's a smaller number of women, it's obviously a very important number. population of women. Dr. Hope Rugo: Last question for you. One question that comes up and sent to me and panels all the time is, if you have done your next generation sequencing and you see an ESR1 mutation and a P13CA mutation, what do you prioritize in terms of your choice of treatment, because we have the choice of either using elacestrant or a fulvestrant in combination with an agent targeting the PI3 kinase pathway? Dr. Nancy Davidson: I don't know that there's a right answer to that medically right now. So, when I talk about it with patients, I suggest to them that it's probably not one or the other. It's kind of the question of which one to use first. So, we talk a little bit about side effect profiles. We talk a little bit about patient preference and neither of these drugs is devoid of problems, but sometimes patients have pretty strong feelings about which set of side effects seems the least unattractive to them or the possibility of having those side effects. And I know that if one isn't well tolerated, you can swap over to the other. Dr. Hope Rugo: Absolutely. I think that's a very important way to think about next therapies in our era of not really knowing what's right. And this idea of shared decision-making is so incredibly important. Nancy, thank you so much for sharing your insights and knowledge with us today. I could talk to you for hours about this. Dr. Nancy Davidson: Hope, thank you so much for the opportunity. It is an exciting area and I really enjoyed talking with you about what we know and the many things that we don't yet know, but we're working on. Dr. Hope Rugo: Indeed, it's certainly an exciting time. Thank you to our listeners for joining us today. And thanks to the ASCO Daily News Podcast for highlighting this important area. You'll find a link to all of the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thanks so much.   Disclaimer:    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Follow today’s speakers:     Dr. Hope Rugo  @hoperugo  Dr. Nancy Davidson     Follow ASCO on social media:     @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Hope Rugo:  Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc Travel, Accommodations, Expenses: Merck, AstraZeneca   Dr. Nancy Davidson: No Relationships to Disclose    
9/28/202330 minutes, 39 seconds
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ASCO Breakthrough: Scientific Innovations and Emerging Technologies in Cancer Care

Drs. Lillian Siu and Melvin Chua discuss scientific innovations, disruptive technologies, and novel ways to practice oncology that were featured at the 2023 ASCO Breakthrough meeting in Yokohama, Japan, including CRISPR and gene editing, CAR T-cell and adoptive cell therapies, as well as emerging AI applications that are poised to revolutionize cancer care.   TRANSCRIPT Dr. Melvin Chua: Hello, I'm Dr. Melvin Chua, your guest host of the ASCO Daily News Podcast today. I'm a radiation oncologist and I currently practice in the Division of Radiation Oncology at the National Cancer Center in Singapore. I also served as the chair-elect of the ASCO Breakthrough Program Committee, and, on today's episode, we'll be discussing key takeaways from this year's Breakthrough meeting. The global meeting in Yokohama, Japan, brought together world-renowned experts, clinicians, med-tech, pioneers, and novel drug developers to discuss scientific innovations and disruptive technologies that are transforming cancer care today. I'm joined by Dr. Lillian Siu, the chair of the Breakthrough Program Committee. Dr. Siu is a senior medical oncologist at the Princess Margaret Cancer Centre and a professor of medicine at the University of Toronto.     You’ll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.    Lillian, it's great to be speaking with you today.    Dr. Lillian Siu: Thanks, Dr. Chua. I'm happy to be here.    Dr. Melvin Chua: We were just at ASCO Breakthrough, and it showcased some incredible scientific innovations, and really showed us how technology innovations in precision oncology, biotech, and artificial intelligence are transforming cancer care. What are your thoughts?    Dr. Lillian Siu: Yeah, it was a really exciting meeting, Melvin. The theme of this year's Breakthrough meeting was “Shining a Light on Advances in Cancer Care.” And our Opening Session featured an illuminating keynote address by the renowned thought leader and tech trailblazer, Dr. Hiroshi or “Mickey” Mikitani, the founder and CEO of Rakuten and Rakuten Medical. In his address that was titled, “Innovative Technology and Oncology,” he spoke so passionately about innovation and really seeing around the corner to predict what is coming and taking risks. And I think that's what medicine is about, not just what we have in front of us, but to predict and forecast what's coming. I totally was inspired by his address, and I think a lot of the audience felt the same way. He also spoke to us a bit about his company's development in photoimmunotherapy using novel technology and light therapy in head and neck cancer. And I think that's also an area of new technology that we should watch in the next few years.    Dr. Melvin Chua: I totally agree with you, Lillian. And one of the quotes that he spoke about really spoke to my heart. He spoke about the 2 choices: whether to do or not to do and not to do is not an option. So, I think that was a very compelling message to a lot of our audience at the meeting.    So, on this same note, innovation is a driving force in oncology, and we saw countless examples of this throughout the Breakthrough meeting. Were there any sessions that really stood out for you?    Dr. Lillian Siu: There were so many exciting sessions. First of all, there is the “Drugging the Undruggable” session. This is a really important session because in the past we felt that certain cancer targets such as KRAS, MYC, etc., are not druggable. KRAS G12C is the poster child in this area. So, during this session we heard about many ways that we are now looking to target these so-called undruggable molecules in the cancer cell. And we talked about molecular glues, we talked about degraders, and really novel ways that are not yet reaching the clinic, called “cyclic peptides” were discussed by one of the speakers.     The other session that is very interesting also is CRISPR and gene editing. Obviously, we all know a little bit about gene editing, really trying to change or knock in some genes that are important perhaps to change the function. And one of the sessions talked about trail targeted induced mesenchymal stem cells, and perhaps this is a way to, again, deliver novel therapies and novel treatments to our patients. There were many examples of how CRISPR and gene editing can be ultimately going to the clinic to benefit our patients in terms of therapeutics.     I want to highlight another session, which is the CAR T-cell and Adoptive Cell Therapies. I think everybody knows about CAR T-cells, but in this session we talk about non CAR T-cells or newer things such as off the shelf NK cells, Natural Killer cells from cord blood. So, this way it is allogeneics, in other words, we don't have to rely on only a patient's donation of their samples, but actually get it from off the shelf from other donors. There are other ways to really use human induced pluripotent stem cells that we can armor them by transgenes and also CRISPR out any unwanted genes, for example, to enhance an effective function of T-cells. So many, many exciting ways to bring these cell therapies to the patients.     And last but not least, I want to highlight Dr. Chris Abbosh, who is one of our keynote speakers, talking about molecular and minimal residual disease and early cancer detection using circulating tumor DNA or liquid biopsy. He talked passionately about the TRACERx study, which he is instrumental in terms of leading together with Charlie Swanson in the UK. This is a study that really has uncovered a lot of science about cancer heterogeneity. And in that study, he also studied circulating tumor DNA and really shed a lot of light about clonal and subclonal dynamics over time that changes.     Dr. Melvin Chua: And just to touch on that point about innovation and how that translates to cancer care, I think it was great that we had those case-based applications in lung cancer, in breast cancer, and the virus-associated cancers. And I like how the speakers were able to bring in the Ying and the Yang, bring the West and the Eastern perspectives in these interactive sessions. I particularly enjoyed all of them. But the session on the lung case discussion where we know that there were this EGFR mutant lung cancers that are prevalent in this part of the world in Asia. I thought the interaction between the speakers was fantastic.     On the same note about therapies and we heard about novel therapeutics at this meeting as well. I wonder what your thoughts are about some of the sessions, and do you think some of these technologies were able to be brought into practice? And your thoughts on the novel therapeutic session that happened at Breakthrough, do you think this will actually impact clinical care?    Dr. Lillian Siu: Oh, for sure, Melvin. The 5 areas that were covered during the Novel Therapeutics session are really drugs already in the clinic. And for example, the first one was about antibody drug conjugates. We know there are now at least 12 antibody drug conjugates already approved by the FDA and many more likely to be approved in the near future. And the session really talked about what's next, how to improve upon ADC, for example, using better drug antibody ratio, talking about new payloads and really new formats that make perhaps ADCs even more potent in the future.     There was a session on oral immunotherapeutics. It was really how to target the innate immunity. And I think novel oral immunotherapeutics is very important because we all know PD-1, PD-L1 inhibitors have been the backbone, but we need another Breakthrough. And having oral immunotherapeutics will make it very attractive for patients because they don't have to come to the cancer center to receive the drugs.     Another part of that session was about T-cell engagers and bispecifics, really how to bring molecules to the T-cell, to the effective cells so that they are able to be phytotoxic to the tumor. We talked about also oncolytic viruses, how are the new ways to utilize this kind of natural agent to target the cancer cells. And lastly, we also talked about personalized cancer vaccine, which is obviously very timely. We all know a lot about vaccine now after the COVID pandemic and how do we use cancer vaccines to be a good therapeutic drug? I think especially important in the earlier disease stages as adjuvant therapy. Some exciting data, for example, in pancreatic cancer, as adjuvant really is groundbreaking for this whole topic of cancer vaccination.    Dr. Melvin Chua: That's great. And for me as a radiation oncologist who's not so deep in drug development, hearing all the talks at ASCO Breakthrough was really informative for me and I learned a lot. In particular, you spoke about the whole session there was oncolytic therapy and the results in glioblastoma multiforme, we know it's a deadly disease, was certainly very impressive. And so, it speaks to the whole notion that in fact, some of this stuff is in fact reaching the clinic and making a difference in deadly diseases. I think there's a lot to take in from there.    Dr. Lillian Siu: Melvin, you're so humble. I know you're a big expert in artificial intelligence and I think the whole session about AI applications in precision medicine really was not just in that session, but a whole theme that went throughout the entire meeting. So, I'm very interested to know what you think about some of the presentations around AI and disruptive technologies in precision medicine, such as next-generation multiomics, etc. What are your thoughts?    Dr. Melvin Chua: Absolutely, I agree with you. And there was so much material within the AI session, the multiomic session, as well as the keynote [address] by Dr. Maryellen Giger, which basically speaks about some of the pre-existing or historical work on artificial intelligence in radiology. And I'd like to first talk about the keynote by Dr. Maryellen Giger. It was very nice that she elegantly showed how AI was in fact already in practice in radiology, where it helped to fulfill or address a need for radiologists. Almost 20 years ago, they were able to show that using computer vision, you were able to basically facilitate the calling of abnormal mammograms. And it was inspiring to see how these early thoughts have now basically accelerated a lot of the advances that we see that are in practice today.     The other thing that was also was to see this global collaboration, the need for global collaboration in the artificial intelligence space and the radiologists are clearly leading the way. And I think part of the impetus for this effort came from an opportunity that arose during the COVID pandemic that clearly affected all facets of healthcare. That was a nice segue to the very sort of dense 1 hour session we had on precision oncology care with artificial intelligence. I think when we designed this session, we were very deliberate that we wanted to address all aspects of how AI could be applied. From real-world clinical data, we saw examples of how having good, well-annotated data sets could actually help to accelerate and facilitate liver cancer screening in Hong Kong. Then we also saw a very simple, practical application of AI in pathology, where apart from just having this tool to be able to extract features that could potentially predict outcomes of patients and predict drug responses, we saw a very practical example that applying AI in digital pathology could actually homogenize or harmonize the ways the pathologists review their cases. And so, I thought that was very neat and could speak to all our clinicians across both developed and developing countries.     We also saw very exciting stuff on the use of AI in terms of calling out mutations because we know that next-generation sequencing is pretty much a cornerstone of how we practice in oncology today. And yet we know that there are prohibitive costs that preclude this technology in certain parts of the world. And it was nice to see how AI could actually lower the cost of some of these sequencing technologies like being used in liquid biopsy.     And then finally, there was some fancy science as well that was showcased in the spectrum when we saw how industry as well as academics are thinking about integrating multiomic data sets to then be able to accelerate drug discovery, help define patients better, and so that we can think about how to look at precision oncology using targeted treatments for specific patient phenotypes. So I think this was a very nice transition to the Next-Generation Multiomic Technology session, where, again, some of these topics were touched on, ranging from liquid biopsies, and this was already covered in Dr. Abbosh’s talk, which you spoke about, and as well as the preceding day session where we heard snippets of it. And it was again reinforced by the speakers when it showcased liquid biopsies. We have heard so much about it in the last decade and we see it made approved now for use in the clinic, but yet so much remains unknown, like the discrepancies between assays, addressing the cost of assays and, importantly, how we deal with the information. So, I think we are just at the tip of the iceberg here. A lot of the clinical evidence needs to be generated in due course to address some of these questions.     At the same time, it was also nice to see some of the new technologies being applied in discovery science. So, we know that immunotherapy is a major player in oncology today, and the Breakthrough represents a forum whereby we're able to bring translational scientists to showcase their work. And we saw examples of that at this meeting where single cell technology, digital spatial technology, being able to apply that in pathology specimens and how the two are integrated to be able to review more novel science to us, to show us how immunotherapy works or doesn't work in some patients. Both of us have touched on so much content that was showcased at the Breakthrough, and I think this speaks to the impact, the learning experience we’ve had from Breakthrough and I think that’s the intended purpose of this meeting.    Dr. Lillian Siu: Yeah, I agree. It truly was a very exciting 3 days. And I particularly like the multiomics session where we see that the technology is so advanced just in a really short period of time. Over the last few years, we've been now able to go into single cell resolution where in the past I don't think we would ever dream of being able to do that. In fact, I recall in the single cell session, we can even see messenger RNA on the slide, which I thought was fascinating, something that I cannot imagine we can see by the naked eye. It really is an exciting time in oncology, Melvin, and the field is advancing with these new innovations and therapies, but at the same time, I think it's important that we do live globally and we need to work really also to help improve access to quality-assured cancer medicines and diagnostics in the low and middle income countries. What do you think about that part? Did we do a good job in addressing that in the meeting?    Dr. Melvin Chua: Absolutely, Lillian. We had a special session that was chaired by Dr. Peter Yu and the lecture was delivered by Dr. Gilberto Lopes from the University of Miami. And we know that he's a strong advocate for this. And the session title spoke to this topic very pointedly, “How Science, Technology, and Practice Can Be Enabled in Lower- and Middle-Resource Settings.” And I thought that the work that he highlighted, the whole ATOM coalition, was important. ATOM basically stands for Access to Oncology Medicines, and it was established last year by the UICC, the Union for International Cancer Control, along with global partners to improve access to anti-cancer drugs and to develop processes for ensuring quality delivery, as well as the optimal utilization of medicines in middle- and low-resource settings. And I think there's a lot more work to be done.     Some of the information they showed was very compelling to me from this part of the world. But we know that Asia isn’t very heterogeneous in terms of the resources, in terms of the culture. And I thought that the drug pricing, for example, how that should be addressed across the different countries is an important topic to pick up. And I hope his lecture only invigorates this conversation going forward.     Dr. Lillian Siu: Yeah. Thanks, Melvin. I totally agree. That was very inspiring. Breakthrough is such a one of a kind, international gathering that we are not only able to network while we're there; we also have a session to really allow attendees to leverage international cancer networks, to learn a bit about them, all the way from, for example, some of the North American groups to Asia Pacific groups to even global groups, and how we interact between pharma and academia, really transcending boundaries. And I think it is really, really important for us to now have these networks address issues such as equity and cancer care innovation, novel approaches and so much more. And I think, I am sure you're going to do a good job in making sure that gets into the agenda in our next year's meeting in 2024. Ultimately, we hope that these collaborations in cancer research will help to improve the outcomes for our patients with cancer.    Dr. Melvin Chua: Thank you again for sharing the great highlights of ASCO Breakthrough, and I'm really appreciative of your work, and your commitment to build a really robust program for this year. So, thank you.    Dr. Lillian Siu: And thank you, Dr. Chua. And you can bet that I will not miss Breakthrough 2024 in Yokohama in August next year. I will be there.    Dr. Melvin Chua: Okay, I'll hold you to that.     And thank you to our listeners for your time today. You'll find links to all of the sessions discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you again.    Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers: Dr. Lilian Siu  @lillian_siu  Dr. Melvin Chua  @DrMLChua    Follow ASCO on social media:   @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Lillian Siu:  Leadership (Immediate family member): Treadwell Therapeutics  Stock and Other Ownership Interests (Immediate family member): Agios    Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen    Dr. Melvin Chua:  Leadership, Stock and Other Ownership Interests: Digital Life Line  Honoraria: Janssen Oncology, Varian  Consulting or Advisory Role: Janssen Oncology, Merck Sharp & Dohme, ImmunoSCAPE, Telix Pharmaceuticals, IQVIA, BeiGene  Speakers’ Bureau: AstraZeneca, Bayer, Pfizer, Janssen   Research Funding: PVmed, Decipher Biosciences, EVYD Technology, MVision, BeiGene, EVYD Technology, MVision, BeiGene  Patents, Royalties, Other Intellectual Property: High Sensitivity Lateral Flow Immunoassay for Detection of Analyte in Samples (10202107837T), Singapore. (Danny Jian Hang Tng, Chua Lee Kiang Melvin, Zhang Yong, Jenny Low, Ooi Eng Eong, Soo Khee Chee)       
8/17/202319 minutes, 43 seconds
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How Oncologists Are Confronting the Cancer Drug Shortage

Drs. Vamsi Velcheti, Taofeek Owonikoko, and Janakiraman Subramanian discuss their experiences navigating the cancer drug shortage in the United States, the impact on patients and clinical trial enrollment, lessons learned, and proactive strategies to mitigate future crises. TRANSCRIPT  Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone. On today's episode, we'll be discussing the impact of the shortage of cancer chemotherapy drugs across the United States. This has been affecting several thousands of patients with adult and pediatric cancers and hampering enrollment in clinical trials. Among the shortages are very commonly used drugs like cisplatin, carboplatin, methotrexate, and fludarabine. Some of these shortages have persisted since the time of the pandemic in 2020.   So today, to discuss this really troubling scenario, I have two outstanding colleagues, Dr. Janakiraman Subramanian, the director of thoracic oncology at Inova Schar Cancer Institute in Virginia, and Dr. Taofeek Owonikoko, a professor of medicine and the chief of the Division of Hematology and Oncology at the University of Pittsburgh Hillman Cancer Center in Pittsburgh.   Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod.  So, a recent survey by the NCCN found that 90% of the nation's largest cancer centers have experienced a shortage in carboplatin, and 70% of the centers have reported a shortage in cisplatin. These are platinum-based chemotherapies we use frequently in patients with cancer, and these are often curative intent treatments for several cancers, and these are used in several tumor types, both solid tumors and hematologic malignancies. So, the scale of the problem is immense.   Dr. Owonikoko, I’d like to hear your take on this situation and how are you dealing with this at the UPMC Cancer Center.  Dr. Taofeek Owonikoko: Yeah, thank you, Dr. Velcheti, and happy to be part of this panel. As you rightly surmised, the chemotherapy drug shortage is what we've all experienced across the length and breadth of the United States. Our cancer center here in Pittsburgh is not an exception. We've had to be proactive as well as think outside the box to be able to manage the challenge. Just like every other cancer center across the country, maybe to varying degrees, we've had to look at patients in need of chemotherapy with these standard-of-care agents such as cisplatin or carboplatin, and to some degree docetaxel, during this past episode of drug shortage that we all went through. And while we did not have to, fortunately, cancel any patient treatment, we all went through it with bated breath; not sure of where the next batch of chemotherapy drugs will come through, but I would say in the past couple of weeks, we've actually seen some improvement in drug availability.   But before then, we’ve had to have contingency plans where, on a weekly basis, we review our patient list and the drug regimens that they're going to need, and must make sure that we have enough drug on hand for those patients. And in situations where we thought we might not have enough drug; we also had a plan to use alternative regimens. We were proactive in having guiding principles that are consistent with ASCO's recommendations in terms of quality care delivery for cancer patients. So, I'm sure that this is more or less the same approach adopted by other leading cancer centers across the country.   Dr. Vamsi Velcheti: Thank you, Dr. Owonikoko. And Dr. Subramanian, you're in a community setting, a large cancer center that serves a lot of patients in the state of Virginia. So, what is the scale of the problem at your institution and how are you handling it?   Dr. Janakiraman Subramanian: First of all, Dr. Velcheti, thanks for having me here on this panel. And as you rightly said, this is a significant problem, and it is across the country like Dr. Owonikoko said. And as medical oncologists, we are not always thinking of drug shortages. Our focus is on taking care of our patients. So, this is one more issue that we need to keep in mind now as we manage our patients with cancer. When this shortage started, the biggest problem, as you know, was when we became aware of this was primarily in cisplatin and we had some of our patients who were getting curative treatment and we had to make a decision - can they get cisplatin or can they get carboplatin. And one of the things we did was to have an ethics committee that will review each patient that is being planned to receive cisplatin-based chemotherapy and come to a decision on how best we can support them.   The template for some of this was based upon some of the triage mechanisms we used during COVID, as well as the ASCO guideline document for managing this chemotherapy shortage, which was one of the blueprints we used. And they have reviewed all cases, all patients that are being planned for cisplatin or carboplatin for that matter, and we come to a decision based on that. And we also have another committee that constantly monitors drug availability on a weekly basis and tries to forecast where the next problem would be as we take care of our patients.   And particularly as a lung cancer doctor, we've had situations where we had to use carboplatin instead of cisplatin and even we also have carboplatin shortage. And so, the committee usually approves two cycles at a time, but thankfully so far we have not had a situation where we could not offer our patients the chemotherapy treatment. But we are very carefully monitoring the situation, hoping that this will improve.   The other aspect of the shortage has been in 5FU. A lot of our GI colleagues; I treat esophageal cancer patients as well, where we've had to forego the bolus 5FU and have a 10% reduction on all 5FU infusions. And we've been using some of that dose reduction to ensure that we can have 5FU available for all our patients. And that's how we've been trying to manage this shortage situation here at Inova Schar.   Dr. Vamsi Velcheti: Dr. Subramanian and Dr. Owonikoko, we are oncologists, we are treating patients, and the toughest part really is telling a patient that we don't have access to certain drugs and we have to switch treatments to perhaps another treatment regimen that may be suboptimal. And it's always a very anxiety-provoking discussion, and especially for patients with metastatic cancer, they're already under a lot of stress and it's a really difficult conversation. How do you handle that, Dr. Owonikoko?  Dr. Taofeek Owonikoko: That's a conversation we all hope we don't have to have. And fortunately, with this current crisis, I've actually not had such misfortune of having to inform a patient that we don't have drugs to treat them or that we have to switch to something inferior. But conceptually, it's possible that could have happened and that would have been very difficult. But the one thing that we did, though, as part of our mitigation strategy was actually to inform the patient ahead of time because the way we handled this was to look at our inventory on a week-by-week basis. And if there are patients where we felt maybe they will be coming in towards the end of the week and we may not have enough drugs for them, to let them know the possibility exists that we might have to switch them to something different. While we did not have to do that for any patient, yes, there are patients that we had to give that heads up to, to say, “We're having this shortage. We're doing everything we can to make sure it's available. But just in case it's not available…” I think what is most important for most patients is to be aware of that decision ahead of time, to be able to process it, and to be transparent.   The other challenge that we face was, if you have to choose between patients, what should be your guiding principles as to who gets the drug and who doesn't get it? I think it's very easy for all of us to say, “Oh, if it's curative intent, we do it. If it's not curative intent, we don't do it.” It's a little more complicated than that because if we put the equity hat on, curative intent doesn't actually mean that that life is more valuable than somebody who cannot be cured. And this is where really, I think having people with expertise in ethics of care delivery and disaster management will be very important for us to proactively anticipate that, should this become a recurrent problem in the future that we actually have a well-vetted approach, just like we did during COVID where you have to ration resources that we have those people with expertise to help us as oncologists because not all of us, at least personally I can speak for myself, that is not my area of expertise and comfort.  Dr. Vamsi Velcheti: Excellent points. Dr. Subramanian, anything to add?  Dr. Janakiraman Subramanian: Oh, absolutely. I echo what Dr. Owonikoko said. These are conversations that we would like to hopefully never have with our patients. But this is a crisis that we are facing now. And personally, I can tell you two situations where we ran into this problem. But overall, though, we never had to stop a treatment or cancel a treatment for our patient. In the first situation, we had a young man with a rare germ cell tumor in the hospital for whom cisplatin was key. He was already in the ICU and sometimes the treatment start dates are not perfect, unlike what we do in the outpatient setting, depending on how well he's doing or the treatment start dates might move by a day or so. So we basically had to hold a certain dose of cisplatin for him.   This brings the next question, which is how do we decide who gets cisplatin versus who can go for an alternative option? And I think Dr. Owonikoko made a great point where, just because it is a curative disease does not mean their life is more valuable. This is where I think trying to make that decision at an individual level, as an individual treating physician can be extremely hard. And that's why at our institution we have this ethics committee where we have oncologists, pharmacists, and ethicists that review these chemotherapy orders, particularly for cisplatin, and try to use some guiding principles that we learned from COVID as well as ASCO's guidance to decide how we assign our resources. That's one option, one way we have done it.    And then in another situation that was faced by one of my GI oncology colleagues was a patient that was originally planned to go on a clinical trial where the chemotherapy backbone was FOLFOX and because we had the 5FU shortage, we could not offer that patient clinical trial enrollment. And that was a tough conversation where they had to tell them that they could not go on a clinical trial that they were looking forward to. And this then brings the next question, which is by foregoing the bolus 5FU and by the 10% reduction in the infusional 5FU, are we providing them inferior treatment? And it's a conversation that's had at a very individual level. I don't envy my colleague who had to have that conversation. It's a challenge and we try to do our best to communicate to our patients that we are trying to provide care without trying to compromise the effectiveness of treatment for them.  Dr. Vamsi Velcheti: Thank you so much both of you. And we had the same issues here at NYU in New York City as well. It appears, you know, the degree of shortage and the drugs that are in shortage has been somewhat different at different locations across the United States. But the theme has been that we are having to ration treatments for our patients. And of course, there are some tumor types where there's really no adequate substitution, for example, GU cancers. I mean, you can't really not give them cisplatin. A lot of these are situations which have curative intent and young patients. So, it's really troubling.   And I think one of the things that really came out of this is there's been a lot of push from professional societies that actually ASCO has been spearheading and some intense discussions with CMS and legislators to kind of provide more long-term fix for these things. And I think all of us have to be more engaged in those discussions with our professional societies like ASCO to kind of help promote awareness. So if you kind of think about it, these drugs are not that expensive. These are generic drugs that we've all been using for such a long time. And the fact that we can't provide these drugs for various reasons is kind of really concerning. We spend so much money on research and more expensive drugs and not being able to manufacture these drugs within the country and kind of having to rely on complex supply chains is troubling, and I hope the situation improves very soon.    So, I know both of you are at large cancer centers that enroll patients on clinical trials. Of course, these drugs, especially carboplatin, for lung cancer, especially, are like core treatments that are used in managing cancer patients with lung cancer. So how is this affecting your clinical trial accrual? Are you prioritizing patients on clinical trials for these drugs? Have you had to make any decisions to hold clinical trial accrual for certain trials? Kind of curious to hear.  Dr. Taofeek Owonikoko: Yeah, so I can maybe weigh in a little bit on that in terms of what we've had to do for patients receiving treatment as standard of care versus those going on clinical trials. As we all recognize that when a patient goes on a clinical trial, even if they are going to receive a standard-of-care regimen as part of that trial, it still has to be administered in line with the protocol. So, during the extreme period of shortage anxiety, we actually had consideration for perhaps not putting patients on trial if we're not sure that they will be able to continue to receive the protocol-mandated treatment, whether it's a control intervention or the experimental intervention.   The good thing to come out of this is at least here at UPMC, we actually did not have any instance where we had to deny a patient clinical trial participation. But there were anxious periods when we already had patients enrolled and they were scheduled to receive a platinum-containing regimen and we were not sure whether or not we were going to have adequate supply of the drug for them while on trial. I think this really raises an important consideration going forward as we come out of this current shortage. I don't by any stretch of the imagination assume that this is going to be the last one we experience, but I think the lessons learned here, we have to also carry that forward both in the design of the trial as well as in the regulatory environment surrounding clinical trial conduct, to say, should another incidence of drug shortage are to happen, how do we actually operationalize that with respect to patients on trial, whether starting or already on trial?   I think it's much more challenging when the patient is already on the trial, they've already started. It's less challenging if you just have to make a decision about somebody starting newly on the trial. But equally important is that by not allowing new patients to go on trial is denying something that potentially could be of benefit to them, albeit it is still a trial, it's not an established treatment option yet.  Dr. Janakiraman Subramanian : I completely agree with Dr. Owonikoko. Those were very key points and issues that we face as well. In terms of my patients with lung cancer, we haven't had a problem in getting them on clinical trials. Even though we have had carboplatin shortage patients who are already on treatment, they were able to get the carboplatin. For new patients, we were still able to provide them carboplatin as well. The biggest problem for clinical trials has been primarily with my GI colleagues who have to use 5FU. And there, as I said before, we are unable to give bolus 5FU and there is a 10% reduction of the infusional 5FU. So, we can't have any of these patients go on clinical trials.    And as a result, anything that has to do with 5FU has come to a screeching halt in terms of clinical trials for our patients. And I think I echo the point of Dr. Owonikoko that by no means this is the last drug shortage we're going to be dealing with and we are here today discussing this, also because this shortage has not ended. It's been ongoing. It's one of the longest drug shortages in my memory as a medical oncologist, and that's concerning. We still see that there is some improvement, but we haven't gotten past it yet.     And therefore, as we develop clinical trials and we need to have methods to address drug shortages and how we manage patient enrollment as well as how do we manage existing patients who are already on a clinical trial and, if possible, what might be their options in that situation. We may not have all the answers, but it is definitely an issue that we need to think about in the future as we develop and implement newer clinical trials for our patients.  Dr. Vamsi Velcheti: I completely agree and great points, both of you. And we've had the same issues with clinical trials at NYU Langone as well due to the shortage. It’s been a challenge, and I think this is a problem that's so complex because of supply chain issues and the way the drugs are priced and incentives for manufacturing these drugs in the United States are not lucrative enough to actually onshore a lot of the production of these drugs.   I think at the end of the day, I think we have to come up with some creative, innovative, reimbursement structures for these generic chemotherapy drugs. I think this would require a very complex economic solution that perhaps ASCO and other organizations should kind of really foster an environment of innovation to kind of help facilitate onshoring some of the manufacturing of these key drugs within the United States. I think ASCO is already trying to do that, trying to collaborate with all the stakeholders to kind of address this problem is very critical, and I think all of us have to be engaged in some of the advocacy efforts that are ongoing to kind of address these drug shortages. And this is not a short-term problem.  So, Dr. Owonikoko and Dr. Subramanian, any final thoughts before we wrap up the podcast today?  Dr. Janakiraman Subramanian: So, Vamsi, you mentioned the whole complex supply chain and the fact that we rely primarily on overseas manufacturers to get these drugs that are off-patent but still a key backbone of our cancer treatment. I think those are all key issues that policymakers and leaders in the field have to keep in mind. As an institution at Inova, one of the key mechanisms that have helped us to sort of stay ahead of the shortage was to have this inventory management team that monitors the inventory out there. And in fact, the inventory management team does have access to what the inventory is in some of their main suppliers in terms of the drugs. And they also have an idea of how many patients are going through treatment, what is the weekly usage of a specific drug like carboplatin. And they try to forecast what is coming down the road and try to prepare for it.   And as we try to look for solutions, maybe a forecasting mechanism in a larger scale like either spearheaded by ASCO or by policymakers level that can, for the overall country, try to see where some of the inventory is for some of these critical drugs and try to prepare for it ahead of time, rather than wait till we hit the shortage and then try to find alternative suppliers to get the drug, which obviously doesn't happen quick enough. It takes months or even longer to catch up and get the inventory back to the level where we can comfortably take care of our patients.  I think that is something we should be advocating for that as well as the professional societies should take a handle on that and see if they can support something like that as well as letting the institutions know ahead of time what's coming might be very helpful.  Dr. Vamsi Velcheti: Yeah, very good point, Janakiraman, and I think that's a key takeaway here. I think we have to learn from other industries and try to– I mean this is not unique to healthcare by any means. I mean these chronic shortages due to supply chain issues, inventory management, there might be some learnings from other industries here that we probably should also focus on inventory management and improve supply chain logistics.   Dr. Owonikoko, any closing thoughts?   Dr. Taofeek Owonikoko: Yeah, I agree as well with all the points made by Dr. Subramanian and yourself. This is a chronic problem that requires a long-term strategy. I think it's both an economic problem as well as a regulatory problem. As we all know, part of the reason why we went through this current crisis is the regulatory decision by the FDA regarding safety of one of the manufacturers. So being proactive in terms of how these audits are conducted and giving people lead time I think will help avoid similar situations in the future.    It’s an economic problem. There's a reason why a lot of the big pharma companies are not producing these drugs. And if the cost of production is such that the amount of money you get paid is enough to cover your price, I think there is an economic issue there to be addressed. That is unfortunately not within the scope of what any one of us can do individually, but as advocates in terms of the structure of incentivizing new drug versus old drug, some of these newer drugs are quite expensive, but oftentimes they are used along with standard drugs that are not as expensive. So, where do we strike that balance where we do not stifle innovation but at the same time, we don't create a perverse incentive system where everybody just wants to come up with the newest, most expensive drug and nobody is interested in really producing the backbone chemotherapy and other agents that will make those new drugs work well.   So, I think we have to pay attention. We have to advocate for our patients through our different institutions and organizations, and I hope that society as a whole that we've learned a lot of lessons from this crisis and that will help us craft some long-term strategies.   Dr. Vamsi Velcheti: Thank you both Dr. Owonikoko and Dr. Subramanian for your time today to speak with me and our listeners and for sharing your insights with us on the ASCO Daily News podcast.   Dr. Taofeek Owonikoko: Thank you.   Dr. Janakiraman Subramanian: Thank you.  Dr. Vamsi Velcheti: And thank you to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  ASCO Resources Related to Drug Shortages are available here.     Follow today’s speakers:    Dr. Vamsidhar Velcheti    @VamsiVelcheti    Dr. Janakiraman Subramanian  @RamSubraMD  Dr. Taofeek Owonikoko  @teekayowo    Follow ASCO on social media:     @ASCO on X (formerly Twitter)    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Vamsidhar Velcheti:     Honoraria: ITeos Therapeutics    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus    Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline      Dr. Janakiraman Subramanian:  Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Daichi, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology, Lilly, Blueprint Medicines, Axcess, BeiGene, Cardinal Health, Takeda, OncoCyte  Speakers’ Bureau: AstraZeneca, Boehringer Ingelheim, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology  Research Funding (Inst.): G1 Therapeutics, Tesaro/GSK, Novartis, Genentech, Novocure, Merck   Dr. Taofeek Owonikoko:  Stocks and Other Ownership Interests: Cambium Oncology, GenCart, Coherus Biosciences  Consulting or Advisory Role: Novartis, Celgene, Abbvie, Eisai, GI Therapeutics, Takeda, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Merck, Jazz Pharmaceuticals, Zentalis, Wells Fargo, Ipsen, Roche/Genentech, Janssen, Exelixis, BeiGene, Triptych Health Partners, Daichi, Coherus Biosciences  Speakers Bureau: Abbvie  Research Funding (Inst.): Novartis, Astellas Pharma, Bayer, Regeneron, AstraZenece/MedImmune, Abbvie, G1Therapeutics, Bristol-Myers Squibb, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Oncorus, Ispen, GlaxoSmithKline, Calithera Biosciences, Eisai, WindMIL, Turning Point Therapeutics, Roche/Genentech, Mersana, Meryx, Boehringer Ingelheim  Patents, Royalties, Other Intellectual Property (Inst.):   Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3  Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto  DR4 Modulation and Its Implications in EGFR-Target Cancer Therapy Ref: 18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor)  Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor)  Other Relationship: Roche/Genentech, EMD Serono, Novartis  Uncompensated Relationships: Reflexion Medical           
8/10/202325 minutes, 17 seconds
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AI Will Allow Doctors to Reclaim Time With Patients

Drs. Douglas Flora and Shaalan Beg discuss the use of artificial intelligence in oncology, its potential to revolutionize cancer care, from early detection to precision medicine, and its limitations in some aspects of care. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science37 and an adjunct associate professor at the UT Southwestern Medical Center in Dallas.   On today's episode, we'll be discussing the use of artificial intelligence in oncology, its potential to revolutionize cancer care from early detection to precision medicine, and we'll also go over limitations in some aspects of care. I'm joined by Dr. Douglas Flora, the executive medical director of oncology services at St. Elizabeth Healthcare in northern Kentucky, and the founding editor-in-chief of AI in Precision Oncology, the first peer-reviewed, academic medical journal dedicated specifically to advancing the applications of AI in oncology. The journal will launch early next year.   You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast are available at asco.org/DNpod. Doug, it’s great to have you on the podcast today.  Dr. Douglas Flora: I'm glad to be here. Thanks for having me.  Dr. Shaalan Beg: First of all, Doug, congrats on the upcoming launch of the journal. There has been a lot of excitement on the role of AI in oncology and medicine, and also some concern over ethical implications of some of these applications. So, it's great to have you here to address some of these issues. Can you talk about how you got into this space and what motivated you to pursue this endeavor?  Dr. Douglas Flora: I think, Shaalan, I've embraced my inner nerd.  I think that’s pretty obvious. This is right along brand for me, along with my love of tech. And so, I started reading about this maybe 5, 6, 7 years ago, and I was struck by how little I understood and how much was going on in our field, and then really accelerated when I read a book that the brilliant Eric Topol wrote in 2019. I don't know if you've seen it, but everything he writes is brilliant. This was called Deep Medicine, and it touched on how we might embrace these new technologies as they're rapidly accelerating to ultimately make our care more human. And that really resonated with me. You know, I've been in clinical practice for almost 20 years now, and the same treadmill many medical oncologists are on as we run from room to room to room and wish we had more time to spend in the depths of the caves with our patients. And this technology has maybe lit me up again in my now 50-year-old age, say, wow, wouldn't it be great if we could use this stuff to provide softer, better, smarter care?  Dr. Shaalan Beg: When I think about different applications in oncology specifically, my mind goes to precision oncology. There are many challenges in the precision oncology space from the discovery of new targets, from finding people to enroll them on clinical trials, ensuring the right person is started on the right treatment at the right time. And we've been talking a lot about and we've been reading and hearing a lot about how artificial intelligence can affect various aspects of the entire spectrum of precision medicine. And I was hoping that you can help our listeners identify which one of those efforts you find are closest to impacting the care that we deliver for our patients come Monday morning in our clinics and which have the highest clinical impact in terms of maturity.  Dr. Douglas Flora: You know, I think the things that are here today, presently, the products that exist, the industry partners that have validated their instruments, it's in 2 things. One is certainly image recognition, right? Pattern doctors like dermatologists and people that read eye grounds and radiologists are seeing increasing levels of accuracy that now are starting to eclipse even specialists in chest radiology and CT or digital pathology with pixelated images now for companies like Path AI and others are publishing peer review data that suggests that the accuracy can be higher than that of a board-certified pathologist. We're all seeing stuff in USA Today and the New York Times about passing medical boards and passing the bar. I think image recognition is actually right here right now. So that's number 1.   Number 2, I think is less sexy, but more important. And that is getting rid of all the rote mechanical mundane tasks that pollute your days as a doc. And I mean specifically time spent on keyboard, pajama time, documenting the vast amounts of material we need for payers and for medical documentation. That can be corrected in hours with the right programming. And so, I think as these large language models start to make their way into clinic, we're going to give doctors back 3, 4, 6 hours a day that they currently spend documenting their care and let them pay attention to their patients again, face to face, eye to eye.  Dr. Shaalan Beg: I love the concept of pajama time. It's sort of become normalized in many folks that the time to do your charting is when you're at home and with your family or in your bedroom in your pajamas, cleaning notes and that's not normal behavior. But it has been normalized in clinical care for many reasons, some necessary and just some not maybe so much. We hear about some of the applications that are coming into electronic medical records. It's been many years since I saw this one demo which one of the vendors had placed where the doctor talks to the patient and then asks the electronic medical record to sum up the visit in a note and then voila, you have a note and you have the orders and you have the billing all tied up. It's been at least 4 years since I've seen that. And I'm not seeing the applications in the clinic or maybe something's turning around the corner because for a lot of people, AI and machine learning was just an idea. It was pie in the sky until chat GPT dropped and everybody got to put their hands on it and see what it can produce. And that's literally scratching the surface of what's possible. So, when you think about giving the doctors their pajama time back, and you think about decision support, trial matching, documentation, which one of those applications are you most excited about as an oncologist?  Dr. Douglas Flora: I'm still in the trenches.  I just finished my Wednesday clinic notes Friday afternoon at 4:30 pm, so I think medical documentation is such a burden and it's so tedious and so unnecessary to redouble the efforts again and again to copy a note that four other doctors have already written on rounds It's silly. So, I think that's going to be one of the early salvos that Hospital systems recognize because there's a higher ROI if you can give 400 doctors back two hours a day. It's also satisfying because the notes will be better. The notes will be carefully curated. They may bring in order sets for the MRI with gadolinium that you forgot you wanted to order; the digital personal assistant will get that. It will set a reminder on your calendar to call the patient back with their test results. It will order the next set of labs, and you're going in the next room, and you're going to be watching that patient in the room. And I've talked to other colleagues about this earlier today. You'll be able to see the daughter getting hives because you're watching her or the look that fleets across the husband's face when you go a little bit too far and you go out too much information when they're not quite ready for that. And I think that's the art of oncology that we're missing when we're flying in a room, and we've got our face on the screen and a keyboard, and we're buried in our own task and we're not there to be present for our patients. So, I'm hopeful that that's going be one of the easy and early wins for oncologists.  Dr. Shaalan Beg: Fantastic. And when we think about the spectrum of cancer care for the people who we care for, a lot happens before they walk into their medical oncologist's office in terms of early identification of cancer, just the diagnosis of cancer, the challenges around tissue acquisition, imaging acquisition. You mentioned a couple of the tools around radiomics, which are being implemented right now. Again, same question: Separate fact from fiction, which ones are we going to see in 2023 or 2024 in the clinical practice that we have? We've been hearing that pathologists and radiologists are going to be out of their jobs if AI takes off, right? Of course, that is a lot of hyperbole there. But how do you view that space and how do you see it impacting the overall burden of care that people receive, and the burden of care that physicians are experiencing?  Dr. Douglas Flora: I'm an eternal optimist, almost infuriating optimist to my partners and colleagues. So, I'm going to lean into this and say, burdens are going be reduced all over the place. We're going to have personal digital navigators to help our patients from the first touch so that they're going to have honest and empathetic questions answered within an hour of diagnosis. The information that they're going have at their fingertips with Chatbot 4 or Med-PALM 2 with Google that's about to be released as a medical generative AI. These are going to give sensitive and empathetic answers that don't put our patients on the cliff, you know, that they're falling off waiting for a doctor's visit 10 days down the road. So, I think the emotional burdens will be improved with better access to better information. I think that the physicians will also have access to that, giving us reassurance that we're going down the right path in terms of really complicated patients taking very, very large datasets and saying a digital twin of this patient would have been more successful with this approach and those sorts of things. And those are probably 3 to 5 years down the road but being tested heavily right now in academic settings with good data coming.  Dr. Shaalan Beg: Robotic empathy sounds like an oxymoron.    Dr. Douglas Flora: Yeah, look at the published studies.   Dr. Shaalan Beg: We've all seen the data on how a chatbot can outperform physicians in terms of empathy. I really find that to be hard to stomach. Help me out.  Dr. Douglas Flora: Yeah, we say that, and we say that to be provocative, but no, there's no substitute for a clinician laying a hand on a patient. We talked about how you need to see that fleeting glance or the hives on the daughter's chest and that you've gone too far and shared too much too soon before that family is ready for it. I have no doubt in my mind, these tools can make us more efficient at our care, but don't get me wrong. There's no chance that these will replace us in the room, giving a hug to a patient or a scared daughter. They're going to remember every word you say; I just want it to be the right words delivered carefully and I don't want us to rush it. So ultimately, as we make our care more human, these tools might actually give us time back in the room to repair that doctor-patient relationship that's been so transactional for the last 4 or 5 or 10 years. And my hope is, we're going to go back to doing what we went into oncology to do, to care deeply about the patients in our care and let the computers handle the rote mechanical stuff; let me be the doctor again and deserve that patient's attention and give it right back in return.   Dr. Shaalan Beg: And I think we're hearing a lot of themes in terms of AI helping the existing clinical enterprise and helping make that better. And it's not your deep blue versus Kasparov, one person is going to win. It's the co-pilot. It's reducing burden. It's making the work more meaningful so that the actual time that's spent with our patients is more meaningful and hopefully can help us make deeper connections.   Let's talk about challenges. What are some of the challenges that worry you? There've been many innovations that have come and gone, and health systems and hospitals have resisted change. And we all remember saying during COVID that we're never going to go back to the old ways. And here we are in 2023 and we are back to the old ways for a lot of things. So, what are the major limitations of AI, even at its... peak success that you see, which our listeners should be aware of, and which may worry you at times.  Dr. Douglas Flora: Well, you've actually spoken to why I started this journal. I want to make sure that clinicians are guiding some of those conversations to make sure that guardrails are up so that we're ethical and we are making sure that we are policing bias. It's no secret now you've seen these things – a lot of language models, a lot of the deep learning was programmed by people that look like me and did not include things that were culturally competent. You can look at data that's been published on Amazon and facial recognition software for Facebook and Instagram and others. And they can identify me out of a crowd as a middle-aged white guy, but 60% of the time they will not recognize Oprah Winfrey or Serena Williams or Michelle Obama. I mean, iconic global icons. And with darker skin, with darker features, with different facial features than my white Caucasian, Eurocentric features, these recognition softwares are not as good. And I'm worried about that for clinical trial selection and screening for that. I'm really, really worried about building databases that don't represent the patients in our charge. So bias is a big deal and that's got to be transparent. That's got to be published how you arrived at this decision. And so that would be number 1. Number 2 is probably that we don't have as much. visibility to how decisions are made, this so-called black box in AI. And that's vexing for doctors, especially conservative oncologists that need 3 published randomized phase 3, blinded, placebo-controlled trials before we move an inch. So, there must be more transparency. And that again is in publications, it's in peer review. They say we need real scientific rigor and not to belabor this, but our industry partners are well ahead of us. We're not generally inclined to believe them until we see it because I've got 150 AI companies coming to my hospital system as vendors some of them are worthy great partners and some of them are a little bit over their skis and selling more than they can actually deliver yet. So, I'd like to give that an opportunity to see the papers. There's about 300 produced a day in AI in medicine. Let's give them a forum and we'll duke it out with letters of the editor and careful review.  Dr. Shaalan Beg: I will say Doug, it is becoming hard to separate fact from fiction. There is so much information which is coming across us in medical journals and through our email, through our professional social media accounts that I sometimes worry that people will just start tuning it all out because they can't separate the high impact discoveries from the more pie in the sky ideas. So, tell us more about how we got here and how you see this curve of enthusiasm shifting maybe in the next 6 months or 1 year.  Dr. Douglas Flora: Yeah, it's a great question. And it's rapidly accelerating, isn't it? We can't escape this. It's entering our hourly lives, much like the iPhone did before, or me having to switch from my BlackBerry to a smartphone that didn't have buttons. I felt like I was adapting. And maybe this is what people felt like when Henry Ford was out there, and all the buggy drivers were getting fired. The reality is it's here and it was here 6 months ago. And maybe we're feeling that urgency and maybe it's starting to catch on in general society because the advent of generative AI is easier to understand. These aren't complicated mathematical models with stacking diagrams and high-tech stuff that's just happening in Palo Alto. It's Siri, it’s Cortana. It's my Google digital assistant notifying me that it's time to get on for my next meeting. And those things have been infiltrating our daily lives and our minds quietly for some time. About November 30th when chatbot GPT-3 came out from OpenAI and we started toying with it, you started to see the power. It can be creative, it can be funny, it can articulate your thoughts better than you can articulate them on paper immediately. English students have figured it out. People in marketing and writing legal briefs have figured it out and it's coming to medicine now. It is actually here, and this might be one instance where I think the hype is legit. and these tools will probably reshape our lives.   There have been some estimates by Accenture that 70% of jobs in medicine are going to be altered irretrievably by generative AI. And so, I think it's incumbent upon those of us that are leaders in healthcare systems to at least assemble the team that can help make sense and separate, like you said, the signal from the noise. I know we're doing that here at St. Elizabeth Healthcare. We've got a whole team being formed around this. We have 5 or 6 different products we bought. that we're using to help read mammograms and read lung nodules and read urinalyses, etc. You need a construct to do that appropriately. You need a team of people that are well read and well-studied and able to separate that fact from fiction. I think we're all going to have to work towards that in the next 6 to 12 months.  Dr. Shaalan Beg: Tell me about that construct. How did you, what is the framework that you use to evaluate opportunities as they come through the door?  Dr. Douglas Flora: It's something I think we're all struggling with. As I mentioned, we've got all of these fantastic industry partners, but you can't buy 200 products off the shelf as Epic add-ons as third-party software to solve 200 problems. So, it's interesting, you've just said this. I just shared a piece on LinkedIn that I loved. “Don’t pave the cow’s path.” It's a really thoughtful thing to say, “Before you build an AI solution, let's make sure we're solving the correct problem.” And the author of that piece on Substack said: Let's not use AI to figure out how to have more efficient meetings by capturing our minutes and transcribing them immediately. Let's first assess how many of these meetings are absolutely necessary. What's the real job to be done and why would you have 50% of your leadership team in meetings all day long and capture those in yet another form? Let's take a look first at the structure around the meetings and say, are these necessary in 2023 and are these productive?   So, my thought would be as we're starting this. We're going to get other smart people who are well-read, who are studying, who are listening to experts that do it six months ahead of us, and really doing a careful contemplative look at this as a team before we dive in with both feet. And there are absolutely tools that are going to be useful, but I think the idea, how do we figure this out without having 200 members of my medical staff coming to me saying, you've got to purchase all 200 of these products, and have a way to vet them scientifically with the same rigor you would for a journal before you put out that kind of outsource.  Dr. Shaalan Beg: Doug, thanks for coming on the podcast today and sharing your valuable insights with us on the ASCO Daily News Podcast. We'll be looking out for your journal, AI in Precision Oncology, early next year. Tell our listeners where they can learn more about your journal.  Dr. Douglas Flora: I really appreciate you guys having me. I love this topic, obviously, I'm excited about it. So, this journal will be ready for a launch in early October in a preview. And then our premier issue will come out in January. We're about to invite manuscripts in mid-August. I guess parties that are interested right now go to Doug Flora's LinkedIn page because that's where I'm sharing most of this and I'll put links in there that will lead you to Liebert's site and our formal page and I think we can probably put it in the transcript here for interested parties.   Dr. Shaalan Beg: Wonderful. Thank you very much and thank you to our listeners for your time today. Finally, if you have any insights on if you value the insights a little. And thank you to our listeners for your time today. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.    Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      Find out more about today’s speakers:     Dr. Shaalan Beg   @ShaalanBeg     Dr. Douglas Flora   St. Elizabeth Healthcare     Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Shaalan Beg:   Employment: Science 37   Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine   Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Douglas Flora:  Honoraria: Flatiron Health   
8/3/202319 minutes, 47 seconds
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Managing the Side Effects of Endocrine Therapy for Breast Cancer

Drs. Hope Rugo and Kristin Rojas discuss advances in the management of menopausal symptoms, fertility preservation, and bone health for women on endocrine therapy for breast cancer. TRANSCRIPT Dr. Hope Rugo: Hello. I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. And I'm also an associate editor of the ASCO Educational Book.   In patients with hormone receptor positive breast cancer, the most common subset of the most common cancer in women worldwide, adjuvant endocrine therapy significantly reduces the risk of recurrence and death. However, prolonged estrogen suppression associated with the use of endocrine therapy can cause life-altering menopausal symptoms, bone loss, and fertility concerns. These issues impact the use of endocrine therapy and potentially breast cancer outcome.    Today, we'll be discussing mitigation strategies to manage the side effects of endocrine therapy, which we hope will improve our patient's quality of life and adherence to treatment with Dr. Kristin Rojas, who addressed these issues in a recently published article in the 2023 ASCO Educational Book. Dr. Rojas is an assistant professor of surgery and a breast surgical oncologist and gynecologic surgeon at the University of Miami Sylvester Comprehensive Cancer Center.    Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod.    Dr. Rojas, thank you for being on the podcast today.   Dr. Kristin Rojas: Thanks, Dr. Rugo, thank you so much for having me. Thank you to ASCO as well. It's truly an honor to be here with you today.  Dr. Hope Rugo: Your excellent article provides an updated overview of the existing approaches and a little forward thinking for improving the quality of life of breast cancer patients who are receiving estrogen deprivation therapy, a really broad term we use for all the hormone therapy we use in ovarian function suppression in the treatment of breast cancer. And then you had a very nice session education session at the ASCO Annual Meeting discussing these issues. Can you briefly discuss the educational session, your speakers and topics, and then we'll get more into the details of this important topic?   Dr. Kristin Rojas: At our educational session at ASCO this year, I chaired the session and presented on managing the sexual side effects and menopausal symptoms of estrogen suppression. And I had two wonderful colleagues with me: Dr. Matteo Lambertini, who shared guidelines regarding bone-targeted agents and managing bone health during endocrine suppression. And then we also had Dr. Terri Woodard, who is a reproductive endocrinologist from MD Anderson, who spoke on managing fertility concerns, which is a very important topic right now.   Dr. Hope Rugo: Yeah, that's great. And it was such a fabulous session. Our listeners can view it online at asco.org if you missed this session. But let's talk a little bit about what was in your article and what was discussed. First, I think the physical and psychological effects of cancer care we know are critical components of survivorship care. Can you tell me a little bit more about that and how we need to understand that as oncologists?  Dr. Kristin Rojas: So, as you know, as treatment continues to improve, our cancer outcomes are improving and the population of survivors continues to grow. So, I think that for many breast cancer patients, or having the diagnosis of breast cancer, becomes more of a chronic illness and less a life-threatening issue for some. I think that the conversation is now changing from “Will you live?” to “How will you live?” And I was thrilled to see that other big organizations, along with ASCO, are prioritizing managing these important symptoms in survivorship. Because I think that, as most patients will be on some form of estrogen suppression, managing the toxicity of these therapies, as you pointed out, probably does influence treatment adherence, which directly translates to an oncologic improvement. So, it's not just managing these soft symptoms, it actually will have a direct influence on probably overall survival along with disease-free survival.  Dr. Hope Rugo: Yeah, I think that's incredibly important and it's not just about doing the exam and finding out symptoms that might signify recurrence, it's really trying to address the effects of the treatment patients have gotten of chemo and their ongoing treatment with endocrine therapy that's so incredibly important. And now, of course, in medical oncology, we're adding on more agents which add to symptoms. That'll be the topic of next year's ASCO educational session. What do you do with the CDK4/6 inhibitors and managing those. But in more than 80% of women who are on the antiestrogen or various, I'm going to call hormone therapies, for early-stage breast cancer, vasomotor symptoms are a big issue. They're typically more severe in younger patients because of course they have estrogen and we take it away. So, how do we mitigate this problem in patients that can result in poor sleep and impact many aspects of one's psychosocial status? And these issues, not sleeping, of course, you make everything worse.  Dr. Kristin Rojas: Yeah, that's a really important point. And you're right, this is a really common symptom experienced by the majority of patients on endocrine suppression. And not only those patients, but patients with triple negative disease who are put into menopause from chemotherapy, etc., along with women with cancer of other disease sites. And so, as the director of our program at the Sylvester Comprehensive Cancer Center, the program is called MUSIC, which stands for Menopause Urogenital Sexual Health and Intimacy Clinic.    This is a very common symptom that patients often report. And one of the important things about this that I've realized is that hot flashes or vasomotor symptoms can actually have a pretty varied presentation. So, it's not just intense sweating. Sometimes these patients can present with palpitations, panic attacks, and they don't even realize that they're hot flashes. This is an effect of estrogen suppression and it's a central mechanism. So, it's probably related to hypothalamic dysregulation regarding how our body senses temperature changes, but it results in widespread flushing and sweating and those other aspects I told you about.   So, we've known for a long time that there are some behavioral modifications that can help with vasomotor symptoms or hot flashes. But now, we actually do have some pretty effective pharmacologic therapies for these patients as well, for whom behavioral modifications aren't completely helping the issue. Or, as you said, when patients are being woken up all night long with these hot flashes, it totally disrupts how their day goes and disrupts coping with their disease and all the other aspects of their treatment.   So, there's some effective treatments that we have. One of those being cognitive behavioral therapy has been shown to be helpful. The data on acupuncture is mixed, but I'm hopeful about this. And then the pharmacologic therapies we have. Traditionally or historically, clonidine, which is an alpha agonist, has been used along with gabapentin. But I think when choosing a medication to prescribe to a patient for hot flashes, you have to take into account the side effect profile. Clonidine does have some issues with blood pressure rebound, and gabapentin is really only effective in large doses, which can be very sedating for patients.    In the MUSIC Sexual Health After Cancer program, we typically stick to low dose SSRIs or SNRIs. I usually go with venlafaxine at a really low dose of 37.5 milligrams, and I can titrate up. I have patients take it at night in case they feel a little foggy when they first start it. But more recently, we've started using oxybutynin, which is an anticholinergic medication originally FDA approved for overactive bladder. I use the XL formulation, or you can do 2.5 or 5 milligrams BID. And this, in a study a few years ago, was shown to significantly reduce hot flashes and improve quality of life in a placebo-controlled trial.   So, important aspects of side effects of these medications with SSRIs or SNRIs working in the MUSIC Sexual Health After Cancer Program, sexual health concerns are often an issue, so those drugs can be libido zappers sometimes. But, the biggest side effect I've come across with oxybutynin for patients is dry mouth, and usually that resolves after a little while. So, we've had a lot of success in managing patients' hot flashes with these medications.  Dr. Hope Rugo: That's great and incredibly helpful. And I will say that as we're talking about these issues on this podcast, this is really important for all of our staff and our clinics because most of us don't have a fabulous clinic like the one you've started. But we are managing this with our staff, our APPs, and other areas that our patients are seeing. If everybody has this education, it will really help in the management of symptoms. And I just want to point out that venlafaxine was the first drug to be studied in this area really successful, but that we can use a whole host of different antidepressants. If people have side effects from one another, one may work really well, and generally low doses work well. The oxybutynin was such a very cool study. I think that's a great additional option.    In addition to hot flashes, we also see genitourinary syndrome of menopause, and that's part of what you deal with every day in your clinic, GSM. And this can be not just vaginal dryness, which is bad enough, but also increased infections, painful sex, recurrent bladder infections and also reduced libido, which is a really big issue, we just don't talk about very much. What's the most effective and safe treatment for GSM? And we use a lot of low dose vaginal estrogen and a variety of delivery mechanisms. What are the risk and benefits when patients really need something more?   Dr. Kristin Rojas: GSM, or genitourinary syndrome of menopause, is this newer umbrella term for what we used to call vaginal atrophy. And you're right, it encompasses not only dryness, but all the other changes that can happen to the vulvovaginal mucosa along with anatomic changes to the pelvic floor. This is critically important, I think, that we address these issues or these potential side effects at the time of endocrine therapy prescription because what we have found in our program is that while hot flashes might get better, these symptoms do not get better. And left untreated, they get worse.   And one of the surprising findings that we have presented earlier at another conference this year was that almost half of our patients, when they had their pelvic exam in the program, were also found to have vaginal stenosis. So narrowing and shortening of the vagina, making penetrative sex actually impossible. So it's really not just dryness, but a host of these other symptoms that go along with that. I like to break this down in a really simple way because I know that a lot of providers may be intimidated when patients might bring this up. But I think about it this way. Number 1, eliminate irritants. Number 2, moisturize. Number 3, lubricate. And 4, address the pelvic floor.   Oftentimes when patients present in the MUSIC program, they've been putting a lot of over the counter topical therapies on the vulva and the vagina using intravaginal washes. One of the biggest offenders of some of these symptoms is artificial fragrance, which we can actually develop an allergic reaction to, which manifests as burning and stinging. So these patients may also report burning and stinging in addition to dryness. These offenders can be in all kinds of products. So not only feminine washes, which I don't recommend in our program, but things like bath bombs, bubble bath, toilet paper. And so we kind of go through an inventory of everything that's touching the delicate tissues of the vulva and the vagina and try to back off those products.   The second thing is moisturization. It's important to talk to patients about the difference between moisturization, which I say is for maintenance, and lubricants, which are for PRN use sexual activity. But I tell patients, "lubricants for love." That's how I differentiate the use of these two different types of products because they have different properties. Usually after eliminating irritants, our first step is to start with a non-hormonal moisturizer because there's some really good high-tech non-hormonal moisturizers out there, specifically those containing hyaluronic acid, which pulls moisture from the environment and holds it on the skin. And by using this first—this is my personal opinion—but I think by improving the mucosa a little bit and kind of improving the dryness, maybe even the elasticity a little bit, I think that when patients do have persistent symptoms after using regularly these non-hormonal moisturizers at least three times a week, that adding in a low dose vaginal hormone at that time, instead of putting it on completely atrophic mucosa, you're putting it on kind of like a pretreated mucosa, which I think might decrease systemic absorption.   I'm so glad you brought up vaginal estrogen. I could give an entire talk just on that, so I’d be happy to do that next year for ASCO if anybody wants. But it is very controversial. Historically, there have not been studies showing an increased risk of recurrence with the use of local estrogen therapy, so estrogen in the vulva and the vagina. However, there was a recent study that came out this year that was a large analysis of breast cancer patients receiving different types of hormone therapy. And in a subset analysis of the group who got local vaginal estrogen, just in those patients on aromatase inhibitors, there was a slightly, but statistically significant–according to their analysis–increase in the risk of recurrence. I think there's some issues with this analysis because it was a large study and there's a lot of recall bias and measuring this in patients is really challenging. But I think it's still important to mention because a lot of patients are going to read about those things, these types of studies.   The way I approach it is to start with the lowest dose and I start with infrequent dosing. If patients have persistent symptoms, I start them with once a week or twice a week, which is different from the original pharmacokinetic studies of higher dose estrogens, which showed a bump in their serum estradiol when they used it every night for two weeks. So I actually do the opposite and taper them up. I'll do once a week to twice a week. And usually, patient symptoms are resolved at that point.   But I do want to point out, that's a great option for patients on tamoxifen because mechanistically, as you know, it probably doesn't matter if they have a little bump in their serum estrogen. But for the patients on aromatase inhibitors, we actually have a new kid on the block, a vaginal androgen called prasterone or DHEA. I dose this in the same way, titrate it up. But this can be really helpful for patients on aromatase inhibitors because the ALLIANCE trial showed that for those patients on AIs that their systemic estrogen levels do not increase. And so that's kind of how I manage that discussion. I do think it takes some multidisciplinary collaboration, so I always involve my medical oncology colleagues on this.    Lastly, lubricants. So, everyone seems to be really into using water-based lubricants, but I try to tell patients, unless you're depending on condoms for STD or contraception protection, silicone-based lubricants that are like preservative-free and don't have a lot of those gimmicks or additives, are great—they stay slippery for longer—and there's some really great brands out there. And then for patients who still have persistent pain with sex, we address the pelvic floor, which is either through the use of dilators, referring them to pelvic floor physical therapy, or other sexual devices that we use in the MUSIC program.  Dr. Hope Rugo: This is really helpful, and I think that for many of us in practice, we really want to get the specifics of what you use. I think this prasterone, the idea of DHEA is really very interesting and something that personally I haven't used, but we did use in the distant past before there was an FDA-approved version.   So I guess I have several questions just to ask about the details. So one is, when you prescribe this, do you find it's generally covered by insurance? And when you say low dose, do you mean just try it once a week? And then do you use the estrogen tablets, the brand names are often Yuvafem or Vagifem, we often use those twice a week. How often do you use them and do you use the estrogen ring also? What are the absolute specifics of what you're recommending to these women? And do you feel like sometimes in patients who are developing these symptoms that early use can help avoid the more severe symptoms and therefore reduce the exposure?   And lastly, just to say, that paper which was so interesting about the slightly increased risk of recurrence, I felt was so flawed in terms of what people were using and if they were taking their hormone therapy and risk of recurrence, the risk of the cancer itself, that I really felt like I couldn't make anything out of it in terms of the risk to patients. But I'm really interested in your specific recommendations.  Dr. Kristin Rojas: Thanks for asking about specifics. And I'm happy to give our treatment algorithms here, which we also discussed in our session and we listed in our EdBook manuscript. We do pelvic exams in the MUSIC program and I often find that there's very specific points in the vestibule or the opening of the vagina that are tender and have pain, specifically, what's known as the posterior fourchette, which is the kind of connection between the right and the left side towards the posterior aspect. So, I usually start with a 1% estradiol cream and have patients tap it to the outside and then bring in a dilator and have patients use not only a silicone lubricant, but put some of the estradiol cream on the dilator. And so that brings the product up to the top of the vagina for patients that have some of those anatomic changes that I discussed.   So this is 1 option, and we really don't have a lot of issues with insurance authorization for the cream, just every once in a while. We can also use a 4 microgram or a 10 microgram dose of estradiol, which is a tablet, which are newer options. This is in contrast to the old pharmacokinetic studies that use 25 micrograms. So this is much, much lower. I do run into some prior authorization issues with those because there tend to be newer versions of this. But as you mentioned, the estradiol ring, which I do think is a great option and when you calculate it out, releases a very low dose of estradiol every day. And it's good for patients who want a more low maintenance regimen. The only challenge I've had with that is it's a large rigid ring. And for patients who already have those anatomic changes, it can be really hard to place that in the vagina.   And so, just like you said, early prevention and treatment of these issues can prevent not only anatomic changes, but even potentially the need for exposure for larger doses of hormones. For all of those options, I tend to do it once or twice a week and then can move up. But we sometimes get kind of creative in how we use these options in terms of placing them on the dilator, placing them externally. For patients that have recurrent urinary tract infections, I also have them kind of tap some of the estradiol cream around the urethra as well to improve the urethral and potentially bladder microbiome and decrease risk of recurrent UTIs.  Dr. Hope Rugo: That's really interesting, and I think those specifics are incredibly helpful. We also will check, although I have to say there's no data to support it, the serum estradiol levels in patients who are using more than our minimal amount. We have plenty of studies that have shown that there really isn't systemic estrogen if people are using very low doses. But we will check sometimes, just sometimes people use these topical creams where they get premenopausal levels of estrogen, which of course we don't want. So, this is an incredibly helpful and useful discussion.    One of the other things that happens for these patients and our younger patients, which breast cancer is still increasing in small numbers in younger patients every year, and many of these patients have hormone receptor positive disease. And it just breaks your heart to see a 38-year-old who is planning to get pregnant next month with their new partner who develops a hormone receptor positive breast cancer. and we want to give people all the options they possibly can. We are strong proponents for harvesting eggs and either freezing eggs or embryos before you start treatment. And we figure we always have 2 weeks for breast cancer. We also use ovarian function suppression during chemo just for whatever help it might have.   But then after patients have finished their treatment and they're on hormone therapy, it's a really big issue for women about when they can have a child because we don't want to wait until they're 45. So, you had noted in your article that some women could take a break from endocrine therapy after 18 to 24 months to try and conceive. Can you tell me a little more about that?  Dr. Kristin Rojas: Sure. Well, this aspect of our discussion was very well presented by my colleague, Dr. Terri Woodard from MD Anderson, a reproductive endocrinologist, and she also put together the aspect of this for our manuscript. She talks about how fertility counseling and referral is probably underutilized, but definitely indicated for most of these patients who are of pregnancy age or premenopausal status. And observational data for a long time didn't show that pregnancy after treatment worsened oncologic outcomes. However, patients as well as many providers had reservations.   So, it's been very helpful that we now have a prospective, large, international trial known as the POSITIVE trial, the early results of which came out earlier this year, which showed that women, after 18 to 24 months, could interrupt endocrine therapy and did not have a worsened short-term oncologic outcome. And those are women with early-stage breast cancer. However, there is a concern that many patients do take longer to get pregnant in that age group or after treatment, potentially if they've received chemo. There is a concern about the duration of time that they're not on endocrine therapy afterwards, which might be further clarified in later analyses. So that's my takeaway from that study, which did show us that very helpful, reassuring information. But I think we're still waiting for the long-term data and it's definitely still a very important patient-centered discussion.   Dr. Hope Rugo: This is a really excellent point, and I think that one of the things of a trial like this, which is sort of a registry study, is that we're always going to speak with our feet to some degree. So, if patients have very, very high risk of recurrence and highly proliferative disease, we might not want them to stop at 18 months because their risks are so high early. So, it has to be a risk versus benefit discussion for individual patients, of course. But I think this data was incredibly reassuring.   It was interesting there were some patients who hadn't restarted their endocrine therapy. In the paper in the New England Journal, it told us that some of those patients were still trying to conceive. But one of the things that's going to be really important for these patients is to really make a big effort on the part of our clinical practices to get patients to restart their hormone therapy. It's very hard to do that, as you can imagine, in that setting.    Another area here is monitoring bone health. And I know that's not part of the MUSIC clinic per se because you're really focusing on GSM and other areas that we've just discussed, which are so incredibly important. And it's funny, bone health is silent, right? So, although some patients don't want to take aromatase inhibitors because they're worried about losing further bone density, they don't feel it. So that's, of course, a different kind of a toxicity. But we know that by suppressing ovarian function in young women, we cause a lot of bone loss, and in older women, already in menopause, that this continuous loss of bone increases the risk of fractures, which can be a huge impact on quality of life and even survival in some cases. So, we're really interested in trying to prevent bone demineralization and reducing the risk of fractures. I believe that Matteo Lambertini from Italy discussed this in your paper and that there's a lot of discussion about use of denosumab and zoledronate. I wonder if you could just comment a little bit on that in our last couple of minutes.  Dr. Kristin Rojas: Well, as you said, my colleague Dr. Lambertini put this aspect of our paper together, but he did put together a very nice summary of bisphosphonates and denosumab and separated their use by premenopausal and postmenopausal patients because the data surrounding those patient populations is slightly different or nuanced. But as you mentioned, it is important to monitor these patients' bone density. We have our standard recommendations such as a calcium-enriched diet, resistance and weight-bearing exercise, and vitamin D for patients, for those patients with a vitamin D deficiency or at risk of bone density loss. And so these pharmacologic agents can also help decrease bone mineral density loss and potentially decrease or likely decrease bone recurrences, which, as we know, influences survival. I think he provides a very nice summary of that, as you mentioned.  Dr. Hope Rugo: I think that's so incredibly important. And thank you for really emphasizing the weight-bearing exercise and checking vitamin D and making sure patients are taking vitamin D and at least some calcium. And then, of course, our institution, we work closely with our endocrinologists specializing in bone as well, when issues come up about risk of osteonecrosis of the jaw, and we require dental clearance for everybody starting medication just to make sure that we've reduced risk to the patient. And then when we're trying to think about stopping denosumab and should we bridge with zoledronate to reduce the risk of fracture, we also talk to our bone doc. So it's really important.   And in our last just 1 minute, I know you were thinking of saying something about measuring estrogen in the blood in patients who are using vaginal estrogens. Do you do that?   Dr. Kristin Rojas: Yeah, great question. I'm glad you brought that up. We actually don't routinely do this in the MUSIC program, but it is an important aspect to think about today, because I don't know about where you are, but here in South Florida we have a lot of patients who are receiving therapies outside of the FDA-approved space and these are typically marketed as bioidentical hormones, which is a marketing term. Oftentimes, they'll get either transdermal formulations or pelleted hormone therapy that can result in really high superphysiologic testosterone or estrogen levels. And so we typically, for those patients, do try to get them off those non FDA-approved therapies because the safety of those is unknown.   Dr. Hope Rugo: That's really interesting and so helpful. Yes, I know this whole idea of bioidentical hormones drives me crazy, but I think that's great that you brought that up, actually. We do measure it. Who knows? I think if you're really worried, measuring “Yeah, everybody's hot flashes went away,” it's probably worthwhile checking.   This was such a fabulous conversation. I learned so much. We really appreciate your contribution to the educational manuscript, to the educational program, and your fabulous insights with us today. Thank you so much for participating on the ASCO Daily News Podcast. I think everyone will find this very helpful.   Dr. Kristin Rojas: Thank you so much for having me.   Dr. Hope Rugo: And thank you to you, our listeners, for joining us today. You'll find a link to Dr. Rojas and her colleagues' article in the transcript of this episode and in the 2023 ASCO Educational Book, which features practice-changing oncology research and a wide range of compelling studies on quality and equitable cancer care.    Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thanks again.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Follow today’s speakers:   Dr. Hope Rugo  @hoperugo  Dr. Kristin Rojas  @kristinrojasmd    Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Hope Rugo:  Honoraria: Puma Biotechnology, Mylan, Samsung Bioepis, Chugai Pharma, Blueprint MedicinesConsulting or Advisory Role: Napo PharmaceuticalsResearch Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals, Astellas Pharma, Seattle Genetics, Macrogenics, Boehringer Ingelheim, Polyphor  Dr. Kristin Rojas:   Honoraria: Pacira Pharmaceuticals  Consulting or Advisory Role: Roche Diagnostics, Merck  Research Funding (Inst): Bristol Myers Squibb Foundation       
7/27/202329 minutes, 12 seconds
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The Emergence of Triplet Therapies in ccRCC in the Frontline Setting

Drs. Pedro Barata and Naomi Haas discuss the emergence of clinical trials investigating triplet combinations in advanced renal cell carcinoma, factors that influence treatment decisions, strategies to personalize therapies in the frontline setting, including response-adaptive treatment strategies, and the use of biomarkers such as gene expression analysis to guide initial therapy. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata. I'm your guest host of the ASCO Daily News Podcast today. I'm an associate professor of medicine and also a GU medical oncologist at University Hospital Seidman Cancer Center, Case Western University in Cleveland, Ohio. I'm also an associate editor for the ASCO Educational Book. Today I'm really delighted to welcome Dr. Naomi Haas, the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center and professor of medicine at the University of Pennsylvania.  Welcome, Dr. Haas. Dr. Naomi Haas: Thank you, Dr. Barata. It's a pleasure to be interviewed. Dr. Pedro Barata: Thank you. As you know, we've seen significant strides in the frontline treatment for patients with advanced clear cell renal cell carcinoma (RCC), and there are multiple doublet regimens that are now the standard of care for those patients. The goal for us to chat today is to discuss the emergence of clinical trials that are really investigating triple combinations and the factors that influence treatment decisions around triplet combinations for patients with advanced renal cell carcinoma. I want to congratulate you for the great work that you did in a recently published article in the 2023 ASCO Educational Book. So thank you for your contributions. And just before we get started, I just want to highlight that our full disclosures are available in the transcript of this episode. So, Dr. Haas, again, it’s great to have you. Thank you for taking the time. Let me get started. So, we know that there are multiple standard of care doublet regimens, all of them immunotherapy-based combos, and they usually include 1 checkpoint inhibitor or 2, such as ipilimumab plus nivolumab or a combination of an immune checkpoint inhibitor with a VEGF TKI. And we have a number of examples like that. Can you tell us about the trials that have emerged exploring triplet therapies in the first-line setting for patients with advanced RCC? Dr. Naomi Haas: Sure, and I'm going to focus just on triplet therapies that are just about ready to go. But as you know, Pedro, there are probably many different combinations that we'll see in the future. Some of the combinations that have already been conducted as clinical trials include combinations of VEGF receptor tyrosine kinase inhibitors along with immune checkpoint inhibitors. I'll highlight one which was batiraxcept plus cabozantinib and nivolumab, and it's a combination of VEGF inhibitor, immune checkpoint inhibitor, and also an AXL inhibitor. So, most of these capitalize on other vulnerabilities with renal cell carcinoma.  So, as you said, they build on the tyrosine kinase inhibitor pathway or on the immune checkpoint inhibitor pathway. Some of them are combining drugs such as CDK inhibitors. There was axitinib plus nivolumab plus palbociclib trial that is getting ready to launch. Others are combining the use of belzutifan, which is a HIF inhibitor in combination with VEGF inhibitor and immune checkpoint inhibitor. There are a couple of those that are ongoing, one of them looking at combinations with lenvatinib. And I think there are also trials getting ready to launch that are using it in combination with cabozantinib and nivolumab.  Additionally, another very interesting direction is trying to affect the gut microbiome. And there was a clinical trial presented by Dr. Monty Pal at the gut microbiome session at ASCO, which combined CBM-588, which is a probiotic, in combination with cabozantinib and nivolumab. And that showed an improvement in progression-free survival compared to the combination of cabozantinib and nivolumab alone. And previously there was work published using CBM-588 in combination with ipilimumab and nivolumab. So that's an area of high interest to patients. But most of these combinations capitalize on either vulnerabilities, signs of resistance in pathways or in adding other pathways that have previously been unaddressed in renal cell carcinoma, and are combined with pathways that we know are effective. Dr. Pedro Barata: Wow, that's a fantastic overview of some of the approaches being considered in the frontline, so thank you for that. And actually to your point, some of them we've seen some data, others more later stages of development. So with that in mind, we also know that we have on one side of the story we have how much of these combos of triplets can actually be effective and help patients. From the other perspective is about tolerability, treatment options, and patient health. They're both very important considerations.  Can you tell us a little bit about the safety profile of these triplet combos? I know we're talking about many different things. The microbiome triplet has a different safety profile than perhaps a combination with a TKI and different checkpoints, for instance. Can you tell us a little bit about what we expect from the safety profile when we start to combine these therapies in the upfront setting?  Dr. Naomi Haas: Sure. I think 2 of the very tolerable triplet regimens have been the combination of the CBM-588 in combination with ipilimumab and nivolumab. Really in those combinations, the authors at least have demonstrated that there has not been a great difference between the two study arms of either the doublet or the doublet in combination with the CBM-588 trial. And that's based on basically changing the bacterial flora of the gut. The Avera trial, which was using the AXL inhibitor in combination with cabozantinib and nivolumab, also seems to have a very tolerable safety profile. Now, this trial was not compared to sort of a standard of care arm, so it's a little bit difficult. A standard of care arm that I would have considered for this clinical trial would have been to use either cabozantinib alone or cabozantinib with nivolumab. Instead, this was more of a dose-finding protocol. So, more work needs to be done with that, but the side effects of that combination additive to what we already know seem to be just infusion reactions from the AXL inhibitor.  The trial that got the most attention so far has been COSMIC-313, which was combining cabozantinib with ipilimumab and nivolumab upfront. And of course, the concern with this triplet combination was that there was more hepatotoxicity seen and it was difficult to know whether the hepatotoxicity was from the combinations of the immune checkpoint inhibitors or the use of the cabozantinib. And although the trial showed an improvement in progression-free survival, it did not show as many complete responses as the comparator arm. And the other concern was that there was quite a bit of dropout due to toxicity. And of course, we don't have the overall survival endpoint for that trial yet. Dr. Pedro Barata: Great, thank you for that. I agree completely. We've seen many different safety profiles with these different triplets.  Let me touch base on a slightly different topic, and that has to do with what kind of strategies can we think to personalize treatment for clear cell RCC in the frontline. And this is not necessarily applicable only to triplet therapy. There are also some efforts with doublets, but the goal is, I would argue, is response adaptive treatment strategies or even the use of upfront biomarkers such as gene expression analysis, for example, to help us guide initial therapy. Can you give us an idea what your thoughts are about what is coming? What do you think the future will look like in terms of developing this like a biomarker-based approach? What kind of factors or markers we can use to select who gets what in the frontline setting? Dr. Naomi Haas: Sure. So, I’ll just highlight ahead of that that one important biomarker that we’re already using is the IMDC criteria, which I think if that algorithm had not been developed, we would be struggling a lot in renal cancer and that’s, of course, the algorithm that uses the thing such as performance status, hemoglobin, calcium, and time for the development of metastatic disease as well as the neutrophil count and the platelet count. And that has helped us divide categories of patients with clear cell renal cell carcinoma into poor risk, intermediate risk, or favorable risk categories. And that was recently validated in the immune therapy combinations that were previously been validated just in VEGF inhibitor therapies.  But the other useful, let’s start with clinical tools that I think are going to be very important are the health-related quality of life tools which primarily measure things such as functional health, as well as toxicity. And one of these is the FKSI-19 score which captures most renal disease-related symptoms, treatments, side effects, and functional well-being. And this has been implemented in some trials and are looked at over time whether the patient’s functional status improves. And patients who are responding to therapies generally will improve as far as their overall well-being. Although that can be difficult as a tool because if patients are experiencing toxicity, those signs might not be apparent. But that’s one tool that’s being used.  Now, people, both patient advocates and patients, have pointed out that it’s very hard to use a tool like this in real life to implement in clinic, but there are efforts being carried out to make these tools a little bit easier so that people can use them day-to-day. So, I can see that being implemented more often.  The others have to do with response assessments, and I think it’s very important to look at immune-related responses which kind of builds on the resist response, but it uses two dimensions of measurement as opposed to one dimension of measurement. And looking at those, we know now that patients who have what we call a deep response, so something better than a 75% shrinkage or even a 90% shrinkage in a very short period of time tend to be those patients who behave like patients who have complete responses. And both progression-free survival and overall survivals seem to be going in a very encouraging way looking at these tools so you could see that this tool could be implemented in real life with treating a patient and if they have a very deep response quickly, you can feel, the physician or the APP, could be very confident that the patient is going to do well for a long period of time. I think the tools that we’re waiting for the most, however, are as you said, the biomarker tools. And this is where we still have a lot of work to do, but one example of this is the transcriptomics which has been conducted in both the atezolizumab-based trials such as the IMmotion trials, and also to some extent with the JAVELIN trials, the avelumab and axitinib trials. And this goes back to looking at the tissues sample and looking at transcriptomics which show mRNA expression as well as some alterations in some of the important genes such as BAP1 and PRBM1.  And those tools have been implemented, especially in the IMmotion trial, there were 7 clusters identified, and two of the clusters are groups of patients whose tumors have transcriptomics that indicate that they would respond well to a VEGF inhibitor. And a couple of them also showed very good responses to immune checkpoint pathways. There were additional pathways which suggested that patients wouldn’t be responsive to either of these. And there is a trial called OPTIC that is funded by the Department of Defense (DOD) which is currently applying these transcriptomics, and then assigning patients to get either a VEGF IO therapy combination or a dual immune checkpoint inhibitor combination, based on their transcriptomics.  And I think what everybody would really like to see is, number 1, that these transcriptomics consistently bear out that there isn't irregularity in using these as predictors. So, they do need to be validated. But I think if there was a quick and easy way to do this, to assign patients to therapies based on these profiles, that would perhaps go a long way in predicting what therapy a patient should start with.  Another useful tool is the development of artificial intelligence. And there are a number of companies that are looking at these tools. We're implementing this retrospectively in the ASSURE trial, which was the adjuvant seraphinib synontib or placebo trial, for patients at high risk for RCC. And we're working with a company to identify, using AI, looking at the slides. And I think that if these kinds of techniques, which are already being used in prostate cancer, are something that can be developed, then what I could see in the future is that a patient's slide could be tested very quickly, and that that might also indicate things that perhaps we can't see under the microscope, as far as either a response to treatment or a risk. So, you could use that in the adjuvant setting to predict whether a patient might need adjuvant therapy or not. So I can see those being implemented.  And then the third is looking at cell-free DNA. And there are many different mechanisms that have been tested in other solid tumors, using either circulating tumor DNA or cell-free DNA. Now, the circulating tumor DNA seems to be a little bit more difficult to assess in metastatic kidney cancer because it doesn't have the mutational burden and doesn't seem to have as many mutations and things floating around that can be captured. However, cell-free DNA, which has the capability of measuring DNA methylation profiles, does seem to be showing some promise, and there have been some publications.  So this has also been tested in cancers of all stages and can be measured in both the plasma and in the urine. And that could be another helpful tool that needs to be validated, but that could be used to start a patient on treatment. And if the amounts of cell-free DNA went down with therapy, that could be a good indication, perhaps in advance of imaging, that a patient is doing well with therapy.  So those are some examples that I see potentially being used in the future to help direct therapy, provided that we can make these tools, that we can validate these tools, and secondly, that these tools are relatively inexpensive and that they're nimble, that they could be used right away, that it wouldn't take a long time to get the results back to help guide. Dr. Pedro Barata: For sure. I couldn't agree more. What a masterclass of all the emerging tools that are being investigated in RCC, this is fantastic.  So, I guess maybe one last question before I let you go. We have now a number of doublets, we have perhaps a triplet, if not more. If you were to guess, who do you think will be the ideal population for a triplet therapy? Some, in addition to all the tools you mentioned, maybe sarcomatoid features, etc. that might be part of the AI complement to what you mentioned earlier. But if you were to guess, do you think that 5 years from now, we're going to be offering a triplet therapy, whatever that triple therapy might be, to everybody, to certain populations? What can you tell us to help us predict what might happen in the near future to make us think about a thoughtful, shared decision-making process and try to predict who might be the ideal population for triplet therapy? Dr. Naomi Haas: So, I don't think we're going to use triplet therapy in everybody. And in fact, I hope we don't use triplet therapy in everybody because I have patients who have responded to single-agent nivolumab and remained in a continuous CR many years after they were treated that way. And I have other patients who really progressed very rapidly or relapsed very quickly after doublet therapy combinations. So, I think that what I would see in the future would be using the triplet therapy combinations in the challenging patients, the patients who we know we're not getting as far along with the doublet approach. And that's really our challenge. And I would see that perhaps some of this transcriptomics which indicates that there are subsets of renal cell carcinoma which are not going to respond well to a VEGF inhibitor or to an immune checkpoint inhibitor, that those are areas where there might be other relevant pathways where maybe the signal isn't quite as good with– maybe they have some response, but not an optimal response. And then combining another pathway into that would be a way forward to achieve a complete response in those populations.  I also want to emphasize that it may be that triplet therapy isn't the way to go, but that triplet therapy can be more of an adaptive design where a doublet therapy is started, and then the third drug, a triplet, is added at a later time. And an example of that is PDIGREE, which is the combination of ipilimumab and nivolumab. And then following imaging, patients are assigned, depending on the response, to get either cabozantinib alone, cabozantinib with nivolumab, or to continue on just nivolumab alone. And that might be a better way to address toxicity. But some of these other triplet combinations, one could also see- you could start, for example, with ipilimumab and nivolumab, and if they were having a response but you wanted to heighten the response, maybe adding the CBM-588 as an adaptive response or adding a CDK inhibitor, but sort of staggering the combination so that you spare patients some of the toxicity. So, I think all of those approaches need to be tested. Dr. Pedro Barata: That is fantastic. Dr. Haas, this is an incredible podcast. You did highlight several triplet combinations that are currently under investigation. You highlighted very, very important ongoing clinical trials. You touched base on what the future might bring as far as tools that might help us decide or optimize patient selection. We talked about adaptive designs. So really outstanding work. And also, I think this reflects the fantastic work in the manuscript that you wrote in the 2023 ASCO Educational Book.  So, thank you so much, Dr. Haas, for the incredible work that you have done and you continue to do in the GU field, and for taking the time to share your insights with us today on the ASCO Daily News Podcast. It's truly been a pleasure to chat with you today. Dr. Naomi Haas: Thank you.  Dr. Pedro Barata: Thank you again. And thank you also to our listeners for joining us today. Really happy with talking about this topic with Dr. Haas. You can also find links to the studies that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  So again, it has been a privilege to be here today with Dr. Haas. Thank you for joining us and have a good day.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:  Dr. Pedro Barata @PBarataMD Dr. Naomi Haas   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures:  Dr. Pedro Barata: Honoraria: UroToday Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon Speakers’ Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas Research Funding (Inst.):  Blueearth, AVEO, Pfizer, Merck   Dr. Naomi Haas: Consulting or Advisory Role: Pfizer, Merck Sharp & Dohme, Calithera, Eisai, Exelisis, AVEO, Roche/Genentech Expert Testimony: Lilly
7/13/202322 minutes, 46 seconds
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Novel Therapies in GI Oncology at ASCO23

Drs. Shaalan Beg and Shiraj Sen discuss notable advances in GI cancers featured at the 2023 ASCO Annual Meeting, including the PROSPECT and PRODIGE-23 trials in rectal adenocarcinoma, the MORPHEUS study in uHCC, and the NORPACT-1 trial in pancreatic head cancer. TRANSCRIPT     Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host for the podcast today. I'm the vice president of oncology at Science 37, and I'm an adjunct associate professor at UT Southwestern Medical Center. My guest today is Dr. Shiraj Sen. He is a GI medical oncologist and the director for clinical research at NEXT Oncology in Dallas.   Today, we'll be discussing practice-changing studies and other key advances in GI cancers that were featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available on our transcripts at asco.org/DNpod.   Shiraj, it's great to have you on the podcast today.  Dr. Shiraj Sen: Thanks so much for having me today, Shaalan.  Dr. Shaalan Beg: We saw exciting new data and great progress in GI oncology at the ASCO Annual Meeting. I was hoping we could talk about LBA2. This was the PROSPECT study that was presented during the Plenary Session. It's a randomized, phase 3 trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemo, followed by the selective use of chemoradiation, followed by TME or total mesorectal excision for the treatment of locally advanced rectal cancer. This is the Alliance N1048 trial. What are your thoughts on this study?  Dr. Shiraj Sen: Thanks, Shaalan. It was great to see another GI study presented in a Plenary Session, and I thought this was a great trial that really took us back to thinking about why we do chemoradiation as well as chemotherapy perioperatively in locally advanced rectal cancer. And asking the important question of is there a select patient set or subset where we might be able to safely omit the chemoradiation piece.  To me, the impressive part was this study enrolled from 2012 to 2018. In 2012, when this treatment really started enrolling, the standard of care was long-course chemoradiation for five and a half weeks, followed by surgery, followed by adjuvant chemotherapy with FOLFOX or CAPOX. During this time, a lot of the practices of these patients have shifted from that to giving total neoadjuvant therapy, where we bunch the chemotherapy and chemotherapy upfront prior to the patient undergoing surgery. And this study really asked us to take a look at both practices and ask the question of which one is better and is it possible to de-escalate care for patients who get upfront chemotherapy and omit the chemoradiation and still have similar outcomes.   I thought it was very interesting that this was done in a non-inferiority-type manner, and we can talk more about that in a few minutes as well. But taking that all into context, the fact that in this study, that the non-inferiority endpoints were met for both disease-free survival as well as overall survival in the patients who were able to omit chemoradiation, I think in the big picture sense told us that there truly might be a patient subset where—this is in patients with T2 node-negative disease or T3 node-negative or T3 node-positive disease—where we might be able to safely exclude the chemoradiation and still have similarly effective outcomes for these patients.  Dr. Shaalan Beg: Those are great points, especially when we have started to think about colon cancer and rectal cancer as many different diseases based on their location. And we know that in some instances their biology can be different as well.   Can you talk a little bit about who those patients are that were enrolled on this trial? Because when I think about the German rectal study that led to us using neoadjuvant chemoradiation, the data was really around pelvic control of disease and sphincter preservation. So how did the patients who enrolled in this trial relate to the typical person with rectal cancer who walks through your doors?   Dr. Shiraj Sen: Yeah, great point. I think we should point out the inclusion-exclusion criteria for this study. These patients were only those who were, again, T2 node-positive or T3 node-positive or negative, patients for whom chemoradiation would be indicated in the setting, and patients for whom they'd be good candidates for sphincter-sparing surgeries. So, tumors that are quite up high. These are not for individuals who have tumors requiring an APR. These are not for patients who have clinical T4 tumors. And this is not applied, again, to those high-risk patients who have 4 or more pelvic lymph nodes that are 1 cm in size or larger in the short access. And so, patients who need essentially an APR and the high-risk T4 tumors who are, I think, better suited by something like we'll talk about later in the PRODIGE study.   I think one last point that might be worth making here on the PROSPECT trial is that it was a non-inferiority trial. And in my opinion, this was really a great use of a non-inferiority study. I believe that when there's a new treatment under consideration used in a non-inferiority study, it should be because that therapy or modality of treatment is safer, more cost-effective, or could help increase access to care without compromising efficacy, and ideally maybe more than one of the above. And in this case, I think really all of those checkboxes are met.   In urban settings where we work, we think about access to radiation being quite plentiful, but when we get to more rural areas, or parts of the world where they may not have access to radiation like we may, I think this data can help drive care for a number of patients there. It can certainly be more cost-effective as it allows the omission of radiation. And certainly, from some of the PRO data that they presented, it certainly can be felt to be safer and help omit some toxicities as well.  Dr. Shaalan Beg: Yeah, you mentioned a total neoadjuvant therapy and we seem to be entering this space in rectal cancer where the decision on which modalities an individual person will need for the management of their disease and what sequence they will need is all up for debate, whether that's chemotherapy or radiation, long-form, short-form radiation. And we also heard some results at earlier ASCO meetings around the omission of surgery in people who've had complete clinical responses as well.   And you mentioned total neoadjuvant therapy and at ASCO this year we heard the results from LBA3504, which is a PRODIGE-23 trial. The investigators reported 7-year results of this phase 3 study from the UNICANCER group in France. This study is really pushing the envelope. What are your key takeaways here?   Dr. Shiraj Sen: Great point. I think this study, especially when taken in conjunction with the PROSPECT trial, highlights the fact that these patients really can have heterogeneous diseases and ones that really require careful consideration and discussion at multidisciplinary tumor boards. Unlike the patient population in the PROSPECT trial, the PRODIGE study did treat patients with higher-risk disease. So these were patients with clinical T3, T4 tumors and so higher risk, and asked the question now with more mature 7-year follow-up of, when compared to receiving the standard of care at the time, which was a chemoradiation followed by TME, followed by adjuvant FOLFOX for 12 cycles or the capecitabine, does TNT giving again now modified full FOLFIRINOX for six cycles followed by chemoradiation followed by TME and then adjuvant FOLFOX, do the improvements in both disease-free survival, overall survival, and metastatic relapse rate, do they hold up, and/or are there any differences in local control?   And again, here they demonstrate that even with longer-term follow-up, that the improvements in OFS, DFS, and metastatic relapse rate, really do hold up even with longer-term follow-up. And so, for these patients with higher risk disease, it does seem that giving induction chemotherapy with modified FOLFIRINOX before chemoradiotherapy really might be kind of best practices. The safety profile, even with longer-term follow-up was unchanged. There was not any increase in local recurrences. And again, looking at quality of life metrics there seemed to be similar or maybe improved quality of life for patients who receive the TNT approach. And now again, I think the next step is, as the presenter mentioned, investigating this even in a more tailored fashion, as was done with the PROSPECT study.  Dr. Shaalan Beg: Let's change gears and talk about liver cancer. Abstract 4010 showed the results of the MORPHEUS-liver study. This was a phase 1b/2 randomized trial of tiragolumab in combination with atezolizumab and bevacizumab for people with unresectable locally advanced or metastatic hepatocellular cancer. It's really exciting to see innovations with immune therapy changing how we've managed hepatocellular cancer in the last few years. And here, we're seeing an addition of a third agent to an already approved regimen of atezolizumab and bevacizumab. I was really curious to hear what your take-home message is from this study.   Dr. Shiraj Sen: Yeah, this was another very interesting abstract that was presented at ASCO this year. It's hard to believe that it was only 3 years ago that we first got the approval of atezo plus bev, and that it took more than a decade to really have us as a field improve on outcomes for patients with liver cancer above and beyond giving sorafenib. And here we are just 3 years later, already launching new phase 3 studies from these sorts of early-phase adaptive signal-seeking studies. The investigators as a whole should be commended for the speed at which new drug development has really progressed in liver cancers after, again, quite a lull we had in the pre-I/O days.   It's encouraging to see that in just 3 years that there's another phase 3 study now being launched in HCC on the heels of this data combining the atezo-bev backbone to the anti-TIGIT molecule tiragolumab. Now, I know there was a lot of discussion and some criticism of this study and what the real effects of adding tiragolumab to atezo-bev might be because of the underperformance of the control arm. In this study, the atezo-bev control arm, it should be noted that was only 18 patients, had a response rate of only 11%. And of course, with longer-term follow-up of the IMbrave150 study, we know that with the atezo-bev, we expect a response rate of about 30%. And so how a real-world population of individuals receiving atezo-bev would compare to those receiving tiro-atezo-bev has been discussed. But I think the only real way to answer that question would be with a large, randomized phase III study. And it's encouraging to see that one is being launched to ask that question.    Dr. Shaalan Beg: Absolutely. Let's change gears and talk about pancreatic cancer. LBA4005 explored short-course neoadjuvant FOLFIRINOX versus upfront surgery for people with resectable pancreatic head adenocarcinoma in the NORPACT-1 study. This is a multicenter randomized phase 2 trial and we're starting to see the reporting of clinical trials evaluating the sequencing of systemic therapies for resectable disease. We've heard studies for neoadjuvant therapy for borderline resectable as well as resectable trials in previous meetings. But there's a lot of discussion around the NORPACT-1 trial which may be causing some people to pause on our current understanding of treatment sequencing for resectable disease. I'm curious to hear what your take homes are.   Dr. Shiraj Sen: Thanks. Yes, I thought this was a very interesting study as well. Depending on which institution one practices in, in recent years, many have shifted their practice for individuals with resectable pancreatic cancer from administering full FOLFIRINOX or adjuvant therapy only after surgery to giving it in the neoadjuvant setting based on, again, a number of smaller studies, some that are single institution. This is one of the first studies that in a randomized fashion has asked the question in just resectable pancreatic cancer. So we're not talking about borderline resectable or other patients.    But in resectable pancreatic cancer, whether there are differences now comes if patients receive surgery first, followed by FOLFIRINOX-only adjuvant setting or essentially getting perioperative FOLFIRINOX and so neoadjuvant, followed by surgery, followed by, as tolerated, four cycles of adjuvant FOLFIRINOX. And I was a little surprised by some of the results and to me some of these data were a little intriguing.  Specifically, I think if we take a deeper look like the discussant had after the presentation, there are, I think, some unanswered questions. Specifically, half the patients were randomized to receive neoadjuvant FOLFIRINOX and half of them received upfront surgery. But in the group of individuals who received neoadjuvant FOLFIRINOX, it looked like only half of them completed neoadjuvant chemotherapy. And some answers into kind of why that was, and what it was about those patients then who were in the neoadjuvant arm, is one thing that comes to mind.    Secondly, what I thought was interesting was this study was that it was designed very well to try to take out as much heterogeneity as possible. However, in both arms, there was actually quite a substantial number of individuals who ended up receiving gemcitabine-based chemotherapy. And that's even in the patients who received neoadjuvant FOLFIRINOX, and individuals who received neoadjuvant FOLFIRINOX, only 25% post-op went on to receive adjuvant FOLFIRINOX. And 75% almost received gemcitabine-based therapy. And again, why so many patients received off-protocol adjuvant therapy is something that kind of struck me.  I think the third and final thing that really struck me was, in the patients that received neoadjuvant FOLFIRINOX, there was a higher rate of R0 resections. 56% of patients had an R0 resection compared to those who got upfront surgery, where there was only a 39% rate and similarly kind of higher levels of N0 resection. And yet, despite all of this, again, the authors did show quite clearly that there were not any significant improvements in outcomes for patients that received neoadjuvant therapy, but kind of how improved surgical endpoints do not translate to overall survival and overall endpoints; I think there are still some questions there.    However, I do agree overall that despite these limitations with the conclusions of the author, that at this time at least, it's not clear; the results don't support the widespread use of neoadjuvant FOLFIRINOX as a standard of care for resectable pancreatic cancer. Fortunately, there are studies ongoing, like the Alliance [for Clinical Trials in Oncology] study and the PREOPANC-3 study that hopefully will kind of help settle this verdict.    Dr. Shaalan Beg: Yeah, it's a stark reminder that we need better treatments. I think we've been shifting the sequencing of these treatments and slicing them in as many ways as we can. And the core challenge is in finding better systemic therapies that have been found to be effective in advanced stage as well as in curative stages like this. And one of the points that bothered me about this trial was the drop-off that they saw at the beginning when the biliary system was being drained, or they were getting biopsies because folks who went for surgery upfront didn't always require those procedures. They didn't require histologic diagnosis either. But as is standard practice, before we give systemic therapy, we require psychologic confirmation. And that may have introduced a delay of a couple of days or a couple of weeks, which could have resulted in some imbalances in how survival is measured and how folks were doing. Because, as you know, a lot of times people diagnosed with this disease can be fairly sick, and a matter of a couple of days or weeks can make a big difference in terms of treatment with those.  I'm really excited to wait and hear how the Alliance study and the PREOPANC follow-up trials pan out and as a very important cautionary note for everyone, both the folks who have adopted neoadjuvant therapy and those that have not followed the data. And kudos to the investigators for completing that trial.  Dr. Shiraj Sen: Yeah, I fully agree. I'm glad to see that these trials are being run. I think we should not take anything away from the fact that these are very challenging trials to run. I think we certainly owe a big kudos to the patients who enroll in these studies who have resectable disease, but they're still willing to go through the process of an extra consent form, an extra kind of screening process, additional testing required to go into a clinical trial. And it's only because of them that we're able to run these studies and, as a field, get some answers on how to best take care of our patients.   Dr. Shaalan Beg: Shiraj, thank you so much for coming to the podcast today and sharing your valuable insights on the ASCO Daily News Podcast.   Dr. Shiraj Sen: Thank you so much for having me, and to all of the ASCO staff for having this podcast.  Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.    Disclaimer:   The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers:   Dr. Shaalan Beg  @ShaalanBeg  Dr. Shiraj Sen  @ShirajSenMDPhD     Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn     Disclosures:    Dr. Shaalan Beg:   Consulting or Advisory Role:  Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen   Speakers’ Bureau: Sirtex   Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics   Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune     Dr. Shiraj Sen:   Employment: Roche/Genentech  Stock and Other Ownership Interests: Roche/Genentech  Research Funding (Institution): ABM Therapeutics, Zentalis Pharmaceuticals, Parthenon Therapeutics, Pyxis Oncology, Georgiamune Inc.      
6/28/202318 minutes, 30 seconds
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THOR, CONTACT-03, and Other Advances in GU Cancers at ASCO23

Drs. Rana McKay and Jonathan Rosenberg highlight key advances in genitourinary cancers featured at the 2023 ASCO Annual Meeting, including the THOR study in mUCC, VESPER in muscle-invasive bladder cancer, CONTACT-03 in mRCC, and TALAPRO-2 in mCRPC. TRANSCRIPT  Dr. Rana McKay: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Rana McKay, your guest host for the podcast today. I'm a GU medical oncologist at the Morris Cancer Center at the University of California in San Diego and an associate professor at the University of California in San Diego School of Medicine. Joining me today is Dr. Jonathan Rosenberg, the chief of the Genitourinary Oncology Service at the Memorial Sloan Kettering Cancer Center in New York. We'll be discussing practice-changing studies and other key advances in genitourinary cancers that were featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests featured on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.  Jonathan, it's great to have you with us today. How are you?  Dr. Jonathan Rosenberg: I'm doing very well. Thanks so much for hosting today.  Dr. Rana McKay: Oh, of course. It's always fun to step back from ASCO and reflect on all the practice-changing and practice-informing studies that were presented.  Dr. Jonathan Rosenberg: Absolutely.  Dr. Rana McKay: Maybe we can dive right in with LBA4619. This is the much-talked-about THOR study of erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer with select FGFR alterations. What are your key takeaways from this study?  Dr. Jonathan Rosenberg: It is indeed a study we've been waiting for, for quite some time, to see the results in the confirmatory study after the accelerated approval of erdafitinib. This is half of the THOR trial. There were 2 cohorts of patients. One cohort were patients who previously received a checkpoint inhibitor randomized to chemotherapy or erdafitinib, and those data were reported at ASCO this year. The other cohort was randomized against a checkpoint inhibitor in patients who have not received a checkpoint inhibitor, and we'll see those data in a future meeting.   The bottom line for the THOR study is that FGFR3 inhibition improved overall survival compared with chemotherapy, and the chemotherapy in this study was a taxane. The overall survival was 12.1 months for erdafitinib compared to 7.8 months for chemotherapy with a hazard ratio of 0.64. This led to the DMC to stop the study and blind the data and cross people over. There was also a PFS advantage. There really weren't a lot of new toxicity signals seen; the usual suspects in terms of mucositis, hyperphosphatemia, diarrhea, dry mouth, and onycholysis.  And so, what it tells us ultimately is that in a patient who's progressed on a checkpoint inhibitor, we can feel comfortable about using erdafitinib knowing it provides a survival advantage in patients who've been previously treated for advanced urothelial cancer and have an FGFR alteration, either an FGFR2 or 3. And hopefully, we'll see more data in the future from the study, maybe not too long in the future from the other part of the study, comparing it to checkpoint inhibition.   Dr. Rana McKay: That's really exciting. I think it's exciting to see the data about the positivity of erdafitinib versus chemotherapy in this context. Looking at the phase 3 data is going to be really important. Looking at the data in the IO naive context is going to be really important. I feel like this sort of reaffirms what we've been doing in clinical practice. But how do you feel that the study is practice-changing?   Dr. Jonathan Rosenberg: I think it gives us reassurance that for these patients, erdafitinib is an appropriate option. There's no randomized data between erdafitinib and other choices, such as sacituzumab, which is also based on an accelerated approval, or enfortumab, which is based on randomized phase 3 trial. But it gives us level-1 evidence. I do wonder whether the comparison against the checkpoint inhibitor may turn out differently, but we'll see. Those data aren’t in evidence. And I do think it was interesting that the majority of patients who were enrolled on the trial were PDL-1 low. We'll see what the comparison to a checkpoint inhibitor is like and whether those patients have similar characteristics.  Dr. Rana McKay: Yeah, you're almost kind of selecting for people that were not primed to respond.   Dr. Jonathan Rosenberg: Exactly.   Dr. Rana McKay: Well, that's really exciting, I think. Moving on to localized bladder cancer, Dr. Pfister presented the results of the VESPER trial. That's LBA4507. I think this study was really important. This was a trial that explored dose-dense MVAC with methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine-cisplatin as a perioperative chemotherapy for muscle-invasive bladder cancer. I think there's always been some discussion around these regimens and how they pair up against one another. Can you tell us about these data?   Dr. Jonathan Rosenberg: It's a very interesting study. It was designed back when it was felt that we could not give patients neoadjuvant therapy. And it was designed as either a neoadjuvant or adjuvant approach. Although, in reality, almost everybody who was enrolled in the study got neoadjuvant chemotherapy, which I think speaks to the shift in practice over the last 10 to 15 years towards neoadjuvant rather than adjuvant therapy. It's an interesting trial in that it used a duration of chemotherapy for the MVAC regimen, the dose-dense MVAC regimen that we don't usually use, which is 6 cycles. And functionally, about 40% of patients couldn't make it to 6 cycles and had to stop sooner, versus 4 cycles of q3-week gemcitabine and cisplatin.   And what the data show is that the progression-free survival for the entire intent-to-treat population didn't reach significance. But if you looked at the neoadjuvant population only, there was an improvement in progression-free survival as well as overall survival. So, it's sort of a negative positive trial. Negative for the primary endpoint, but positive for key secondary endpoints. They did a very interesting analysis looking at the number of cycles that patients received regardless of arm, but looking at it by arm. And it's clear from that analysis that the more chemotherapy they got, the better they did.   Although, the flaw in that analysis is that the healthier patients are, the more chemotherapy they're able to tolerate, and therefore that may translate to an improved overall survival irrespective of the amount of chemotherapy. And this was not necessarily a pre-specified analysis. I think some of the statisticians were clutching their chests during the report of this trial, having talked to several afterward. On the other hand, it does say to me that for a fit, younger patient, it is important to consider dose-dense MVAC instead of gemcitabine and cisplatin.   I'll also note, reading the publication from the first part of the trial, that it appears that nobody over 70 was enrolled from everything I could tell. And so, I question the validity of the tolerability of the results for the average 75-year-old that I see in my practice. Although age is not a bright line cut-off for anybody in terms of cancer treatment. But my own experience has been that dose-dense MVAC has been harder to tolerate for a lot of patients in their 70s, whereas I think we should feel quite comfortable giving it to patients in their sixties. And if you ask me how many cycles I would give, I probably wouldn't say 6, for dose-dense MVAC, I would probably say 4.   Dr. Rana McKay: Was there a predilection that there was a more aggressive disease like nodal disease or other things to prompt the 6 versus 4?  Dr. Jonathan Rosenberg: I think that they stopped primarily for toxicity reasons, but it wasn't clear to me that it was a disease-based issue. And for the neoadjuvant therapy, everyone was supposed to be clinically node-negative on entry, so that probably wouldn't have explained it.  Dr. Rana McKay: Very exciting. I know that the data were quite provocative, but I think it's always difficult to interpret these sorts of subgroup of subgroup analyses, and there's a lot of bias in why people may get more versus less. And I think trying to reduce these data to clinical practice is going to be really important, as you've stated.  Dr. Jonathan Rosenberg: Rana, I'd also like to talk about some key advances in renal cell carcinoma that were reported at ASCO. Dr. Choueiri presented data on LBA4500, the CONTACT-03 study, which really was the first study of its kind in solid tumors because it addressed a major question in the kidney cancer field and in other fields: Is there a role for immunotherapy rechallenge after progression on immunotherapy? Specifically, the study looked at the efficacy and safety of atezolizumab plus cabozantinib versus cabozantinib alone after progression with prior immune checkpoint inhibitor therapy in metastatic RCC. I'd like you to tell me what you think of this study and the results and how they may affect our practice.   Dr. Rana McKay: Absolutely. This was a critically important study looking at the role of IO post-progression on IO. It was a large phase 3 trial that enrolled patients with clear cell and non-clear cell patients. It actually allowed patients with papillary RCC, unclassified RCC, to enroll in the study, whereas most of these studies are excluding patients with non-clear cell disease. Patients had to have progressed on an immune checkpoint inhibitor given either as adjuvant first line or second line, given either as a single agent or in combination with one of the other combos, whether a VEGF or IO. And patients were randomized one-to-one to receive the combination of atezolizumab plus cabozantinib versus cabozantinib alone. And the dosing of the cabozantinib here is at 60 milligrams in the combination, which is the standard dosing of cabozantinib monotherapy. And the primary endpoints for the trial included PFS and OS.   And in essence, this trial was a completely negative study. The primary endpoint, which was centrally reviewed, rPFS, was negative. The hazard ratio there was 1.03. Overall survival was also negative with a hazard ratio of 0.94. And when you look at the subgroup analyses, there really wasn't any specific subgroup that seemed to derive any benefit, potentially those that had a prior response to an immune checkpoint inhibitor, but in essence, a negative study.   And I think these data are really informative because the discussion at ASCO was conducted by Dr. David Braun, and he actually had conducted a very highly scientific Twitter poll to help guide how to interpret the data and what people do. And from that, about 30% of individuals that completed the poll were actually layering on IO therapy, and continuing IO therapy after somebody progressed on therapy layering in a TKI while keeping the IO backbone going.   And I think what this study proves is that we really don't have any really robust data to guide doing that at the present time. And what we may end up doing is compromising the efficacy of the oral TKI or dose-compromising the oral TKI to try to maintain an ineffective IO. And so, I think at the present time these data, while negative, were truly practice-informing. There are other studies that are looking at this strategy as well. I think one of the criticisms here is that atezolizumab really has not had a great track record in renal cell carcinoma in every single context where it was tested, either alone or in combination. It has not met its primary endpoint and it's not utilized as a treatment in RCC. So, there's some discussion that could this be the fact that this is a PDL-1 inhibitor and that it's atezolizumab. And additionally, I think the thing to point out for is that in the modern era if we look at the cabozantinib control arm, cabozantinib in the refractory setting had a PFS of 10.8 months, which is pretty impressive for a later line PFS, if you will. So, there is another study currently ongoing called the TiNivo-2 study that's looking at tivozanib plus nivolumab versus tivozanib alone in a similar patient population. That trial is enrolling only clear cell patients that had progressed on prior IO. So, I think we'll have additional data, but very, I think, informative. I think this question comes up in a lot in other tumor sites as well because of the broad use of checkpoint inhibitors across hematologic and solid tumor malignancies.   Dr. Jonathan Rosenberg: I think this was the most informative negative study and the most negative trial I've seen in a while as well. But it did highlight the importance of asking these questions where people assume they know the answer already, and in fact, we often don't, and our assumptions are wrong. So, I thought that was fascinating and very well described.    Staying in the kidneys arena. I'd like to talk to you also about the phase 2 KEYNOTE-B61, that's Abstract 4518. It looked at first-line lenvatinib and pembrolizumab across non-clear cell carcinomas. Tell me what you thought of the trial and what your takeaways were.   Dr. Rana McKay: This is an important study. I think the treatment of non-clear cell RCC has lagged. I guess the advances have lagged behind clear cell RCC, and really robust phase 3 randomized studies in people with non-clear cell histologies are very limited. This was a single-arm phase 2, so I think we need to kind of take that for what it's worth, that enrolled patients who had non-clear cell RCC per investigator that had received no prior systemic therapy. So, this was a frontline study, and patients received pembrolizumab plus lenvatinib until disease progression or toxicity.   The study enrolled a very robust 158 patients, which is pretty impressive for a modern-day non-clear cell cohort. We've seen data from nivo-cabo that had gotten presented previously by Dr. Lee. That study was a single institution, about 40 patients or so if you will. The primary endpoint of this study was objective response rate, and the bulk of the patients that were enrolled were papillary RCC. As you would imagine, around 60% of patients were papillary. It did include around 18% with chromophobe RCC. And when we break things down by IMDC risk category, about 44% of patients were favorable-risk disease. I think the percentage of patients who were favorable is higher than if we were to take an all-comer metastatic RCC patient population.   But the objective response rate was pretty impressive at 49% with this combination. The CR rate was right around 5.7%. So, I think certainly a pretty solid signal of efficacy. But again, this is a single-arm phase 2 study. I think what's also really interesting, and I think we have to take subset analyses with a grain of salt if you will, but there were responses that were seen across all histologies. And the prior nivo-cabo study that I had shared with you had previously done a futility analysis for patients with chromophobe RCC, and that cohort actually closed down. And in this study, the response rate for the chromophobe patients, though it wasn't a lot of patients, 29 patients with chromophobia RCC, was around 27.6%, so I think these data are certainly informative. If you look at the waterfall plot, there were some deep responses that were certainly observed, and the bulk of patients had some degree of tumor shrinkage with very little patients that had primary PD.   Dr. Jonathan Rosenberg: It's really provocative. So, are we getting to a point where we might start thinking about randomized trials in the non-clear cell population to try to establish the best standard of care?  Dr. Rana McKay: Well, I think PAPMET2 is currently enrolling patients. That study is looking at the combination of cabozantinib with atezolizumab versus cabozantinib alone for frontline papillary. PAPMET1, which was led by Dr. Pal, I mean, these studies are really magnanimous because it takes all hands on deck to get these patients enrolled because they're few and far between. So, I definitely think we need to be moving in that direction. And I think we need to be moving away from lumping all non-clear cells into one bucket because I think what we're seeing is that, one, the biology of these tumors is very distinct and unique, and they don't all behave the same to any one given therapy. So, we really need to move away from just lumping all non-clear cells into one bucket and try to actually conduct studies for each specific subtype.    Dr. Jonathan Rosenberg: Understood and agree. Let's switch gears for a second and talk about prostate cancer. Can you talk about the data from Abstract 5004, the TALAPRO-2 study of talazoparib and enzalutamide compared to placebo and enzalutamide as a first-line treatment with metastatic CRPC that have HR homologous recombination repair gene alterations?    Dr. Rana McKay: Absolutely. So the TALAPRO-2 study is one of three studies that have looked at the combination of PARP inhibitors with an ARSI in the frontline mCRPC setting. And this trial randomized patients to talazoparib and enzalutamide versus placebo enzalutamide. And again, this was first-line mCRPC. Patients were allowed to have received prior docetaxel or prior abiraterone in the castration-sensitive setting, and the primary endpoint was overall survival.  At GU ASCO this year, we saw the top-line data from TALAPRO-2 first get presented. And what was actually presented at this meeting was the subset of patients that were HRR-mutated only. They had two cohorts: an all-comer cohort that was previously presented, and then now they're presenting the subset of the patients that were HRR-mutated. And I think what we've seen across the board is that the efficacy of PARP inhibitors kind of differs by underlying HRR mutations.     When we look at the entire population of HRR-deficient patients, the study was positive, talazoparib plus enzalutamide resulted in an improvement in rPFS compared to enzalutamide placebo. The hazard ratio there was 0.45. And then when we break things down by selected gene groups, they did this subset analysis in patients with only BRCA1, only BRCA2, only PALB2, only CDK12, ATM CHEK2 if you will. The data are most robust for those patients with a BRCA1/2 alteration with hazard ratios of 0.17, 0.19. Again, this is for rPFS.     But then, when we look at some of these other mutations, like ATM CHEK2, hazard ratios are higher, 0.76, 0.90. So, the effect size really kind of drops off for those non-BRCA1/2 altered HRR genes. But if we look across the different subgroup analyses, the interim OS data for the HR deficient, the time to PSA, time to cytotoxic chemo, all of that favored the combination versus placebo enzalutamide for patients that were HR deficient if we just lumped everybody all together.  Dr. Jonathan Rosenberg: How does this fit into the general landscape around this question with selection versus not selecting for HRR alterations?  Dr. Rana McKay: The data that were presented were for the selected patients, and I think that that's not where the controversy is. I think that the selected patients are the ones that seem to derive the most benefit. It's interesting because in looking at the data from PROpel and the final FDA label based off of the PROpel data, the label is only for BRCA1 and 2 patients and not for all comer HRR. It's even a more restricted label than olaporib monotherapy. So, I think it's going to be interesting. I don't know what the right answer is. I think it's going to be interesting to see how this is going to unfold for TALAPRO-2 and even for MAGNITUDE, if you will, like, how select is the selected population going to be. But at the present time, I think the label is what it is for olaparib plus abiraterone in those BRCA1/2 frontline. My hope is that this population is shrinking because everybody should be getting escalated in the metastatic hormone-sensitive setting, and we shouldn't be having people who are naive to an ARSI in frontline mCRPC.  Dr. Jonathan Rosenberg: Understood and agreed.   Dr. Rana Mckay: Well, thank you so much, Jonathan, for joining me today. It's really been a pleasure kind of going through all of the compelling advances in GU cancers from ASCO. I think it was a really exciting meeting, and thanks for your time. Dr. Jonathan Rosenberg: My pleasure. It's been great to talk to you today.     Dr. Rana Mckay: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Follow today’s speakers:    Dr. Rana McKay  @DrRanaMcKay  Jonathan Rosenberg  @DrRosenbergMSK    Follow ASCO on social media:     @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:    Dr. Rana McKay:   Consulting or Advisory Role: Janssen, Novartis, Tempus, Exelxis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Pfizer, Bayer, Tempus   Dr. Jonathan Rosenberg:   Honoraria: UpToDate, Medscape, Peerview, Research To Practice, Clinical Care Options, Physician Education Resource, MJH Life Sciences, EMD Serono, Pfizer  Consulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol-Myers Squibb, Bayer, BioClin Therapeutics, QED Therapeutics, Pharmacyclics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Merck Therapeutics, Immunomedics, Tyra Biosciences, Infinity Pharmaceuticals, Gilead Sciences, Hengrui Pharmamedical, Alligator BioScience, Imvax  Research Funding (Institution): Genentech/Roche, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas Pharma  Patents, Royalties, Other Intellectual Property (Institution): Predictor of platinum sensitivity      
6/27/202323 minutes, 25 seconds
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Spotlight on Immunotherapy at ASCO23

    Drs. Diwakar Davar and Jason Luke discuss KEYNOTE-716, KEYNOTE-942, RELATIVITY-047, and other key advances in melanoma, including the promise of mRNA vaccines in melanoma and potentially other cancers, as well exciting advances in neoadjuvant therapies across malignancies featured at the 2023 ASCO Annual Meeting. TRANSCRIPT  Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh Hillman Cancer Center. I'm delighted to have my colleague and good friend Dr. Jason Luke on the podcast today to discuss some practice-changing studies and other advances in immunotherapy that were featured at the 2023 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapy Center, as well as the associate director of clinical research at the University of Pittsburgh's Hillman Cancer Center.     You can find both of our disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.   Jason, there was a lot of exciting data in the immunotherapy space highlighted at the Annual Meeting, and it's great to have you back on the podcast to discuss some of this work.   Dr. Jason Luke: Thanks for having me.    Dr. Diwakar Davar: So, the abstracts that we had selected have several key themes. We'll be covering some of the early advances in melanoma in the stage 2 and stage 2B/C space with KEYNOTE-716. I think this is a study that you know a little bit about seeing you are the presenting author and the principal investigator for the study, as well as the pivotal KEYNOTE-942 trial. And then going on to themes with using third-generation checkpoints, neoadjuvant therapy in non-small-cell lung cancer, and cutaneous squamous cell carcinoma.    But we'll start with KEYNOTE-716. So, this is LBA9505, the study which evaluated pembrolizumab versus placebo as adjuvant therapy in stage 2B and stage 2C melanoma patient population for which historically there was no real effective therapy other than remotely interferon. And these are the final results of the DMFS analysis from this phase 3 trial. So, Jason, what are your thoughts about this, and can you contextualize the results relative to the recent publication?   Dr. Jason Luke: Thanks. I think the important point to level set on this was just a few years ago; this was a population of patients that we didn't treat in clinic. In fact, sometimes they weren't even referred to medical oncology for evaluation. And that was despite the fact that we knew from historical data that the risk of melanoma-specific survival, death from melanoma, was just as high for this population of patients as it was for the patients with stage 3 melanoma, where obviously adjuvant immunotherapy has been a standard for quite some time. And so we launched this clinical trial, KEYNOTE-716. It was a global, randomized phase 3 study of almost 1,000 patients, randomizing patients to either get pembrolizumab or placebo. Importantly, these patients being those with deep primary lesions, stage 2B and 2C with negative sentinel lymph node evaluation.    People will recall that this study hit its primary endpoint on the first protocol-specified analysis at a year. And what we updated at ASCO this year was the final analysis of distant metastasis-free survival. Obviously, an important secondary endpoint because if patients eventually going to develop metastatic disease and pass away, it's the distant metastasis that we worry about. And what we saw in this trial with a landmark 36-month follow-up median of 39 months was that the benefit was increasing. In other words, the magnitude of the hazard ratio change was increasing over time as would be expected, such that at this analysis there was a 41% reduction in the risk of distant metastasis for patients treated with pembrolizumab versus placebo. And we saw a consistent benefit in the recurrence-free survival also out through that same period of time and importantly no change in the safety summary with of course the adverse event profile of pembrolizumab being what it is and well understood across oncology.    So I think these are very important data because they really kind of set the stage for the field. It is now the case that at least discussing adjuvant therapy for patients with stage 2B and 2C is the standard of care; it should be offered to all the patients. Of course, it's always a risk-benefit about whether or not patients want to pursue adjuvant therapy versus consideration of treatment at the time of recurrence. But in my clinic at least, many patients do prefer to try to eliminate the possibility of recurrence and distant metastasis as much as possible.    So I think these are very important data because they really level set the field for what to expect in this population of patients and then they also start to set the table for what's going to come after this. And that's going to be sort of the next step in our conversation here because the next generation of adjuvant studies in melanoma are now going to think about all of melanoma in the adjuvant setting as really one entity, starting from stage 2B going all the way through stage 4 resected. And that'll be relevant actually as we talk about the next abstract that will come in this discussion.   Dr. Diwakar Davar: Just to underscore, positive RFS data, positive DMFS data, and now this therapy has currently got regulatory approval in this investigation and is approved in the United States and certainly in Europe and Australia. One interesting point that we will probably have to contend with, and some of the listeners may be thinking about, is overall survival. So the last adjuvant study that demonstrated overall survival benefit was actually ipilimumab, and increasingly, the Illuminati in melanoma do not believe that we will ever see OS benefit in this disease going forward, even though it has to be an endpoint in all registration phase 3 trials. So, Jason, what are your thoughts about whether or not we'll have a positive OS readout, and even if we don't, why this is still a very important advance in this disease at this time?   Dr. Jason Luke: Your points are well taken. I think it's unclear, probably trending towards unlikely, that we would see an overall survival advantage in this trial given that we have not seen that in the stage 3 adjuvant studies. Now people can debate if, whether or not overall survival is the only meaningful endpoint for patients. I personally do not believe that's true. And to me, preventing recurrence has a value in and of itself, whether or not that's connected to overall survival. And part of the reason that I say that is that for an average patient, the median patient on a trial, of course, we can tell them treatment now, treatment later. It's a wash when you look at the overall study. And yet at the same time, for an individual person who's facing melanoma or cancer, generally they're not going to be the average patient; they're going to be one patient. And it's very possible they could end up with the type of recurrence that in fact is not highly treatable at that time.     So I think that's really the nuance that goes into those adjuvant discussions. The regulatory endpoints have been recurrence in melanoma for a long time. And I think it's important that patients understand the pros and the cons of each. The complexity in adjuvant therapy and neoadjuvant therapy is you don't necessarily know that you had to have it. You're only really going to know whether or not it didn't work if you recur later on. But to me and in my clinic, most patients are willing and interested to want to pursue those therapies in the perioperative setting to try to reduce the possibility of ever developing metastatic disease.    Dr. Diwakar Davar: Excellent. So I think key advance [is] positive DMFS data to add to the earlier reported RFS data and truly practice-changing.     So, moving on to the next study, LBA9503. This is the phase 2 trial of the Moderna vaccine. This is the trial that almost every medical oncologist knows intimately or has been called about by either the press or patients. So what is this study? This essentially is a phase 2 trial evaluating the personalized cancer vaccine PCV Moderna, made by Moderna, the mRNA vaccine, that is being studied in combination with anti-PD-1 pembrolizumab in the stage 3 BCD and stage 4 resected setting. And so there are really two very interesting results here because this is an update of the RFS data that was presented at AACR earlier this year, which was positive. What are your takes on the DMFS results, and maybe a quick blurb on how is this vaccine generated for those who may not be aware of this particular platform?    Dr. Jason Luke: Yeah, certainly. So this individualized neo-antigen therapy, as we're now calling it, is a technology platform that allows us to develop an individualized treatment for each patient based on their own cancer. So taking the actual tumor specimen, whole exome sequencing is performed to try to identify changes in the DNA, and then through a reasonably complex bioinformatic pipeline, those mutations that are likely to generate proteins that can be bound within class 1 MHC molecules are then identified in the computer and then synthesized with an mRNA, very similar to the way that the COVID vaccines were made. And then that becomes the actual drug.    So in the clinical trial, which was KEYNOTE-942, about 160 patients were randomized 2 to 1 to receive either pembrolizumab for a year as per standard adjuvant therapy but then with the addition of the individualized neoantigen therapy starting with dose 3 and throughout the rest of the year versus the control arm of pembrolizumab as the standard of care. As you mentioned, the recurrence-free survival were highly positive in this trial when it was first presented earlier this year, and at the updated ASCO we see the 18-month RFS in which the hazard ratio continues to be maintained. But I think most impressively is that distant metastasis-free survival, where we saw an even greater advantage for distant metastasis-free survival – hazard ratio here being 0.35. And so that's a huge advantage for distant metastasis-free survival in this population of patients.     And very interestingly in the clinical trial, when you follow the Kaplan-Meier plots, what you see over time is that they overlap almost the entire first year. And it's really at about a year, basically after the vaccine has had time to kick in and these neoantigens have been identified, that we then start to see the separation of the curve, which looks very flat over time. And so I think this is a very, very exciting kind of technology platform and very exciting results because there was minimal increase in toxicity – just at the site of the local injection – for the addition of the individualized neoantigen therapy.    And beyond that, hypothetically, this is not necessarily just a melanoma thing. So, of course, based on these phase 2 results, a phase 3 clinical trial called KEYNOTE-V940 is going to be launching later this year to compare pembrolizumab versus pembrolizumab plus this V940 individualized neoantigen therapy. And we're very, very excited in the field to see what those results will look like because the concept here is you could really, really enhance adjuvant therapy with this kind of an approach. Meanwhile, we're just about to talk in a little bit about all the exciting things happening in the neoadjuvant space as well. And with no increase in toxicity, obviously, that looks really good.    Suffice it to say that this technology is not specific to melanoma but rather could be applied almost to any cancer where we think about an adjuvant therapy platform. So I think the results are very, very exciting. It is a phase 2 study and it does have some caveats about not being the largest study and some other things, but you can't help but be impressed by the data that have been presented here so far.   Dr. Diwakar Davar: One important plug, I guess, in addition to that is that you mentioned that there's data using the platform in other diseases. And one really exciting paper that came out recently was Dr. Vinod Balachandran's paper; for those who haven't read it, it's in Nature, and really in a very provocative proof of concept study, they studied the platform, the vaccine plus checkpoint inhibitor therapy plus chemotherapy in a highly adverse tumor patient population. So these are patients with resectable pancreatic cancer who had the vaccine generated from pancreatic cancer that was resected after Whipple surgery. And extraordinarily, out of the 16 patients who had immune responses, 8 of them did not have relapse at a median follow-up of almost a year and a half, which is really quite extraordinary given the lack of really any effective drug outside of chemotherapy in that setting.     So, the point that you're making regarding the benefit of this therapy, suggesting that it could potentially be extended to not just melanoma, potentially other tumors such as highly immunogenic tumors, and potentially even nonimmunogenic tumors such as pancreatic cancer, really suggests that this is going to be a very exciting landscape. And potentially this area, adjuvant therapy and neoadjuvant therapy, like we'll talk about, is potentially an area in which other drugs and potentially combinations will be developed.    So next, we will be discussing 3 abstracts evaluating the theme of combinations, and these abstracts are 9501, 9502, and 4010. Abstract 9501 is an evaluation of the combination of fianlimab and cemiplimab anti-LAG-3 and anti-PD-1, respectively, in advanced melanoma, specifically focusing on the post-PD-1 experience in this disease by Dr. Omid Hamid. 9502 is the updated 2-year survival results from RELATIVITY-047, which evaluated nivolumab and relatlimab against nivolumab alone in frontline metastatic melanoma. And Abstract 4010 are the results from the MORPHEUS platform study, specifically looking at tiragolumab and atezolizumab in patients with advanced unresectable HCC.    But focusing on 9501 and 9502, Jason, what do you make of the combination of fianlimab and cemiplimab post-PD-1 setting?   Dr. Jason Luke: I think the data look very intriguing for this second combination of PD-1 and LAG-3 combination. When nivolumab and relatlimab, the approved LAG-3 inhibitor, kind of burst on the scene a couple of years ago, it was somewhat to the surprise of a lot of people in the community who had really come to think that while PD-1 and CTLA-4 were core molecules for therapeutics and cancer, that we just weren't ever really going to see something else come along in checkpoint blockade. And so nivo and rela got approved. We'll talk about them again in a second. But the data now coming forward for another PD-1 LAG-3 combination, again with cemiplimab PD-1 and fianlimab LAG-3, looks very, very promising.    So in Abstract 9501, they updated a phase 1 expansion cohort, phase 2 cohort looking at patients across the various different settings. And whereas in the treatment naive frontline metastatic setting they had previously described about a 63% response rate, they saw a similar level of response rate in patients who had previously gotten adjuvant anti-PD-1, had a period of time off treatment, and then were treated again. And that was reassuring because it suggested that this is still an active combination even with prior exposure to IO in the past.     Now, the thing that I found to be the most interesting about this combination was whereas with nivo and rela, at least from the RELATIVITY-047 phase 3 trial, it looked like there was less benefit in some of the high-risk population cohorts, at least for this combination in early testing for cemi and fian; like we talk about it sometimes, we saw there was a high response rate even in patients with liver metastases and some other high-risk features. And so I think this combination looks quite potent, and I'm very excited to see what the data will look like. I think it's very unlikely we'll ever actually get a randomized trial of two PD-1 LAG-3 combinations against each other. But suffice it to say that the data we've seen so far for fianlimab LAG-3 with cemiplimab PD-1 looks very intriguing. It certainly justifies the frontline metastatic phase 3 and the adjuvant phase 3 trials that are already in planning or ongoing.   Dr. Diwakar Davar: So one thing to consider is on the RELATIVITY-020 trial – the early trial that was led by Dr. Ascierto that really took a long time to read out – the response rate in patients with prior checkpoint inhibitor therapy was quite low. In fact, the data was quite surprising, as you'd mentioned that we had even seen this movement in the frontline setting because the response rate by BICR was only about 12%. So do you feel like the 2 LAG-3 inhibitors are fundamentally different? And if so, can you speculate as to why that might be? Again, with the caveat to the fact that these are very early data and we don't have enough information. And maybe we can also talk a little bit about the 2 pending trials that are ongoing in the advanced and adjuvant therapy landscapes perspective.   Dr. Jason Luke: I think we don't have enough data yet to truly understand whether or not they're really different. The trials that have been run so far are so different that it's hard to compare things back and forth. You can notice that the dose, the milligram dosage of fianlimab in terms of anti-LAG-3 is quite a bit higher, like a log fold higher almost than with relatlimab. And so there's some question of whether or not just merely more drug-blocking LAG-3 might in fact be more efficacious relative to the dose that's approved for relatlimab in melanoma. But beyond that, I think the data hold up very well for this new combination, again noting all the caveats about cross-trial comparison to, say, it looks to be at least as potent, possibly more potent than the relatlimab combination. But again, I think probably we need to see the data from randomized trials and how that fits into the landscape when the trials actually read out because there's a lot of things going on in melanoma that are likely to change between now and then.   Dr. Diwakar Davar: So just to draw people's attention, there are actually 2 ongoing pivotal phase 3 trials: fian plus cemi versus pembro in patients with advanced metastatic and locally advanced, previously untreated melanoma, as well as an adjuvant trial of the combination against pembrolizumab. Again, highly high-risk resected melanoma. These trials are ongoing. We don't have the results yet and we are looking forward to them.    Now, 9502, a 2-year RELATIVITY-047 result presented by Dr. Hussein Tawbi.    Dr. Jason Luke: So this is the study we were just alluding to before, the randomized phase 3 study of nivolumab versus nivolumab plus for relatlimab. To me, the most useful data sort of updating with this two-year survival follow-up is to show the maintenance of benefit between the 2 arms. And so, consistent with what we saw with nivolumab and ipilimumab, there seems to be a persistent delta between the arms for both progression-free and for overall survival out over that extended period of time, where we can see with that updated data now, at 2 years, that it's 52% of patients still alive on the relatlimab combo versus 42 with nivolumab. And it does seem like this is probably a higher-risk population of patients than participated in CheckMate-067.    So it's a little bit difficult to compare the landmarks except to notice that that difference between the control and experimental groups is consistent over a long period of time and that there were no new safety signals either, and so that was also reassuring. To me, the most interesting nugget of data in the abstract, though, is to look at what happened to patients after they were on the first-line treatment. So one of the big questions in our field is really “If patients get nivolumab and relatlimab upfront, what should they get after that?” Should they then get nivo plus ipi, or vice versa? And I think we don't have an answer clearly to that question just yet.    There was an important letter to the editor of the New England Journal now going on about a year ago by Alex Menzies and colleagues that suggested that the use of ipilimumab was attenuated, the utility of it, after a prior exposure to nivolumab plus relatlimab. They quoted a response rate on the order of only about 10% for patients who got an ipilimumab-containing regimen after initial LAG-3. In the data from Hussein Tawbi at ASCO, however, in a small number of patients, caveat, the response rate was more in sort of the low 20% range, 22% to 25%. And so that would be a much more meaningful and important sort of consideration. If we do have independent activity, then lining up sequential therapies and the toxicities associated with each will become increasingly important as we think about how to maximize these kinds of treatments for our patients, but important longer-term data to show that the benefit is holding up and it's safe, and some new insights into what to do after progression on one of these regimens.    Dr. Diwakar Davar: So, pivoting slightly to combinations, we are going to be discussing a combination of TIGIT plus checkpoints. So tiragolumab is the FC-active TIGIT inhibitor from Regeneron-Roche and this is currently in multiple pivotal phase 3 trials, several of which have been negative, including SKYSCRAPER-01 in non-small cell lung cancer and SKYSCRAPER-03 in small cell lung cancer. The MORPHEUS platform trial essentially is a platform study evaluating multiple different combinations, in this case in liver cancer. And so we have a very interesting Abstract 4010, which is giving us an early readout of the evaluation of tiragolumab plus atezolizumab along with bevacizumab in unresectable, locally advanced or metastatic hepatocellular carcinoma giving us a result that is a little different from what we had seen from the prior negative results of TIGIT. So Jason, what do you make of these early results in the advanced HCC setting?   Dr. Jason Luke: I think these are cautiously intriguing results to really highlight the point is the third checkpoint possibly being LAG-3, now a fourth checkpoint maybe with TIGIT, but with all the caveats that you talked about. In this study, the flow is that there's a continuously accruing control arm which in hepatocellular carcinoma is a combination of atezolizumab plus bevacizumab, and then other arms are added where you add in a third agent. In this case, it's the anti-TIGIT tiragolumab. And in an intriguing fashion, the response rate to the triplet was 42.5% compared to the doublet which was only 11%. So that's a pretty big difference in this population.     Now, it wasn't the largest study, only 58 patients, but it was a randomized clinical trial. And so I think those data really make people kind of open their eyes again. It's worth a little bit of a caveat here that HCC is an unusual cancer in that what is deemed to be unresectable and therefore amendable to systemic therapy is a moving target and that requires multidisciplinary evaluation of patients. And so I think a larger number of patients would really be needed to fully understand this. But certainly, a fourfold increase in the benefit or in terms of response rate looks quite intriguing.    I think the other piece of this is to be just cautious a little bit was when the initial data in non-small cell lung cancer in the CITYSCAPE study came forward, and they looked roughly sort of like this: There was more than a doubling in the PFS and the response rate, which is what triggered all of those phase 3 studies. So to me, this is enough to continue to be very interested in TIGIT as a therapeutic target. And there are many phase 3 trials already ongoing. And so I think, I'm cautiously optimistic that some of those actually will be positive and we could see more movement around TIGIT becoming a standard of care agent.    Dr. Diwakar Davar: To your point about TIGIT being an interesting target, recent data looking at the neoadjuvant landscape in melanoma from Merck, with Merck, also FC-active TIGIT and also some data from authors looking at that TIGIT also presented in this case at ASCO specifically from the ARC-7 study. So very interesting target. Several pivotal trials have been announced. Do you know of any trials that are ongoing in the adjuvant setting in other diseases?   Dr. Jason Luke: Well, as you alluded to, the vibostolimab data in melanoma for TIGIT in the neoadjuvant setting was interesting. And in fact, that has been enough to trigger a global, randomized phase 3 adjuvant study of pembrolizumab and vibostolimab versus pembrolizumab in melanoma. And that sort of takes us back to the beginning of our discussion here, building on the KEYNOTE-716 data. So, yes, TIGIT will be moving forward in the adjuvant space in melanoma and obviously at a static setting for several different tumor types with a PD-1 or PD-L1 backbone.   Dr. Diwakar Davar: So now pivoting towards neoadjuvant therapy and non-small cell lung cancer. The standard of care in this setting was established by the CheckMate-816 trial that essentially established nivolumab plus chemotherapy in the setting of resectable non-small cell lung carcinoma path. Response rate in this setting is approximately 21%. And we have several studies that are essentially looking at novel combinations or in this case, different PD-1 inhibitors in this setting. So Abstract 8500 essentially looked at nivolumab plus relatlimab from a NEOpredict-Lung trial. Jason, do you want to tell us a little bit about this?    Dr. Jason Luke: Yes, I think this is a very interesting study and that this is sort of our first peek at targeting LAG-3 in the context of lung cancer. So obviously we talked about LAG-3 for melanoma. Although the audience is probably aware that there have been neoadjuvant data for LAG-3 with relatlimab in melanoma that substantiated the phase 3 data for the metastatic setting. So one of the questions as we start to apply the LAG-3 in other diseases would be, “Do we see it hold up in both metastatic disease and in the neoadjuvant space?” But in this study, while there were no changes in the safety profile; it didn't impact on whether or not patients could have surgery. There really didn't look to be a big difference in this study between nivolumab and nivolumab plus relatlimab, with the major pathologic response as you alluded to right around 30% for both arms.    Now, it wasn't really the biggest study, but that's certainly quite a bit in contrast with what we've seen in melanoma, where with a PD-1 inhibitor you get again 25%-30%, but with adding on LAG-3, that pushes you up closer to 60%. So I think these were very interesting data that probably put a little bit of an eyebrow raise to say, “Well, let's see what happens in the metastatic setting in lung cancer with the addition of relatlimab LAG-3 on top of a PD-1.” I think it might not be quite so straightforward as what we saw in melanoma, but we'll look forward to those results because those phase 3 trials in metastatic lung cancer should be maturing sometime in the next year or two.   Dr. Diwakar Davar: The theme of neoadjuvant therapy non-small lung cancer, LBA100, which has again previously been discussed in an episode of this podcast by Dr. Jack West and Dr. Velcheti is KEYNOTE-671. And this is a study essentially that looked at pembrolizumab or placebo with platinum-based chemotherapy doublet and followed by resection. So again, a direct parallel to CheckMate-816. What do you make of the results that were reported by our colleagues in this setting, Jason?   Dr. Jason Luke: So not to rehash this, because our colleagues in the lung cancer group have already discussed this at length and obviously they're experts in that disease, but we'll just note that there was a threefold increase in major pathologic response, which turned into a major advantage for event-free survival. And so I think this is at least the third PD-1, PD-L1 combination regimen for neoadjuvant lung cancer that looks very, very promising. It certainly, to me, seems like neoadjuvant consideration really should be the standard of care already moving forward.   To me, what the big question that is left with is “Do we still need the adjuvant component after we give the neoadjuvant?” So, some of the trials are including neoadjuvant and adjuvant, some of them are only neoadjuvant. And I think that's going to be a really important question as we move into the future, both in terms of what is that contribution of the adjuvant component, and then again, going back to earlier in our discussion here, if there could be a major advantage to adding individualized neoantigen therapy, maybe it is important to have both. But I think that's one of the big questions we have to get teased out by the field over the next couple of years.   Dr. Diwakar Davar: And finally pivoting towards cutaneous squamous cell carcinoma. We have 2 abstracts discussing perioperative therapy. So cutaneous squamous cell carcinoma is a high-TMB tumor. The median tumor mutation burden in this disease is threefold that of melanoma. This is a disease in which checkpoint inhibitor therapy is approved as a single agent both with pembrolizumab and cemiplimab on the basis of nonrandomized phase 2 trials. And increasingly, there has been early development in the perioperative setting. The first data in this space came from our colleague Dr. Gross at MD Anderson, who reported in a small, nonrandomized phase 2 trial of 20 patients, a path CR rate with two cycles of cemiplimab at approximately 50%.    A larger multi-institutional phase 2 trial demonstrated that a longer duration of perioperative therapy of four cycles or 3 months of cemiplimab did not particularly improve the path response rates. The response rates were similar at approximately 50% as well. And what we have right now are 2 other trials. The first is the MATISSE trial, Abstract 9507 ,that evaluated nivolumab or nivolumab plus epilimumab in this disease. And the other one was the NEO-CESQ trial, or Abstract 9576, that evaluated neoadjuvant plus adjuvant therapy that's cemiplimab in the high-risk patient population. So we're starting with 9507. Jason, what do you make of the ipi and ipi-nivo data reported in this setting?   Dr. Jason Luke: So I think this is a really interesting study because I think part of the intent is the clinical aspect of how you manage patients with cutaneous squamous cell carcinoma. For those that don't do cutaneous oncology, many of these patients have the development of lesions, which can be actually quite difficult to resect in a way that's not otherwise mutilating or cosmetically quite problematic. And that was part of the impetus for this trial where, again, they looked at either monotherapy PD-1 or a PD-1 plus CTLA-4, and they saw great success. As was predicted based on the other data that you alluded to, response rates are more than 50% near 60%, with actually a substantial number of patients on the trial actually refusing to have surgery after they received their neoadjuvant therapy because they were so certain that they had had a good outcome.    So I think these data are quite reassuring in the context of all of this emerging data around cutaneous squamous cell carcinoma. We'll talk about this NEO-CESQ trial in just a second, but I think it really is emerging to be the standard of care very soon for the use of perioperative PD-1 for cutaneous squamous cell.   Dr. Diwakar Davar: What do you feel about the dose and schedule of checkpoint inhibitor therapy used here? So the dose of ipilimumab used was ipi-1 and not ipi-3, and they waited 4 weeks. So when patients only got two cycles of Q2 weekly nivo, and one cycle of ipilimumab, do you think the responses would have been deeper if they'd waited longer?   Dr. Jason Luke: I think it is possible that they might have been deeper, although I'm not totally sure about that. One of the other abstracts we're not directly mentioning here was a study in Merkel cell carcinoma which suggested that in fact, adding ipi and that also highly immuno-oncology-responsive tumor type did not add to the response rate. So I'm not totally sure about that. I think rather what would be most interesting here is sort of the sort of next generation of biomarker work.    As part of their presentation, the MATISSE trial team showed gene expression profiling that really strongly identified which patients were going to do well on the trial. And I think that's probably eventually going to be how we need to think about this. There are patients in the neoadjuvant setting who are going to do really well with anti-PD-1 alone. And then for those who aren't, that's where we probably really need to think about do we need combos, how long to give the treatment, etc. And I think we're really only on the cusp in the beginning of this, which is exciting as we think about moving into the future.    Dr. Diwakar Davar: Certainly, many combinations are being evaluated in this space and we are very excited for the data that it's about to hopefully come in the next couple of months to years.    So the NEO-CESQ – it’s quite a puzzle as to how to pronounce this acronym – and this evaluated cemiplimab in the high-risk setting. So it's worthwhile noting that Dr. Gross's first trial looked at high-risk stage 2, 3, and 4 disease. So the context of cutaneous squamous cell carcinoma that's node-positive disease and distant metastatic disease that is in one location or patients with node-positive disease invention. And his multi-institutional cemiplimab trial of four cycles evaluated included patients with stage 2, 3, and 4 disease.    So here in a study just in stage 3 and 4 diseases, Dr. Ascierto reported the results of 2 cycles of cemiplimab and importantly, these patients had both the neoadjuvant and the adjuvant portion of cemiplimab. So, Jason, you mentioned earlier that one of the key aspects that we start thinking about neoadjuvant therapy is exactly how much do you need. Do you need both the pre-surgical therapy and the post-surgical therapy? Is the presurgical therapy enough? After all, neoadjuvant response equals cure. How much benefit are you getting from post-surgical portions? So what do you make of the results that they've seen here and what is the impact? How do you think we'll be disentangling the impact of the neoadjuvant and the adjuvant portion of the immunotherapy upon response and survival?    Dr. Jason Luke: So just to leverage those comments, I think these data are reassuring because in this higher-risk group of patients, they saw excellent outcomes very similar to what Gross et al had previously reported. So that's good. To your question about how we are going to disentangle this adjuvant versus non-adjuvant question, there's a trial in melanoma called the NADINA trial which is ongoing now in which the use of the adjuvant therapy is actually risk-adapted. So after patients have an initial neoadjuvant treatment they're evaluated, and if they have had a pathologic complete response, they're actually going to stop that treatment and they're not going to give the neoadjuvant therapy. And so I think obviously it's a slightly different disease, but those kinds of data, I think, will be very meaningful to help us sort this out.    And I'm not sure whether or not in cutaneous squamous we would need a different trial than in melanoma, although I think in a different tumor, maybe like, say, lung cancer, you probably would need a dedicated study to try to look at that because I think just the responsiveness to checkpoint blockade is going to vary quite a bit once you get outside of cutaneous oncology. But to summarize, reassuring that a similar pathologic response rate, and I think this question of adjuvant or nonadjuvant, I think that's the next question we've got to answer in the field.    Dr. Diwakar Davar: We have now come to the end of our back-and-forth discussion on these very, very exciting abstracts. So Jason, thank you for highlighting these advances and for engaging in a robust discussion.    Dr. Jason Luke: Thanks for having me.    Dr. Diwakar Davar: And thank you to our listeners today for taking the time to listen to this podcast. You will find the links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear in the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Follow today’s speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:      Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy    Dr. Jason Luke:      Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio        
6/26/202334 minutes, 23 seconds
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Highlights in Hematologic Malignancies at ASCO23 

Drs. John Sweetenham and Marc Braunstein discuss advances in hematologic malignancies featured at the 2023 ASCO Annual Meeting, including the potentially practice-changing SWOG-S1826 study in Hodgkin lymphoma, the promise of bispecific antibodies in B-cell malignancies, and a novel approach to deliver vital anti-myeloma medications that could improve patient quality of life and alleviate barriers to care. TRANSCRIPT   Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and the host of the ASCO Daily News Podcast.    The 2023 ASCO Annual Meeting featured some exciting new data on hematologic malignancies. I'm delighted to have Dr. Marc Braunstein return to the podcast to discuss some of these potentially practice-changing studies and new approaches in the heme space. Dr. Braunstein is a hematologist and oncologist at the NYU Perlmutter Cancer Center.    You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.   Marc, it’s great to have you back on the podcast, and thanks for being here again.   Dr. Marc Braunstein: Thank you, John. It's great to be back.   Dr. John Sweetenham: Marc, we already mentioned that there are some potentially practice-changing studies that were reported at ASCO this year. And among those, LBA4, which was presented in the Plenary Session, was a study which explored the treatment of advanced Hodgkin lymphoma. This was the Southwest Oncology Group study S1826. Could you give us your insights on this?    Dr. Marc Braunstein: Sure, happy to discuss S1826. So as background, you know, the ECHELON-1 study, which was published in the New England Journal of Medicine in 2022 showed a 40% decrease in the risk of death at six years follow-up by adding brentuximab to AVD compared to bleomycin AVD. And that was in high risk or advanced-stage patients and that led to adoption of brentuximab for upfront use in patients with classical Hodgkin lymphoma in advanced stage.    Also of note, immune checkpoint inhibitors such as pembrolizumab or nivolumab do have activity in the relapse setting. The SWOG S1826 study was a randomized control study looking at the use of the PD-1 inhibitor nivolumab plus AVD versus brentuximab AVD in patients with advanced stage classical Hodgkin lymphoma who are at least twelve years of age. And the primary endpoint in the study was progression-free survival.     It was a large study which enrolled 976 patients and randomized them one to one to either nivo AVD or brentuximab AVD. The median age in the study was 27 and the median follow-up was 12 months. And what the study found, which could be practice-changing, was that the primary endpoint of progression-free survival was superior in the nivolumab arm with a hazard ratio of 0.8 and a one-year PFS of 94% versus 86%, favoring the nivolumab arm. And while there were side effects associated with the class of medications, for example, hypo or hyperthyroidism was more frequent in the nivolumab group, whereas peripheral neuropathy was higher in the brentuximab group, I think that these results are particularly encouraging for how we can continue to improve outcomes for patients with advanced-stage classical Hodgkin lymphoma. And this may be practice-changing in terms of whether we use upfront immune checkpoint inhibitors in combination with our standard chemotherapy backbone.    Dr. John Sweetenham: Yeah, absolutely. There are a couple of things that occur to me. One in particular which is unique about this study, and the fact that it was for patients who are 12 years and older in many respects represents a first because I can't think of another large, randomized study of this type which has attempted to align pediatric and adult care of patients with Hodgkin lymphoma. So, I think it's something of a landmark in that regard. I don't know if you'd agree with that.    Dr. Marc Braunstein: I agree, especially with the range of ages from 12 to 83. It's a pretty broad population by age, but I agree it does kind of reconcile those two groups in a disease that has a bimodal presentation and clearly shows that immune checkpoint inhibitors are both potent and well tolerated in different age groups.    Dr. John Sweetenham: The other question that I have about this study is we haven't seen so far in this study an overall survival benefit to the nivo arm, which is maybe not surprising, but in terms of the practice-changing potential of this study, do you think that will matter?   Dr. Marc Braunstein:  I think that's an excellent question, John. Initially, the ECHELON-1 study only showed progression-free survival, and then the update did show overall survival. And so if we take the lead from that study, we expect to see an overall survival benefit in the SWOG study as well with nivolumab, but it remains to be seen. But I think that the data presented thus far at the Plenary Session is compelling enough to consider using nivolumab upfront.   Dr. John Sweetenham: Yeah, I absolutely agree. And then I guess the other question that we're going to have to wait probably several years to know is what happens in terms of relapse? So, for the minority of these patients who do relapse, how salvageable, if that's the right word, are they going to be with a second- or third-line regimen? But I think that's clearly something for the future, and it's a very interesting, exciting outcome from this study.   Dr. Marc Braunstein: Absolutely.    Dr. John Sweetenham: Let's move on. Marc, again, we're still in the lymphoma world here, but looking at high-risk follicular lymphoma. And this was Abstract 7506, looking at epcoritamab plus the R2 regimen in patients with follicular lymphoma. Could you walk us through this one?    Dr. Marc Braunstein: Yeah, absolutely. Bispecific T-cell engaging antibodies are showing impressive efficacy in relapsed and refractory non-Hodgkin lymphoma. Epcoritamab is a bispecific antibody that binds to CD3 on T-cells and CD20 B-cells. And this antibody is currently approved for diffuse large B-cell lymphoma patients after two or more prior lines of treatment.    In this study presented by Merryman and colleagues, they explored the addition of epcoritamab to standard lenalidomide-rituximab. In 109 patients with relapsed or refractory follicular lymphoma who had at least one prior therapy, and, of note, the study was enriched for high-risk patients for progression, including those who had progression of disease within 24 months of their initial treatment and those patients who had been refractory to prior anti-CD20 treatment. This study enrolled 109 patients with relapsed refractory follicular lymphoma. The median age was 65 and 56% of patients had FLIPI scores on the higher end of the spectrum from three to five, and 61% had stage 4 disease. Also of note, 38% of patients had progression of disease within 24 months of their prior treatment. So at a median follow-up of 8.8 months, the overall response rate was impressive at 97%, and 82% of patients were still on treatment at that time.     Now, of course, with this mechanism of action of bispecific antibodies, there is a risk of both cytokine release syndrome and immune-related neurotoxicity. The rates of CRS were primarily low grade, there were only 2% grade 3, and of note, most occurred after the first dose. And in terms of ICANS or neurological toxicity, there were no grade 3 adverse events, and those occurred in only two patients. Finally, the estimated six months progression-free survival was 93%. So, if we cross-compare these results historically to the R-squared regimen, which was published to be about 80%, just cross comparing, so it's not exactly the same study, this clearly shows high activity on par or better with R-squared alone. Although this study was not a randomized study, I think the addition of epcoritamab certainly shows high overall response rates and we'll need randomized data to confirm the efficacy, but it's definitely encouraging in high-risk follicular lymphoma patients.   Dr. John Sweetenham: Thanks, Marc. I agree. I think these data are really enticing, in as much as the response rates are so high, but of course, it is follicular lymphoma, so we'll have to wait a while. But the thing that it does make me reflect on is that bispecific antibodies really are turning out to be remarkably effective in a range of B cell malignancies, so, it's very interesting to continue to watch this space.    I'm going to change gears now and talk about something completely different for a moment. And this was Abstract 1536. I think that many of us are in a position where we're now looking at how we deliver our clinical services, and particularly inpatient services, to patients with hematologic malignancy. And this study addressed that very specifically. Can I have your thoughts on that?   Dr. Marc Braunstein: Sure. In the context of how our therapies are improving, our approaches to how we manage patients clinically is changing too, in many ways for the better. So, various models exist for, you know, which practitioners manage oncology patients who happen to be admitted to the hospital. This abstract, which was performed by authors at a large medical center in New York, describes the use of a dedicated hematologic malignancy hospitalist for managing medicine-related issues. And the authors did comparisons of that service to a service primarily managed by oncologists. The authors compared things such as length of stay, whether the patients were discharged by noon, which is a hospital metric that's used for facilitating turnover of patients and space availability, as well as 30-day readmission rates among patients cared for by an oncology attending versus this heme malignancy hospitalist between July of 2021 and July 2022.    The outcomes showed that admissions to the heme malignancy hospitalists were, although less because that service was primarily for patients who required medicine-related issues as opposed to primarily oncologic issues, there were 95 admissions to that service versus 669 to the oncology service. There was a significantly shorter length of stay on the heme malignancies hospitalist service by about 2 to 5 days compared to the oncology hospitalist service. The rates of patients who were discharged by noon or the length of stay were similar between the two groups.    So, while this study is confounded by differences in acuity of disease between the services, using a dedicated heme malignancy hospitalist has many benefits, not just to offload the oncology-managed service, which may have a higher level of acuity, but also allow for a deviation of care for medicine-specific issues, to a hospitalist that's specifically trained in managing patients with hematologic malignancies and then dedicating the oncology specialty service to those who need acute oncologic care, such as those with leukemia or other high acuity diseases.    Dr. John Sweetenham: Thanks, Marc. I think it is really interesting to see some outcome data for this model of care. A number of centers I know are looking at an APP-led inpatient service for these types of patients, too, so it's going to be very interesting to see how further studies of these kinds of approaches continue to develop.    And on a related theme of changes in patterns of care, Abstract TPS1609 looked at home infusion and of course, this is something that really started to attract a lot more attention during the COVID-19 pandemic. But I wonder if you could walk us through some of the details of this poster.    Dr. Marc Braunstein: This study was presented as a poster proposing a prospective study looking at home infusion of the anti-CD38 monoclonal antibody daratumumab, which has a vital role in managing patients with newly diagnosed or relapsed multiple myeloma. And monoclonal antibodies have really revolutionized the care of patients with multiple myeloma, but often their infusion schedule is weekly or biweekly, and it does require relatively frequent visits to an infusion center.    So, this single-arm, open-label study is going to examine whether we can provide home administration of subcutaneous daratumumab and assess whether it improves quality of life and assess its safety. So, in this study, a visiting nurse will come and deliver the medication after patients take their pre-medications at home prior to the arrival of the infusion nurse. And then the investigators will provide quality of life questionnaires prior to and after the infusions and at the end of the study, and they'll be looking at any barriers to adherence, any barriers to the logistics of this home infusion arrangement.    And I think that this has a lot of potential not just to improve quality of life, but also to facilitate care to patients who may be frail, who may not have good caregiver support, who may have barriers in traveling to an infusion center or perhaps in places that are more resource-deprived and don't have local infusion centers. This could be a potential approach to delivering vital anti-myeloma medications at home, and I'm looking forward to seeing the results.    Dr. John Sweetenham: Yeah, I agree. I think a lot of us still have anxieties about the safety of this approach, but I think there are increasing data to suggest that home infusion is not only safe but also, as you mentioned, is a big enhancer of the quality of life of these patients. And so, very interesting to see how this plays out in prospective studies.    So, to close out, I wonder if you could walk us through Abstract 7072, a poster looking at the issue of clonal hematopoiesis.    Dr. Marc Braunstein: Clonal hematopoiesis, which is a phenomenon in which the blood cells acquire somatic mutation, is associated with both cardiovascular disease adverse outcomes as well as hematologic malignancy. It's been shown to be a precursor for diseases such as leukemia. So, this relatively small study from MD Anderson Cancer Center examined clonal hematopoiesis in 78 patients with malignancies, 70% of which had a history of cancer, and the authors described outcomes associated with clonal hematopoiesis.    So, again, 78 patients were examined, and 76% of them had a history of malignancy, and 73% had other comorbidities. And the authors demonstrated clonal hematopoiesis by the finding of specific mutations in the blood associated with clonal hematopoiesis. The authors essentially looked at outcomes such as mortality. They noted that only 20% of the patients developed a myeloid neoplasm, and that's relevant because, again, clonal hematopoiesis is a precursor for myeloid neoplasms. They also noted that most patients had died from a primary malignancy rather than a myeloid neoplasm, which is not too surprising considering that most patients with clonal hematopoiesis will not develop a hematologic malignancy, but it is a marker for the potential transformation.    And so, I think the authors conclude that clonal hematopoiesis is important for monitoring patients who are at risk for potential myeloid transformation and hematologic malignancy, but it's not necessarily the case that patients who have a background of malignancy will often develop a myeloid malignancy. I think there are many implications of clonal hematopoiesis for cancer in general in terms of the risk of secondary malignancies in those treated with adjuvant chemotherapy, in terms of how we monitor patients who actually more and more are going to have this detected as we use more next-generation sequencing and liquid biopsies.     So, I look forward to future studies that are exploring how to actually prospectively assess clonal hematopoiesis and use it for clinical stratification for things like adjuvant chemotherapy or monitoring for risks of hematologic malignancy.    Dr. John Sweetenham: Thanks, Marc. I agree. Very important for the future, especially as we gain more and more sequencing data.    So, Marc, in conclusion, I want to thank you very much for sharing your insights with us today on the ASCO Daily News Podcast. It's been great to talk with you again.    Dr. Marc Braunstein: My pleasure. Happy to be back, and I look forward to a future podcast session.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in the transcripts of this episode. Finally, if you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers:   Dr. John Sweetenham   Dr. Marc Braunstein   @docbraunstein      Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn       Disclosures:   Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness   Dr. Marc Braunstein:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp   Speakers’ Bureau: Janssen Oncology   Research Funding (Institution): Janssen, Celgene/BMS        
6/23/202318 minutes, 10 seconds
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ADAURA, KEYNOTE-671, and Other Key Advances in Lung Cancer at ASCO23

Drs. Vamsi Velcheti and Jack West discuss ADAURA, KEYNOTE-671, and KEYNOTE-789 trials in NSCLC and the first pivotal study of sunvozertinib for the treatment of NSCLC with EGFR exon 20 insertion mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. My guest today is Dr. Jack West, a thoracic oncologist and associate professor in medical oncology at City of Hope Comprehensive Cancer Center. Today, we'll be discussing practice-changing studies and other key advances in lung cancer that were featured at the 2023 ASCO Annual Meeting.   Our full disclosures are available in the transcript of this episode and disclosures of all guests on the ASCO Daily News podcast are available at asco.org/DNpod.   Jack, there was a lot of exciting new data that emerged from the ASCO Annual Meeting, and it's great to have you back on our podcast today to talk about all the key updates in lung cancer.   Dr. Jack West: Absolutely. Thanks so much. It's always a high-energy meeting, and there was a lot to talk about in the lung cancer sessions this year for sure.  Dr. Vamsi Velcheti: Let’s begin with LBA3, the ADAURA trial. This was presented in the Plenary Session at ASCO; we've heard previously the DFS updates from previous meetings, and overall survival updates were presented at the ASCO 2023 Annual Meeting. So, Jack, what was the highlight of the presentation for you? And could you put things in context for us? We have known about the DFS data for a while now. What gets you so excited about this study?  Dr. Jack West: Well, we've actually been focused on this trial for literally 3 years, since Dr. Herbst presented it at another Plenary presentation back in the ASCO Meeting in 2020 when we saw tremendous differences in the DFS data. Again, this was a trial of patients with resected stage 1b to 3a EGFR mutation-positive non-small cell lung cancer. Nearly 700 patients were randomized to after-surgery, and for many, but not all, patients undergoing chemotherapy, it wasn't mandated. But after that, they were randomized to get adjuvant, placebo, or osimertinib for up to 3 years. And we saw huge differences in the disease-free survival from the first presentation, with a hazard ratio in the range of 0.2.   We have notably seen significant improvements in disease-free survival before with other EGFR TKIs for this population after surgery, but nothing in this range. And it's also notable that in the various other trials of other EGFR inhibitors in the postoperative setting, we've seen a DFS benefit, but that didn't translate to an improvement in overall survival. So, seeing a press release that this was associated with a significant and, in fact, highly significant by report, improvement in overall survival, as well as DFS, was really notable.   What's also, I think, particularly important as a focus of this is that in the later presentations of this work, with longer follow-up last year, we saw that the DFS curves showed a drop in the DFS starting after these patients had completed 3 years of treatment. So, really suggesting that at least some, if not many or most of these patients who had been on adjuvant osimertinib were subject to a higher risk of relapse once they completed that. So, again, making the endpoint of overall survival particularly important. It's always been to me the endpoint we should care about most in a curative setting. Although the DFS was the primary endpoint of the study and it was powered and built around specifically focusing on the DFS difference, so overall survival was reassuring, I think, when we actually saw it, but not what the trial was centered around.    And what we saw was a very dramatic improvement in overall survival with a hazard ratio of 0.49. That was essentially the same for the patients with stage 2 to 3a disease, as well as the broader population with stage 1b to 3a disease. When we look at the absolute numbers for overall survival at 5 years, there was an improvement from 73% to 85% with osimertinib, and in the population from 1b to 3a, an improvement from 78% to 88%. So, many things to comment on here. Really remarkable to see an 88% 5-year survival in the osimertinib arm that includes patients with stage 3a disease.    I would say that there's still some controversy, some questions about this, and it really centers around a few things. One is, like many global trials, this one enrolled patients from many places that did not have the same standard of care staging that we follow in the U.S. There wasn't any specification or mandate for PET scans, which would be very routine in the U.S. And brain MRIs were not mandated either. And so there were almost certainly some patients with more advanced disease that was not detected that would be a big advantage for the osimertinib arm, but really not characterized. And also, the crossover was made possible to osimertinib starting in April of 2020, but only 38.5% of the patients on the control arm actually received osimertinib at the time of relapse. And even though many of the other patients who had a relapse did get another EGFR inhibitor, I don't think there's much question that osimertinib is the preferred and optimal EGFR TKI.   And so there were a couple of important factors kind of going for this trial. One is the long, long, long duration of treatment at 3 years, though with a drop-off, I think some questions about whether even that is enough, and we might be tempted to treat beyond 3 years. And then how much did the inability of most of the patients on the control arm to get osimertinib later contribute? My personal view is that it is a troubling aspect of this trial. But also so many other trials that they're run globally in places where we arguably perpetuate these disparities by running these trials that, in part, magnify the differences between the two arms because some patients just will not have access to what is our best standard of care in the U.S., or many other parts of the world, but weren't necessarily available to many of the patients on the control arm where it was conducted. So, I think that's always a concern. It's definitely an issue of this trial, but I would not say it's unique to this one.  Dr. Vamsi Velcheti: Very good points, Jack, and I completely agree with you. I think those certainly are concerns. But on the other hand, this is a pragmatic trial and that's the real-world scenario in terms of access issues, in terms of osimertinib globally, correct, in the stage 4 setting, even though we all agree that osimertinib is the best option for patients with metastatic EGFR-mutated lung cancer, I think that's obviously a reflection of global access issues and global disparities and changes in standard of care in terms of workup as well. So, it's somewhat of a pragmatic trial in some ways and I completely agree with you, I think that may have potentially had some impact on the overall survival.  Dr. Jack West: Well, I would clarify that I don't think that this really highly significant difference in overall survival is undermined completely by this. There's no question in my mind that with the huge difference in disease-free survival that we'd already seen for 3 years, it has become our standard of care really for this population at least to offer it, if not to strongly recommend it. But I would say that most of us have been quite inclined to recommend it, perhaps with caveats. And I would say that this overall survival benefit mostly corroborates that, even if there are some concerns about how these trials are done, but it's still an impressive difference that would lead me to only cement my practice of pursuing it in this setting. I just would love to re-examine how we conduct these trials and potentially potentiate disparities that exist and don't want to have our trials be more positive by capitalizing on that.   Dr. Vamsi Velcheti: Let's move on to the next abstract, LBA100; this is the KEYNOTE-671 trial. This was featured during the meeting’s Clinical Science Symposium. This is a study of pembrolizumab or placebo plus platinum doublet followed by surgical resection and pembrolizumab or placebo for early-stage non-small cell lung cancer. Jack, what was the key message from this trial, and do you consider this as practice-changing?  Dr. Jack West: This has been an area where we've seen really dramatic evolution in our practice patterns, specifically, at least for patients who don't have a tumor harboring an EGFR mutation or ALK rearrangement. I would say that there has been some momentum toward preoperative neoadjuvant therapy, specifically based on the CheckMate-816 trial that gave chemo with nivolumab versus placebo and showed a significant improvement in the pathologic complete response rate at surgery as well as event-free survival. The overall survival looks encouraging but is still early and hasn't met the threshold for statistical significance, and that's FDA-approved.   But we still question whether there's a value to doing anything in the postoperative setting. And the CheckMate-816 trial did not include that as part of the trial. It allowed postoperative management at the judgment of the treating physician but didn't really prescribe anything. We now have the results of several trials in the last few months that have added a component in the postoperative setting in addition to three or four cycles of preoperative chemoimmunotherapy. And the first one that gave us a glimpse was the AEGEAN trial presented by Dr. John Heymach at AACR in April of this year that looked at chemo and durvalumab versus chemo placebo and then followed by a year of durvalumab versus placebo after surgery. That showed results in terms of major pathologic response and event-free survival that are significantly better with immunotherapy. Not clearly superior to what we would see with CheckMate-816.   And then even more recently, we saw a monthly Plenary presentation from ASCO with the Neotorch trial presented by Dr. Shun Lu of China. This was a Chinese trial only that presented results just for patients with stage 3 disease thus far. This included patients with stage 2 or stage 3, but what we saw is stage 3 results and that looked at chemo with toripalimab for 3 cycles versus placebo and then a year of checkpoint inhibitor or placebo. This also shows a benefit with the addition of immunotherapy, but not clear if that's better than what we can already achieve with neoadjuvant alone with the Checkmate-816 approach.   And then what we have now is a presentation and simultaneous publication by Dr. Heather Wakelee of KEYNOTE-671. And this is really almost the exact same trial design as AEGEAN. It's 4 cycles of platinum doublet chemotherapy and it is for patients with stage 2 to 3a disease. And this gave 4 cycles of chemotherapy with placebo or pembrolizumab. And then after surgery, patients would go on in the investigation arm to a year of pembrolizumab or to the additional year with placebo. And this shows a significant improvement in event-free survival with a hazard ratio of 0.58. It's most prominent in patients with high PD-L1, where the hazard ratio is 0.42. But there's still a benefit in patients with PD-L1 less than 1%, where it's 0.77. And there was a trend toward better overall survival here, hazard ratio of 0.73. It does not reach statistical significance at this early point. It's still preliminary but certainly looks encouraging. And there are also significant improvements in major pathologic response, where less than 10%, about a threefold difference from 30.2% with immunotherapy compared to 11% with placebo. And a very impressive improvement in pCR rate, which is 18.1% with the chemo and pembro compared to 4% with chemotherapy alone. Not surprisingly, when we look at event-free survival, it's best in the patients who achieve a pathologic complete response, but pembrolizumab improved outcomes in event-free survival even for those who didn't achieve a pCR.   The real question I would say is does the addition of a year of checkpoint inhibitor therapy postoperatively add to what we already achieve with those first three cycles with chemo-neo or 4 cycles with maybe one of these other options? And these trials can't answer that question because they just include them as a package deal. There's no way to tease apart right now the component of what incremental benefits you get from that. And it certainly adds a year of time coming in for every 3-week infusions. Even if you space that out, it's still a year of coming in and getting infusions, potential cumulative immune-related toxicities, and a lot of cost versus potentially being done. And I think that really is the big question at this point of do you want to recommend something when we don't really have a precedent for much benefit beyond the first 4 cycles? Perhaps. Certainly, we give maintenance pemetrexed and other immunotherapies and there can be benefit there. So, I wouldn't say you necessarily cap that. But if there is resistant disease after the first 4 cycles you've already given 3 cycles, how much benefit is there? How likely is it that you're going to eradicate the last cancer cells with more?   That said, I think many patients, and oncologists myself perhaps included, are going to be inclined to err on the side of possibly over-treating, but at least trying to give everything that is part of a widely studied, FDA-approved approach once these options become available. I just think it's going to end up as a careful discussion with each patient about whether they'd prefer to just say they're done or do that extra year and really feel that even if it comes back, they've done everything that made sense to try.  Dr. Vamsi Velcheti: Very good points, Jack. So let's move on to another abstract, which is the LBA9000. This is the KEYNOTE-789 trial. In my opinion, this is the most important negative phase 3 trial in lung cancer in a while. This is a trial looking at pemetrexed platinum with or without pembrolizumab in patients who have EGFR mutation-positive metastatic non-small cell lung cancer. So, what are your key takeaways, Jack?  Dr. Jack West: Well, I would say essentially we've been waiting to figure out what is the best treatment approach for patients with acquired resistance after osimertinib. And most of the patients had received osimertinib for their EGFR mutation-positive non-small cell. This is essentially KEYNOTE-189 being run in the EGFR mutation-positive patients after they've exhausted at least the major benefit of EGFR TKI therapy.   What we saw was a hazard ratio for progression-free survival of 0.8. It didn't quite make it across the threshold for efficacy, a significant difference. And so it missed that efficacy boundary. And overall survival, the hazard ratio is 0.84, also missing the efficacy boundary. When you look at the actual curves, they show modest separation, nothing eye-popping, certainly compared to some of the other trials we're talking about. But I wouldn't say they show no benefit. And I think that's, to me, why there's really still a role for a nuanced thought process and maybe some discussion about how negative this is. This is not, in my mind, stone-cold negative with no patients benefiting from immunotherapy. This is a trial that really suggests that there's a subset of patients who are benefiting from immunotherapy.   And we've also seen going back to subset analysis of the IMpower150 trial and also the ORIENT-31 trial with sintilimab and a bevacizumab biosimilar, another anti-VEGF inhibitor. These trials both really indicated a benefit in this population after EGFR TKI therapy of immunotherapy combined with VEGF. I think there could still be a value in there. I don't want to be a Pollyanna or too open-minded, but I think that there was at least a suggestion that this could still be a fruitful avenue. I think that this is still something we should do additional studies on that could bear fruit. I wouldn't close the door and categorically say this is just never going to translate to any benefit for any of these patients.   Dr. Vamsi Velcheti: The key thing, though, is, like in EGFR mutant patients I think in the previous studies as well, the response rates with single-agent PD-1 have been very minimal. And I think one of the things that's actually very important to highlight is in the operative setting, the early-stage setting, unfortunately, some of the trials with immunotherapy have included patients with an EGFR mutation. And now we have a treatment option for those patients within the adjuvant setting, especially osimertinib. We just heard from the ADAURA trial, which has a clear significant overall survival benefit. So I think it's really important to test for EGFR mutation in all stages. And if somebody with the early stage has an EGFR mutation, adjuvant immunotherapy, or perioperative immunotherapy may not be the best option for those patients.  Dr. Jack West: Right. I agree with that, although it is interesting that the KEYNOTE-671 trial did have some small population of patients with an EGFR mutation, and in that subset analysis, they seem to benefit from the pembrolizumab. I would not say that we should divert from ADAURA, but I'm just not as sure that our previous statement and mindset that immunotherapy just categorically doesn't work for patients with driver mutations is that simple.   First of all, there is some heterogeneity about which driver mutation, and the ALK-positive patients seem to really get no benefit. But I think there's still some questions about immunotherapy for EGFR. Certainly, patients with KRAS or BRAF V600E seem to benefit like the broader range of patients. And I would also say maybe it's different whether you're giving immunotherapy combined with chemotherapy versus as monotherapy. So that's why I'm just not that sure we really can characterize this that well yet.   The one additional point I would make about KEYNOTE-789 and the potential role of immunotherapy is that some experts in thoracic oncology and general oncologists alike may prefer to introduce chemotherapy at a time of progression, but keep the osimertinib going, maybe particularly for patients with brain metastases, whether current or a history of them, where we really feel that the osimertinib adds a critical component to CNS control. We don't want to ever give osimertinib or probably other EGFR TKIs concurrently with immunotherapy. So that's just a factor that we'd really want to consider when we're prioritizing where to fit in immunotherapy, if at all.  Dr. Vamsi Velcheti: Thank you, Jack. And let's move on to the next abstract, Abstract 9002. This is a pivotal study of results from the sunvozertinib, which is an EGFR exon 20 insertion site mutation drug. There's some very promising data. Jack, how do you feel this study is going to influence practice?  Dr. Jack West: Well, this is not an agent we have access to broadly yet, but I was quite impressed by it overall. I didn't mention it. We talked about it in the pre-ASCO discussion, and it was really one that I would mark as potentially practice-changing when we can get it. DZD 9008 or sunvozertinib is a potent inhibitor of exon 20 insertion mutations, and this was 97 patients, and the majority had had a couple of lines of prior therapy. They had to have gotten chemo, and the response rate was 60%, and it was really comparable efficacy with the different mutation subtypes.   I think that the main thing that I would want to clarify a little better in my own patient population is how well the drug is really tolerated. We talked about that there was not really much grade 3 toxicity and that's true, but diarrhea rates were 67%, even though it was grade 3 and just about 8%. But grade 2 diarrhea or grade 2 rash in patients who are on this therapy, we hope for a long time, I think is something we shouldn't minimize. And I think that particularly our mindset about toxicity needs to be different when we're talking about giving a treatment for 2 or 4 cycles and then being done with it versus something we hope we're going to be giving longitudinally. And we really don't want to minimize the potential impact on the quality of life of patients who are experiencing grade 2 rash, diarrhea, or paronychia for months and months, maybe more than a year at a time.   But that said, this is twice the response rate if not more than that of what we have already had for patients with this molecular aberration with an exon 20 insertion. So I think it's compelling and I think that it's going to be really valuable to offer to our patients. I just would like to clarify better how well patients who are actually on it are feeling when you incorporate the potentially chronic toxicity issues.  Dr. Vamsi Velcheti: Thank you, Jack. And let's move on to the last abstract. This the LUNAR study, LBA9005. This is a positive phase 3 study that looked at tumor-treating fields or TTF therapy with standard of care treatments in metastatic non-small-cell lung cancer following platinum failure. This has been talked about a lot at ASCO, and Jack I'm eager to hear your key takeaways about this study.  Dr. Jack West: Well, we knew from a press release several months ago, I think back in February, that there was a significant improvement in overall survival with the addition of tumor-treated fields. Again, this concept that electric fields can lead to antimitotic effect and potentially downstream induction of immunogenic cell death and enhanced immune response, that's at least the concept. And it's of course established, has utility in patients with glioblastoma, although kind of, I would say underutilized because it can be cumbersome. And I think that's one of the things we need to factor in is that this is not the easiest approach to pursue.   But we don't have that many therapies that improve overall survival significantly in previously treated patients with non-small cell lung cancer. So, I think there's good reason to focus on this and ask how beneficial it is. It was notable, it was pretty much an even split of patients enrolled on the trial, 276 patients total, but about half had gotten chemo but not gotten immunotherapy before. And then the other half, I would say the clear majority, had gotten immunotherapy as well as chemo and got docetaxel-based treatment.     And the overall survival benefit was significant for the intent to treat total population with a hazard ratio of 0.74 and a difference in 3-year survival of 18% favoring the addition of tumor-treating fields on the chest versus 7% in the patients who didn't. It really seemed to separate between the patients who had not had an immune checkpoint inhibitor and got tumor-treating fields with the checkpoint inhibitor where the hazard ratio is 0.63 and those who got tumor-treating fields with docetaxel where the hazard ratio was 0.81. So it really wasn't significant in this population.  Toxicity, no real surprises compared to what we already knew about tumor-treating fields. Mostly dermatitis, but I would say that one of the kind of unmeasured issues is that this is a device that people have to wear on their chest carrying a battery pack with them all day long. It's essentially all the waking day, and so I think that's at least cumbersome. I wouldn't call it prohibitive, but it's a challenge. And I think we need to really ask whether the juice is worth the squeeze, whether the benefit is that compelling. And I question that when we're talking about an agent that doesn't significantly move the needle against docetaxel alone.   Again, this is a population where in the U.S. we have ramucirumab to add to docetaxel. Not everyone does that. It's not uniform, but that has a statistically significant, though modest survival benefit associated with that. We don't do better than that with tumor treating fields. And so, I think that this is an option that merits discussion and some patients may opt for it, but I suspect that most of my patients would not find the absolute difference to be that compelling for the challenges it incurs. I don't know what your perspective is here.  Dr. Vamsi Velcheti: I completely agree, Jack. And I think the study design and just the fact that the standard of care has changed over the last 5, actually 6 years since the study has been open. And I'm not really so sure I could really make much sense of the data in terms of the standard of care combination with TTF providing more benefit. And I think there are more questions than answers here and I'm not so sure which populations would benefit the most. And I think, I hate to say this, but this is a nice proof of concept. I hate to say this because it's a phase 3 study and it's a positive phase 3 study, but it's clinical relevance with the current standard of care, I think, I'm not really sure how much of an impact this would really have.    Well, Jack, I've really enjoyed speaking with you about these key advances in lung cancer that were featured at the 2023 ASCO Annual Meeting. Our listeners will find links to all the studies discussed today in the transcript of this episode. Thank you so much, Jack, for joining us today.  Dr. Jack West: Always a pleasure. Thanks so much.  Dr. Vamsi Velcheti: And just like that, we've reached the end of another enriching episode. But remember, like all good things, this too must come to an end, but only until we meet again. We really would like your feedback on the podcast. If you enjoyed the podcast, please rate, review and subscribe wherever you get your podcasts.  Disclaimer:    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:   Dr. Vamsidhar Velcheti   @VamsiVelcheti   Dr. H. Jack West   @JackWestMD   Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:    Dr. Vamsidhar Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline     Dr. Jack West:   Honoraria: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati, Regneron, Amgen, Abbvie   Consulting or Advisory Role: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati Therapeutics, Regneron, Amgen, Abbvie, Summit Therapeutics   Speakers’ Bureau: Takeda, Merck, AstraZeneca        
6/22/202331 minutes, 9 seconds
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SONIA, NATALEE, and Other Advances in Breast Cancer at ASCO23

Drs. Allison Zibelli and Arielle Heeke discuss the NATALEE trial’s novel approach to high-risk HR+ breast cancer, the potential of delaying CDK4/6 inhibitors in HR+, HER2-negative mBC to decrease toxicities and costs in the SONIA trial, and de-escalation strategies in HER2+ early-stage breast cancer. TRANSCRIPT Dr. Allison Zibelli: Hello. I'm Dr. Allison Zibelli, your guest host for the ASCO Daily News Podcast today. I'm an associate professor of medicine and a breast medical oncologist at the Sidney Kimmel Cancer Center at Jefferson Health in Philadelphia. My guest today is Dr. Arielle Heeke, a breast medical oncologist at the Levine Cancer Institute at Atrium Health in North Carolina.  Today, we'll be discussing practice-changing studies and other key advances in breast cancer that were featured at the 2023 ASCO Annual Meeting.   Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.   Arielle, it's great to speak with you today.   Dr. Arielle Heeke: Thank you so much for having me.  Dr. Allison Zibelli: Let's start with LBA500. This was the NATALEE trial of ribociclib and endocrine therapy as adjuvant treatment in patients with hormone receptor-positive HER2-negative early breast cancer. What are your key takeaways from the study, and how do you think this changes our approach to high-risk ER-positive breast cancer?  Dr. Arielle Heeke: Yeah, this was definitely the study for which many of us were waiting to see the results. It was exciting to see the results come through so quickly. As you mentioned, the NATALEE trial was a phase 3 study that evaluated three years of adjuvant ribociclib at a dose of 400 milligrams, which is a little different than what we're used to in the metastatic space at 600 milligrams. But essentially, it randomized patients to receive this 400-milligram dose with their adjuvant aromatase inhibitor therapy versus just the standard of care adjuvant endocrine therapy in patients that are high risk with early-stage breast cancer.   What made NATALEE somewhat unique is they defined high risk a little bit more broadly than we've seen in previous studies, such as monarchE. So, what I mean by that is NATALEE enrolled patients with stage 2 and 3 early-stage breast cancer. And notably, they allowed for patients that were lymph node-negative but had some other high-risk features, such as a grade 3 tumor or a grade 2 tumor with high-risk genomics, such as oncotype or a high Ki-67. So, by broadening who was eligible, NATALEE captured more patients at risk for recurrence. Of course, we know that recurrence is not specific for patients with lymph node-positive disease. We can see recurrence even with stage 1, but certainly, we start to see more recurrence risk as patients drift into stage 2 and stage 3.   In the NATALEE study, the majority of these patients did receive prior chemotherapy, which I also think is interesting. We've kind of seen in the metastatic space that sometimes chemotherapy can augment patients' responsiveness to CDK4/6 inhibitors. But specifically in NATALEE, 88% of patients had received prior chemotherapy, and ultimately, about a third of the patients were lymph node-negative.   So, diving into some of the results with this first analysis that we saw at ASCO, with the median follow-up for invasive disease-free survival of just 27.7 months, they were able to show that the risk for invasive disease was reduced by 25.2% with the addition of ribociclib plus endocrine therapy compared to endocrine therapy alone. And this three-year invasive disease-free survival rate was 90.4% for the combination therapy compared to 87.1% for endocrine therapy alone, which is an absolute difference of 3.3%. Additionally, patients treated with ribociclib and endocrine therapy had a 26.1% reduced risk for distant disease-free survival compared with endocrine therapy alone, and this was a rate of 90.8% for ribociclib with endocrine therapy compared to 88.6% with endocrine therapy alone, which correlates to an absolute benefit of 2.2%.    They did show results for overall survival as well, but again, follow-up was just a median of 27.7 months. So, data was essentially immature to show any true overall survival benefit from this approach. And in fact, only 20% of patients had completed three years of ribociclib at this data cutoff. And as a reminder, again, NATALEE involved ribociclib for three years compared to two years, which we've seen with other studies in this space.   Also, what was encouraging from NATALEE were the readouts for toxicities. Neutropenia is definitely a concern with this class of medication, and they were able to show that rates of neutropenia were overall lower than what we've seen in the pooled data in the metastatic space. And also that problematic QTc prolongation for which we have to get EKGs baseline two weeks and four weeks. They also showed that the likelihood of having QTc prolongation on this therapy was significantly less at that 400-milligram dose compared to 600.   I think the key takeaway is yes, this drug is effective as adjuvant therapy, which is perhaps not surprising since we've seen such promising results in the metastatic space, but numerically not as striking as what we have at this point with adjuvant abemaciclib, but of course, this is a newer study. We hope to see that continued separation of the curves as we were fortunate enough to see with the abemaciclib data, but obviously we'll be looking for additional analyses from NATALEE.    And then how this will change practice, of course, we'll have to wait to see if the therapy is approved for use in the adjuvant setting for early-stage hormone receptor-positive breast cancer, but it certainly will be a nice option for patients that struggle with GI toxicity kind of at baseline. But also, if they were previously on abemaciclib and were not able to tolerate due to the GI toxicity, this would be an option for them. Also, as mentioned, it's a broader patient population, so we can consider this perhaps for a patient with lymph node-negative disease.   Although we will have to ask ourselves that just because someone meets eligibility for the NATALEE  study, and if the therapy is ultimately approved, is it appropriate to give it to all those patients? Or do we need to still kind of think of this in the setting of the highest-risk patient, not just any patient with stage 2 plus disease? There was a lot of talk at the meeting, certainly about biomarkers and potentially using ctDNA to try to find these predictors of benefit from CDK4/6 inhibitor therapy, but obviously, still a long way to go before we can use that type of technology in this space.  Dr. Allison Zibelli: Thank you. Staying on the topic of CDK4/6 inhibitors, everybody was excited about the SONIA trial, which was LBA1000, and this trial was asking if we can delay using CDK4/6 inhibitors for newly diagnosed ER-positive HER2-negative metastatic breast cancer as a way to decrease both toxicity and cost. Tell us about this study.  Dr. Arielle Heeke: The SONIA trial was such a cool study to see, and the presenter reported findings in such a thought-provoking way. Really great to see this sort of work being done because I think we all wonder deep down in our gut, if more is more, or if we do need to kind of be a little bit more thoughtful about how we introduce these therapies certainly from a patient perspective. Patients that participate at ASCO [meetings] have been saying for years how important it is to consider the toxicities in terms of side effects, but also, of course, financial toxicities. So, it was great to see the SONIA trial at center stage.   Essentially, as you mentioned, it was a study that randomized patients in the first-line setting with metastatic hormone receptor-positive breast cancer to receive either first-line CDK4/6 inhibitor therapy or second-line CDK4/6 inhibitor therapy. So basically, there was a mandated crossover, so patients that received the CDK4/6 inhibitor first-line did not receive a second line and vice versa. Patients that were randomized to receive their endocrine therapy as monotherapy first line went on to receive CDK4/6 inhibitor at second-line. And the second-line endocrine therapy was fulvestrant in both of those situations.    We kind of run into this problem with patients now where we have so many therapies available to us that we don't typically run out of treatment options, but rather we run up against treatment toxicity or ultimate failure of the human body to keep up with the demands of ongoing therapy. So, again, while it’s maybe somewhat attractive to start treatments earlier using things first-line rather than second-line or longer, just kind of post-CDK4/6 inhibitor progression, you know using this CDK4/6 inhibitor again with a different endocrine therapy backbone is probably not offering a meaningful benefit to that many patients. So this type of study is so necessary to really try to help us frame who needs those therapies sooner and longer or perhaps is there a substantial portion of patients that we don’t need to put them through that sort of toxicity.   So that’s the SONIA trial. Some things to note about the patient population, these patients were a bit older than what we’ve seen in some of our metastatic CDK4/6 inhibitor trials. There was a median age of 64 and 87% were postmenopausal. Additionally, just 40% had received prior chemotherapy. And as is true for most of our studies, 91% have received palbociclib on study with just 8% receiving ribociclib. And the choice of the CDK4/6 inhibitor was per the treating provider, and at the time of the of study globally, palbociclib was the more commonly prescribed CDK4/6 inhibitor. But over the last year or so, data has certainly emerged favoring ribociclib in the metastatic setting.   On the SONIA trial, patients were monitored for a median of 37.3 months. And looking at the primary endpoint of the second progression-free survival, which is defined as the time for random assignment to the second objective disease progression or death, for those patients who received first-line CDK4/6 inhibition, had a PFS2 of 31 months compared to 26.8 months with second-line CDK4/6 inhibitor use. And this slight difference was non-statistically significant. So the conclusion was that time to second progression was not impacted by whether or not a patient received first-line CDK4/6  inhibition or second-line CDK4/6 inhibition. Additionally, there were no differences in overall survival between the 2 arms with a median overall survival of 45.9 months with first-line CDK4/6 inhibitor use versus 53.7 months in second-line CDK4/6 inhibitor use.  And that actually equates to significant differences in time on drug. The median duration of CDK4/6 inhibitor use with first-line therapy was 24.6 months compared to 8.1 months with second-line use. And by being on therapy for an additional 16.5 months if you use CDK4/6 inhibitor first-line, this, of course, leads to increased toxicity and certainly increased financial burden. And it was estimated that for each patient that receives this therapy first-line, there is an additional $200,000 spent on getting them the CDK4/6 inhibitor first-line, whereas the results from SONIA suggested that whether you use it first-line or second-line, the outcomes are essentially exactly the same.   And then specific for the SONIA trial, by conducting the study, they saved approximately €25 million on drug expenditure during the conduct of the trial. It’s just amazing when you take it to that scale. And then lastly just to mention, they looked at quality of life assessments as well and there were no differences in the two arms whether they got first-line or second-line CDK4/6 inhibition.  Dr. Allison Zibelli: I thought this study was remarkable, and it got a long ovation when it was presented at the meeting. I'm certainly going to use this strategy and prioritize who needs upfront CDK4/6 inhibitor therapy.  I think that we have to think of not just drug toxicity for our patients, but financial toxicity. A lot of these drugs have very high copays and the number one cause of bankruptcy in the United States is medical costs. So that's something we really have to keep in mind. I also thought it was very interesting that the study was designed in cooperation with the patient advocacy group and patients themselves were very enthusiastic about this study and helped design it and helped recruit to it. So all in all, I thought this was a remarkable study.    So moving on, LBA1013 was the TORCHLIGHT study of toripalimab versus placebo in combination with nab-paclitaxel for patients with metastatic or recurrent triple-negative breast cancer. Many of us are not familiar with toripalimab. Can you tell us about the drug and how it was used in this study?  Dr. Arielle Heeke: Yes, toripalimab is essentially an immunotherapy agent. It's an IgG4K monoclonal antibody that targets PD-1. In this study, TORCHLIGHT, patients were randomized to receive toripalimab versus placebo in combination with nab-paclitaxel in newly metastatic triple-negative breast cancer. The patients on study were randomized two to one to receive drug or placebo. The drug is given on day 1 of a 3-week cycle at 240 milligrams and then patients of course also receive nab-paclitaxel on a day 1 and day 8 schedule of a 21-day cycle. They did look at outcomes on the study based on PD-L1 positivity status and they assessed for PD-L1 with an IHC assay JS311 antibody that ultimately generated a combined positive score. And PD-L1 positivity was defined as a CPS of greater than or equal to one based off of this assay. In the study population, about a third of patients were- patients' tumors were CPS negative, a third had a CPS of 1 to 10 and about a quarter had a CPS of greater than or equal to 10. And then approximately 7% of the tumors had an unknown status.   And then getting right into the results, we were provided results in the PD-L1 positive subgroup as well as the whole patient population. Looking at the primary endpoint of PFS, there were significant improvements seen in median PFS with the addition of toripalimab to nab-paclitaxel, again in the first line setting with a median PFS of 8.4 months with the addition of the immunotherapy agent versus 5.6 months with placebo. And this was statistically significant.  And then in the intent to treat population, there were some numeric improvements, in median, progression-free survival at 8.4 months with the addition of toripalimab versus 6.9 months with placebo.   We also got some results with overall survival that were quite intriguing, although this initial analysis was not designed to necessarily prove statistically significant differences in overall survival. But again, there were some promising trends. Looking first at the PD-L1 positive subgroup, the median overall survival was 32.8 months with the addition of toripalimab versus 19.5 months with placebo. Breaking it down a little bit further based on CPS values, for a CPS of 1 to 10, median overall survival was 32.8 months versus 19.5 months. And then for those very high CPS or greater than or equal to ten, median overall survival was not reached in this group versus 18.3 months with placebo. Also, looking in the intent-to-treat population, there were also improvements in overall survival with the addition of toripalimab with a median overall survival of 33.1 months with the addition of immunotherapy versus 23.5 months with nab-paclitaxel alone. So potentially, depending on next steps of this study, we would potentially have an option to add immunotherapy that is not biomarker specific, meaning we can potentially provide toripalimab to all patients regardless of their PD-L1 status.  Dr. Allison Zibelli: Very interesting new drug to look forward to. So, one of the major themes of this year's meeting was de-escalation strategies. For example, LBA506 reported the three-year invasive disease-free survival of the PHERGain trial, which looked at eliminating chemotherapy for HER2-positive patients getting neoadjuvant therapy. Tell us about the design of this study and how will it impact the care of these patients?   Dr. Arielle Heeke: The design was very complicated. I had to look at it a few times to really make sure I got my head around it. But I think once you do figure it out, you can see how there might be a path forward in clinical practice. Although I think for all of this work, it's maybe not ready yet for primetime, but certainly thought-provoking. But the PHERGain clinical trial, I feel like we've heard about this study for a little while and this concept of de-escalation really kind of started in the HER2-positive space. But this study was a randomized study of chemotherapy de-escalation and early HER2-positive breast cancer using PET/CT as a marker of response to therapies that don't involve chemotherapy.   Patients were eligible for the study if they had stage 1 to 3a HER2-positive breast cancer with no prior therapy for breast cancer, and ultimately 356 patients were enrolled in a 1 to 4 randomization scheme with the majority of patients ultimately enrolled into the experimental group, which is called Group B. So, to break down Group A and Group B, Group A essentially were patients that receive typical standard of care, which at this point is TCHP for six cycles, neoadjuvantly or prior to surgery. Once they complete those cycles they move into surgery and then Herceptin-PERJETA adjuvantly for additional twelve cycles.  I should also note that this study was conducted prior to results of the KATHERINE trial that showed benefit of switching to adjuvant T-DM1 if there's residual disease. So, patients in Group A as well as Group B did not receive T-DM1 at any point. So, again, Group A is kind of your standard of care. Group B was the “experimental arm.” And so, what they did in this arm to assess potential de-escalation strategies, patients first received Herceptin-PERJETA alone for two cycles with or without endocrine therapy, if they were also hormone receptor-positive. But after those two cycles, they underwent a PET/CT, and then if a response was garnered, they would continue with Herceptin-PERJETA and again plus or minus endocrine therapy to complete six cycles total before proceeding on with surgery. Then if they were fortunate enough to achieve complete response at the time of surgery, then they just continued with Herceptin-PERJETA maintenance, whereas if they did not achieve a complete response at the time of surgery, then they actually received TCHP 6 times adjuvantly. So, the chemotherapy was introduced after surgery.   And then going back to that PET/CT time point, if patients did not achieve a response at that check-in point, after 2 cycles of Herceptin-PERJETA, at that point they were transitioned to chemotherapy with TCHP, again, for six cycles. So, either they could kind of ride all the way through if they got that complete response at the time of surgery with Herceptin-PERJETA only, or if at surgery there was residual disease, they went on to receive TCHP after surgery, or if they did not have a response on that interim PET/CT after 2 cycles of HP then they would go on to receive TCHP neoadjuvantly.    So, looking at the results, they actually had 2 primary endpoints. The first primary endpoint was rates of a complete response at the time of surgery in patients that had a PET response. So, PET responses were actually seen in nearly 80% of all the patients treated with Herceptin-PERJETA without chemotherapy. And in those PET responders, a complete response rate at the time of surgery was seen in approximately 38% of patients. So, 37.9% of PET responders actually achieved a complete response when they went to surgery after receiving Herceptin-PERJETA alone, which is pretty amazing. I mean, we're used to seeing higher complete response rates with neoadjuvant therapy for HER2-positive disease, but again, this is a chemo-free regimen so that is encouraging for that 38% of patients that really didn't need chemotherapy.   And then the second primary endpoint, and this was what we saw basically for the first time with the 2023 ASCO Meeting, was results for the 3-year invasive disease-free survival in Group B or this experimental de-escalation group. And ultimately it was shown that the three-year invasive disease-free survival and the intent to treat group B population was 95.4%, which met its statistical endpoint, or, basically the null hypothesis was rejected. They just needed some sort of outcome that was not worse in terms of the 3-year invasive disease-free survival of 89%.   And then looking actually at the patients that kind of did the best. So, the patients that were PET responders and achieved a complete response at the time of surgery and therefore really only ever received Herceptin-PERJETA, their three-year invasive disease-free survival was 98.8%. So, really very good. Additional endpoints they looked at in Group A and Group B were favorable in terms of three-year invasive disease-free survival in Group A, and then three-year distant disease-free survival and three-year overall survival in both groups, all approximately 98%. So, very favorable.   So, ultimately, these findings reflect a potential role for a chemotherapy-free treatment approach for some patients with early-stage HER2-positive breast cancer. And this particular study, they used PET/CT to influence chemotherapy decision-making, which potentially identified 1 in 3 patients who can omit chemotherapy. With that, 80% of patients receiving the response with a PET/CT, and then of that, 80%, again, 38% actually having that complete response. And ongoing work is also being done to look at other mechanisms to assess for an opportunity to de-escalate with MRI imaging or HER2DX testing to again try to identify patients who can potentially defer chemotherapy in this setting. I did not see from the results what proportion of patients were hormone receptor-positive, which I think is also interesting when thinking about chemotherapy de-escalation, can you lean a little bit more heavily on endocrine therapy? Perhaps we'll get that data in the future.   Dr. Allison Zibelli: That's a very important point.  I would like to thank you, Dr. Heeke, for coming on the podcast today and sharing your valuable insights with us. We really appreciate it.  Dr. Arielle Heeke: Absolutely. It was a great meeting to dive into. It's always exciting to see what comes out of ASCO in the breast space. We're usually well represented there, and I hope that these studies will lead to further exploration.   Dr. Allison Zibelli: And thank you to our listeners for joining us today. You'll find links to all abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Follow today’s speakers:   Dr. Allison Zibelli   Dr. Arielle Heeke  @HeekeMD     Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:    Dr. Allison Zibelli:    None Disclosed   Dr. Arielle Heeke:   Honoraria: Merck  Consulting or Advisory Role: Jazz Pharmaceuticals, Caris Life Sciences, Amgen, Daiichi Sankyo/Astra Zeneca, Pfizer, AstraZeneca, Menarini, Genome Insight  Speakers’ Bureau: Daiichi Sankyo/Astra Zeneca      
6/21/202325 minutes, 11 seconds
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Addressing the Impact of Prior Authorization on Access to Cancer Treatment

Drs. Nathan Pennell and Nancy Lin discuss emerging data on the growing problem of prior authorization and insurance denials in cancer care, their potentially harmful impact on patient outcomes, and what can be done to fix the problem. TRANSCRIPT Dr. Nathan Pennell: Hello, I'm Dr. Nathan Pennell, your guest host for the ASCO Daily News Podcast today. I'm the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research for the Taussig Cancer Institute. More importantly, today, for this podcast, I'm also the editor-in-chief for the ASCO Educational Book. On today's episode, we'll be discussing the growing problem of prior authorization and insurance denials, and how that impacts both providers and patients in their ability to access cancer care.  Joining me is Dr. Nancy Lin, a breast cancer medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School. She's addressed this problem in a recently published article in the 2023 ASCO Educational Book, and she's joining me today to highlight some emerging data on the possible harms from prior authorization and insurance denials, and what we can do to fix this problem.  Nancy, thanks so much for coming on the podcast today. Dr. Nancy Lin: Thank you for inviting me. Dr. Nathan Pennell: Some of our listeners may have noticed that we also did a podcast a number of years ago on a similar topic when we were with the Journal of Oncology Practice, and I was kind of hoping that prior authorizations would not be as big a problem, now, probably 8 or 9 years later, and unfortunately, it seems like it has gotten even worse.  Before we begin, I should mention that our disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org\DNpod. So prior authorizations were, of course, originally intended as a cost control on the overuse of expensive medical care. However, in recent years, it seems like prior authorization has been extended to, more or less, all medical care, including supportive care medications and essential cancer care interventions that we need to use in almost every patient. We're also hearing more and more reports on patients who are denied coverage, and I think the doctors can sympathize with this, with their increasing peer-to-peer requests. And this is leading to patients being forced to wait to receive second-best options, impacting their out-of-pocket costs. And potentially, we all fear this is impacting patient outcomes, although we really would like to learn more about how this is really impacting their care. So, Nancy, can you talk to us a little bit about how prior auth is impacting patient access to cancer care today? Dr. Nancy Lin: Of course, we all have to acknowledge that part of the impetus for prior authorization is just the increasing cost of cancer care. There are some recent statistics that the U.S. spends over $200 billion annually on cancer care and that oncology drugs are a huge part of the overall drug cost in the nation and a large part of the oncology drug budget. So, I think we can't deny that the increasing costs of cancer care are in part driving this drive for more prior authorization. But this has costs, and there are costs in terms of direct patient costs as far as their quality of care, and also costs in terms of the health care providers and health care system.   And so we, as part of our article, actually solicited patients to provide their stories. And in fact, in our article, we have selected, with their permission, 3 patients who share their experiences. And these are experiences that, as a practicing oncologist, you'll be very familiar with. A patient wrote that she had been on capecitabine for a year, her disease is responding, and all of a sudden, on a Friday late in the day, she's told, “No, you need a prior authorization now, and you can't get your drug refilled.” And that led obviously to stress and delay and whatnot. And then another example is of a patient whose oncologist requested what sounds like next-generation sequencing, some sort of tumor panel and was denied. And the peer-to-peer here had apparently indicated that they are not aware of the data for the use of genomic testing and cancer treatment, which clearly there is a role for the use of genomic testing in cancer treatment. And in fact, we now have many articles that show that there's unequal access and, if we look at underrepresented minorities or other marginalized groups, that there is a dramatic difference in the utilization of advanced molecular testing. And then just the overall experience on patients and their families feeling like, at a time when they're sick, need to take charge of all of this paperwork and back and forth with insurers that is very stressful.   And then, from a provider or health care system standpoint, many, many hours are expended on prior authorizations for things like very new drug approvals that are maybe not on a pathway yet, or very commonly, simple things like a CAT scan for restaging of somebody who has advanced breast cancer where every scan requires prior authorization or antiemetics, or somebody receiving highly immunogenic chemotherapy and these kinds of death by a thousand cuts I think is how people in the health care experience the aspect of prior authorization.  Dr. Nathan Pennell: It's one of these things where we used to get a peer-to-peer for say, atypical reason for a PET scan, which made perfect sense, and you'd have to talk to an experienced expert to explain what you were doing and try to get a good rationale for that. And now, it's come to the point where a routine 2-month, 3-month CT scan is getting denied and having to be talking to someone who's not as experienced in this. Again, it feels still like a collection of anecdotes though in many ways. Is there any sort of published data on denials of care and prior auths and how this is impacting approvals and patient access? Dr. Nancy Lin: There are survey data, which one has to admit is not necessarily gold-standard data, but there are data from the American Medical Association, as well as a 2022 ASCO member survey. And in that ASCO member survey, over 90% of oncologists reported that they had personally experienced, in their patients, a delay in treatment related to prior authorization. Over 90% had issues getting needed diagnostic evaluations. Over 90% reported that they were, "forced to go to a second choice of therapy." And about a third of oncologists reported that they believed that the prior authorization, either delays or denial of care, led to changes or worsening of patient survival, which I think is the most concerning statistic of all.  Now, I think that one can argue that these are essentially physician self-report and what's the gold standard as far as whether there has been an impact? But I think that the fact that these reports are so prevalent means that, even if the reality is half of what has been reported, it's still a lot. And I think that  the power of these kinds of surveys is just enormous, that a high prevalence of the problems have been reported, I think, points to something even if we don't have gold standard quote data now.  Within our institution, Dana-Farber, we have done an analysis of oral medication prescribing. So, we do have gold standard and very granular data on patients that we've seen. And we've seen denials and requirements of prior authorization not only for expensive cancer medications and growth factors but also for even medicines like generic tamoxifen, which, honestly, how does that need prior authorization in this day and age? Medications like supportive care, antiemetics, and really things that ultimately, we were able to get approved 97% of the time, but [prior authorization now] introduces a delay and introduces stress. And although one may not be able to measure a so-called negative outcome from a patient recurrence standpoint, I think that there are other kinds of negative outcomes that are important, including just the experience of a cancer patient undergoing treatment, the stress of all of the denial letters and the delays that can occur as a result. Dr. Nathan Pennell: And it's not just patients. Obviously, we want to be patient-centered in our care and focus on how this impacts them. But this is also significantly impacting practitioners and cancer centers and physicians and the administrative burden of having to do the prior authorizations, which of course are not standardized in any way and vary from payer to payer and geographic area to geographic area. Is there data on how the changes in prior auth have impacted practices and physicians? Dr. Nancy Lin: Yes. In fact, there have been several surveys as well as in the practice types of studies trying to understand the staffing that is required to manage the prior authorization requests. And some of the estimates are an additional 40 hours per week per oncologist, that’s a full-time position. Some of these tasks can be carried out by non-oncology-trained providers but many of them do require either the oncologist or a nurse practitioner equivalent to be on the phone for the peer-to-peer or a full-time clinical provider and you are given a 4-hour window to do a peer-to-peer in the middle of clinic, that’s very disruptive. And I think that that’s fine if it’s every now and then for drugs that we all agree are perhaps outside of their usual indication. But if this is every CAT scan and every brain MRI and every time we prescribe an oral drug, it really does affect both clinic workflow, and just the psychology; I think it really contributes to burnout.  There was a very interesting survey actually of oncology trainees who, not even to the point where one is an attending physician, but at the trainee level indicating that this was something that was causing them a lot of distress, and in some cases, questioning the whole idea of going into medicine. And then when you think with the attrition that we’re seeing in the health care workforce, we do really have to be careful about these burnout issues because we really can’t afford to lose a lot of oncology staffing as the patient population ages and we’re seeing higher prevalence of cancer. I think it’s imperative that we take care of our oncology workforce. And I think this survey was very interesting because it went beyond the attending physician to other levels of oncology care, all of which are affected.  And there have been, as you know, many growing or nascent attempts at various residency programs to think about unionizing and what are the kinds of concerns or complaints that trainees bring up. And one of [the complaints] that  comes up a lot is, “We have to do these prior authorizations and there’s all this administrative paperwork that doesn't require an entry-level person.” I’m not saying that they should or shouldn’t do it - I’m not going to take a position on that - but the fact is that somebody has to do it in the current system, and whoever does it, it causes burnout. And I think that that is important. And the other piece of it has to do with equity and access to care because we’re coming from academic institutions. We have a staff of people who help with prior authorization. That's not true in every practice in the United States. And I really worry about not so much denial of care but even a step beyond that, which is if you are in an under-resourced office and it’s too hard to get certain things done, you don’t do them because you just don’t have the ability or you don’t have the staffing to be able to find insurance. And I think that is very concerning to me in terms of access to care, access to some of our immune-targeted therapies, and access to the optimal support of care medications. We come from very well-resourced places as far as the administrative staff, relatively speaking, and that’s just not true everywhere.  Dr. Nathan Pennell: This whole idea kind of falls under the idea of creating friction in the system to try to slow things down. I've seen data suggesting that things like peer-to-peer requests for appeals actually lead to a majority of physicians not having time or taking the time to actually do that. And that may be sometimes because they know it's indefensible and don't want to go through the process. But probably a lot of the time it's just because they don't have time to do it in their busy day and those patients then don't get their care covered. So, it's really a problem.  Now, the other thing that is really remarkable to me is, this is 2023 and everything is so technologically advanced. You can make major financial transactions electronically on your phone in just a few seconds, really complicated things. And yet this kind of [prior authorization] process really is still often done over the phone and by fax and with 100 different systems that don't talk to one another. And at the same time, oncology is becoming more and more guideline-driven where what we do actually have is really good evidence behind it. And there are even published guidelines for almost every disease and line of care about everything that we do from scan intervals to what kinds of treatment and how often and what supportive care is necessary. So, this would seem like an optimal situation for a technology solution where we tie in guidelines to what should and shouldn't be covered. What's going on out there in terms of trying to fix this? Dr. Nancy Lin: Some important questions are: Who makes the guidelines? What are the regulations as far as which guidelines insurance might adopt - their own internal guidelines or NCCN or comparable organizations? And what do you do when somebody wants to deviate from the guideline or pathway? And then finally a practical question, which is you don't really want to have a different platform and a different guideline for every insurance plan for every patient. And I think that is a little bit of even if we move to a purely electronic system, that will still be a problem.  The state of Florida had done this pilot study that tried to use or incorporate the NCCN guidelines as part of their approval or review process for prior authorization requests and at least based on the report that's published, saved $15 million in costs. And we would hope if the care was more NCCN guideline-concordant, which has been shown to improve outcomes, that would have been done without a detriment to patient outcomes. I don't think we have enough granular information to be 100% sure of that, but I would assume that that's most likely the case. I do think that some amount of guideline use could be useful.   And one of the things that we proposed in our article was the idea that one could create a sort of gold card system such that if a provider or a practice, for example, adheres to certain pre-agreed-upon guidelines or pathways more than 80% of the time, which is sort of considered good adherence and taking into account patient preference and comorbidities and whatnot, that that practice or provider could be sort of gold carded, so to speak, and actually have many of the prior authorization requirements go away so long as that is adhered to. And so that's one idea.  One of the concepts that Dario Trapani, who was the first author of our paper, put forward is that you don't necessarily need every person to be compliant with every guideline. Generally, you need for there to be compliance and that there could be different categories of treatment so that supportive care medications, pain medications for cancer-related pain, could potentially be exempt from prior authorization requirements completely. And then at the same time for other kinds of prior authorization requests, it's not enough to just change a fax form to an electronic form. That's an improvement from having faxes going back and forth by paper, but really isn't a fundamental change in the prior authorization process or vision. And so, this idea of the pathways and then only when something is deviated in some sort of major way in various categories to be determined that sort of triggers a peer-to-peer review that would both hopefully serve the purpose of reducing overuse of unnecessary or non- indicated treatments and save money. But also, in a way, I think that is less burdensome to the health care system. And I fully acknowledge that I am not a policy expert, I mostly research metastatic breast cancer, but this issue really affects us all very personally every day.   Dr. Nathan Pennell: I know you just said you're not a policy expert, but can you talk to us a little bit about what Congress and ASCO are doing to help from a legislation standpoint or a regulatory standpoint to help make this a little bit less painful? Dr. Nancy Lin: Yeah. So ASCO has endorsed the so-called “Improving Seniors Timely Access to Care Act.” And for those out there listening, particularly patients, you might say, “Well, I'm not a senior.” But it's important because how Medicare deals with issues often is then adopted by private insurers. And so starting with “Improving Seniors Timely Access to Care Act,” the intent is that it will also affect people with cancer at all age groups. But some of the provisions or the proposals are to convert to an electronic prior authorization system, to put systems in place for timely and efficient communication between providers and insurers, to ensure a process for real-time decisions that have some timeframe or timeline or deadline associated with it, to facilitate guidelines and pathway-informed decisions, and to also, importantly, be fully transparent about approvals and denials, portions that are denied, these sorts of reasons for denials, to really have transparency in that process which at the moment does not really exist. I think these are all very, very important steps with the overarching goal to promote timely and appropriate access to medications, procedures, and evaluations for oncology patients. Dr. Nathan Pennell: I'm just curious, in your opinion, do you think that there is actual inertia to try to change some of these things from a policy perspective? It can be kind of frustrating sometimes. It seems like the insurance industry has really kind of taken command of this by implementing these and we see the problems and we talk about them. But from a regulatory standpoint, it really seems like things are kind of maybe being a little bit neglected. Dr. Nancy Lin: I think that this is really something where I do think there will be some movement; maybe it's that I'm an optimist and that's what you need to be to be an oncologist.  I think that a big part is going to be really a focus on the impact on patients because although we certainly feel the impact on ourselves as providers and our staff, I don't know that that in and of itself is going to be enough to move the needle, like doctors complaining that they are having to spend too much time on the phone. I think the real impact is really related to the impact on patients. And as I said, I think that the AMA survey and the ASCO survey, those are very important because they really put the focus on [assessing] the impact on patients living with cancer.  Again, the limitations of a survey-based study are profound. And I do think that the current [White House] administration is very, very engaged in improving care for people with cancer. And in fact, part of this revised Cancer Moonshot [initiative] is not only better science around cancer and better molecular understanding of cancer but at the end of the day, if we can't get the right treatment to the right patient, it doesn't really matter how good the science is. And part of getting the right treatment to the right patient is not just training, guidelines and education. Part of it is just the practical aspect of insurance coverage as one important aspect of that. And so, I do think that there will be some movement on this because I think that it's really gotten to a point where this is not just inconvenient for doctors. I don't think that that's enough to drive anything forward personally, but I think that when you start to see impact on patients, that is really a big deal.  I was struck that one of the studies that we had identified was a study looking at over 13,000 chemotherapy requests and understanding how many were denied and why they were denied. And basically, about 11% of the requests ultimately were denied after peer-to-peer and all sorts of other appeals. And this was essentially the gold standard, so to speak. In this study was the oncologist's opinion as assessed by the so-called board certified oncologist, which is what was described in the publication employed by the insurer. We have these competing narratives and that is ultimately the problem: We have the AMA and the ASCO surveys which are survey-based asking the oncologists, and we have these data which are based on the insurer essentially as the gold standard arbiter. So it's hard to reconcile those two pieces of information because they're not really coming from the same place. And then I think you could also argue that, think about 13,000 chemotherapy requests, that means that essentially 90% were fine.  When we looked at our pathways employed at Dana-Farber where we check to make sure that our physicians are adhering to the pathways, we basically want to aim at about 80% with the idea that some patients decline a standard regimen, and we go to something else. They don't want alopecia with the idea that some patients have comorbidities, that you don't want to micromanage how oncologists are managing their patients. And honestly, in most pathway programs, we consider 80% to be pretty good. In this study, 80% were approved. And you might argue, is it worth reviewing 13,000 requests to this level of scrutiny for 90% to be approved? And again, I think that that really raises this idea of like rather than just switching a fax system to an electronic system to really rethink where's the low-hanging fruit? Where would prior authorization really serve a positive purpose? I think there are places where it could serve a positive purpose and where is it just adding unnecessary friction. Dr. Nathan Pennell: Yeah, it's a complicated picture and there are valid arguments on both sides. One of the things that is very appealing to me about the proposed legislation is requiring the payers to actually report and disclose their levels of denials and prior authorizations and this allow us to maybe take it beyond the anecdotal evidence to actually being able to document what they're doing. Because once you shine a light on things, sometimes it becomes a little bit harder to abuse the system.  Dr. Nancy Lin: Yes, I agree.  Dr. Nathan Pennell: Well, Nancy, thanks so much for coming on the podcast today to discuss this challenging problem. I know we could have talked about this for an hour or more. We really appreciate your work to highlight the impact of this problem both on providers and on patients, as well as outlining some efforts to find solutions. Dr. Nancy Lin: Great, thank you for having me. Dr. Nathan Pennell: I also want to thank our listeners for joining us today. If you value the insights you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Have a great day. Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers: Dr. Nathan Pennell @n8pennell Dr. Nancy Lin @nlinmd   Follow ASCO on social media:     @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi  Dr. Nancy Lin: Stock and Other Ownership Interests: Artera Inc. Consulting or Advisory Role: Seattle Genetics, Puma Biotechnology, Daichi Sankyo, Denali Therapeutics, AstraZeneca, Prelude Therapeutics, Pfizer, Olema Pharmaceuticals, Aleta Biotherapeutics, Artera, Johnson & Johnson/Janssen, Blueprint Medicines, Genentech, Pfizer, Seattle Genetics, Merck, Zion, Olema Pharmaceuticals        
6/8/202325 minutes, 13 seconds
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ASCO23: RELATIVITY-047, CheckMate-038, and Other Advances in Immunotherapy

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in melanoma, including targeted therapy and the addition of LAG-3 inhibitors to checkpoint therapy, as well as promising checkpoint inhibitors in cutaneous squamous cell carcinoma and Merkel cell carcinoma in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to welcome my colleague and friend, Dr. Jason Luke. Dr. Luke is an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh's Hillman Cancer Center. He is a very, very well-renowned physician-scientist who has done fundamental work in developmental therapeutics and also in melanoma.  Today, we'll be discussing some key oral abstracts highlighting advances in immunotherapy in the cutaneous malignancy space that will be featured at the 2023 ASCO Annual Meeting.   You will find our full disclosures in the transcript of this episode and the disclosures of all guests on the ASCO Daily News Podcast are available in our transcripts at asco.org/DNpod.  Jason, thank you for coming on the podcast today. Dr. Jason Luke: Well, thanks so much for the opportunity. Dr. Diwakar Davar: So, we will go right ahead into the abstracts and the first one we thought we'd discuss is Abstract 9502, which is the RELATIVITY-047 study, specifically the 2-year results. This is the update. This has also been concurrently published at the New England Journal of Medicine Evidence online. And so in this publication and oral presentation, Hussein Tawbi, Georgina Long, and colleagues are talking about the nivo-rela data in the context of metastatic melanoma. So what is your take on this? What is your take on the data both presented and published and how would you contextualize this for the audience? Dr. Jason Luke: Right, so the RELATIVITY-047 study, as people will remember, randomized treatment-naive patients with metastatic melanoma to either receive nivolumab as standard treatment as a monotherapy or the combination of nivolumab and the anti-LAG-3 antibody relatlimab. And that study reported out a couple of years ago showing the improvement in progression-free survival as the primary endpoint. And at the time we saw that difference was approximately a 6-month absolute difference. And eventually, we saw there was an increase in the overall response rate also, again, approximately on the order of about a 10% change. What was interesting was that the overall survival initially was immature and that was an interesting follow-up point that we wanted to see. So I think what's important in seeing now this 2-year update of these data are the maintenance of the benefit for nivolumab plus relatlimab as compared to nivolumab alone across those measurements of progression-free survival and overall response rate.  Interestingly, the overall survival in the clinical trial actually did not meet the pre-specified threshold for statistical significance. That being said, when you look at the data presented in the Kaplan-Meier plots and you think about the difference, it really does appear that there's a clinically meaningful difference between these 2 groups. And the statistical cut point only missed by about .01. And so this is one of those areas where one wonders whether or not subsequent therapies may have impacted on the overall survival calculation because obviously, patients in this trial had not received ipilimumab or a PD-1 CTLA-4 combination. So the take-home message from me in this data set was that the benefit of nivolumab and relatlimab was sustained over time and there was no suggestion of any late toxicities that might make us concerned.   One advantage of this combination of nivolumab and relatlimab is the dramatically improved side effect profile relative to nivolumab and ipilimumab. So whereas immune-related adverse events that were serious, grade 3-4 is approximately 50% for nivolumab and ipilimumab, in the RELATIVITY-047 study, we see that the incidence of grade 3-4 toxicities for nivolumab and relatlimab is 17.2%, so that's less than half. So that's pretty attractive. And when we think about frontline management of patients, I think these data really support that nivolumab plus relatlimab is a reasonable consideration for some patients. And now I think the future question is really going to be, okay, well then who should get nivolumab and relatlimab versus who should still get nivolumab plus ipilimumab? Obviously, these data do not address that, and I think that that's probably the most important question for metastatic disease that's probably on the horizon. Dr. Diwakar Davar: Thank you, Jason, those are all fantastic points. It is interesting to note that as a result of the data, or really the lack thereof, the combination is actually not being launched in certain countries. So, for example, the German Health Authority, GBA, the Federal Joint Committee in Germany has decided against the acceptance of this agent because it does not accept event-free survival (EFS) as a patient-relevant endpoint. So it's interesting that we have an agent that is now going to be FDA-approved. It's already FDA-approved and available in the United States, but it will not be at least available in Germany and there may be other countries that decide favorably or unfavorably depending on how this OS data is viewed.   So pivoting to another LAG-3 inhibitor in this case fianlimab, we're going to discuss Abstract 9501. So Abstract 9501 essentially is describing a phase II trial that evaluated the LAG-3 inhibitor, fianlimab, along with the anti-PD-1 inhibitor, cemiplimab from Regeneron. The data is slightly different from what we have seen with RELATIVITY-047, the Opdualag combination. So Jason, how would you contextualize the fian-cemi combination in advanced melanoma in the context of what we've seen with RELATIVITY-047? If you could help us with that, please. Dr. Jason Luke: Yeah, absolutely. So before we dive into this specific abstract, it's, like you mentioned, probably useful to just put all of this in context. Targeting LAG-3 as an immunomodulatory approach has actually been in clinic for a decade approximately. And so the relatlimab phase 1 started quite a long time ago. And there was data for nivolumab and relatlimab in PD-1 refractory patients with melanoma that showed not a tremendously obvious level of activity. And so it was thought there that the only place they would see that activity was to go to a frontline randomized phase 2 and then phase 3 trial, as we just discussed.  In contrast to that, given all the data that had come forward about LAG-3 targeting with relatlimab, the group developing fianlimab took a different approach and rather treated a cohort of patients with treatment-naive melanoma to try to get an initial assessment right away of the activity as read out by overall response rate for this PD-1 plus LAG-3 combination, which is cemiplamab plus fianlimab.   And these authors have previously presented data about this combination from cohorts of patients who are treatment-naive who received this combination and described approximately a 64% overall response rate. And that's an impressive number in the treatment-naive setting. There's sort of a tension there to sort of say, well, wait a minute, the response rate in this single-arm study is 64%, but in RELATIVITY-047, the response rate was lower for the LAG-3 combination and I think that's not a fair comparison. We have to realize this is a much smaller group of patients that has the potential to have been somewhat biased towards a better cohort just because of where and when they were recruited to participate in this trial. All the same, I think that number does look impressive and suggest that this combination is active in the frontline.   Specific to this abstract, though, what the authors presented here was to update those previous data and then specifically also to focus on a cohort of patients who are allowed to have had previous treatment in the perioperative setting. So either neoadjuvant or adjuvant therapies. And in a subgroup of patients, they observed that even in the patients that had received adjuvant anti-PD-1 who went on to then progress later, they got actually a similar overall response rate at approximately 60% even in that group. And so I think that that seems like an exciting number as well. One would on first principles think that if patients got an adjuvant anti-PD-1, then a PD-1 LAG-3 combo could be less active. When and how the patients progressed or did not on that adjuvant therapy, however, I think makes a big difference. And given the relatively small sample size of patients that were included in this report, which is on the order of 20-ish patients who were in the previous PD-1 treated adjuvant cohort, I don't know that we can make super broad analyses trying to compare across the development programs.  What I would take from this abstract, however, is that it does appear that this other PD-1 LAG-3 combination cemiplamab plus fianlimab is also very active and certainly deserves to be investigated in similar clinical trial contexts as the nivolumab plus relatlimab combination that we previously discussed. And while it's not specifically stated here, that is happening, there is a frontline phase 3 trial for this combination of fianlimab and cemiplamab as well as adjuvant considerations, also ongoing. Dr. Diwakar Davar: So, thank you. We've seen a lot of LAG-3 data this last 2 months, the phase 2/3a RELATIVITY-020 trial has just been published in the JCO, I encourage people to read that. And so that was the evaluation of nivolumab and relatlimabin the post-PD-1 patient population that Jason alluded to, where the response rate that was observed was 12%. So we've seen a lot of interesting data, a lot of interesting survival data, and now a new potential combination with LAG-3 with fianlimab and cemiplamab from Regeneron. So it'll be a very interesting next couple of years as we see whether or not this new combination, how it shakes up against the established nivu-rela combination, again, albeit with the limitations of cross-trial comparisons and also how it performs against cemiplamab in this ongoing, as you alluded to, ongoing global phase 3 trial.  So, pivoting away from melanoma, now addressing the context of another cutaneous malignancy, a very high-risk one, Merkel cell carcinoma. So, Merkel cell carcinoma for those who are not necessarily treating a lot of this is a very rare and very aggressive cutaneous tumor. It's a neuroendocrine tumor of the skin. It's a cancer that's typically associated more than about 60% of the time with a cancer-causing virus, an oncogenic virus known as a Merkel Cell Polyomavirus.   And in this setting, checkpoint inhibitor therapy has been approved for the last couple of years, initially with a PDL-1 inhibitor, avelumab, and then more recently with a PD-1 inhibitor, pembrolizumab. And, at this point in time, there are three FDA-approved agents that are checkpoint inhibitors that are available for the treatment of this disease.   And CheckMate-358 was essentially a trial of nivolumab plus/minus ipilimumab in the setting of this Merkel cell carcinoma. So, Jason, what are your thoughts on how the addition of ipi did in this setting [in Abstract 9506]?  Dr. Jason Luke: Yeah, so I think this is a really interesting abstract because there's a slightly more context even than what you alluded to there. This study is an open-label, multi-cohort, but single-arm investigation where one cohort of patients received nivolumab alone and the other cohort received ipilimumab. It needs to be buttressed by a previous publication in The Lancet last year by the group at the Moffitt Cancer Center who also did a prospective study looking at nivolumab and ipilimumab. In that previous study that the Moffit group did, they got a response rate of 100%. All patients responded to the combination of nivolumab and ipilimumab in their study and that was quite provocative, suggesting that while anti-PD-1 alone has about a 50% response rate, adding ipi in that scenario then took it to 100. So these data were very much of interest because this could be a confirmatory data set to suggest for this rare tumor that perhaps a combination regimen should be preferred. Of course, one has to remember that adding ipilimumab to anti-PD-1 substantially enhances the toxicity profile. And these patients tend to be elderly that develop this kind of cancer, Merkel cell carcinoma. So that's a rather important caveat.   Just to get to the crux of what happened in this trial. As opposed to the previous Moffit trial, there actually did not appear to be a major increase in the benefit of adding ipilimumab, at least in this trial. Because again, in parallel cohorts, the NIVO monotherapy arm had a 60% response rate, which is roughly a little bit higher, but roughly in line with what we've seen previously. And the response rate to nivolumab plus ipilimumab was 58%. So, I mean basically the same. So, how can it be then, that we have this previous very high-profile publication that says 100% response? Now, we have a second publication that says adding ipi doesn't do anything - that's confusing, and I think it'll be really important to try to look at what were the differences between these two cohorts of patients. Did one of them have higher risk features, greater disease burden, et cetera? We don't really know that just yet, but trying to tease that out will be important.  This data also emphasized, though, the complexity around the dosing of ipilimumab. And in melanoma, we never really figured out what the best dose of ipilimumab was to give either alone or even in combination with a PD-1. And we don't really have time to get into all of it right away here, but there are multiple studies in melanoma that would suggest that giving ipi on an every 3-week dosing schedule is superior to giving it on a 6-week dosing schedule. In this study, they did use the 6-week dosing schedule. So, whether or not that could have made a difference, I guess, is unknown. But I would notice that in the previous Moffitt trial, they also used that six-week dosing schedule. This one's a head-scratcher for why did these data not confirm a previous data set? But for the time being, I think this emphasizes that PD-1 monotherapy really is the standard approach that should be considered for patients with metastatic Merkel cell carcinoma.  Dr. Diwakar Davar: That's great, Jason. And so, again, it's a very tough patient population. These are very rare patients. The Moffitt trial that Jason alluded to essentially was a trial that had in each arm, there were approximately 25 patients, of which 13, or between 11 to 13 patients were actually checkpoint inhibitor naive, wherein the dramatic 100% response rate was seen. And this is a trial where at least in this update, we've got about 25 patients in nivo monotherapy, I mean in 43 patients. And so, in a disease that is thought to be extraordinarily sensitive to checkpoint inhibitor immunotherapy because of the role of the virus and the high TMB that it's associated with, it is very interesting that the addition of an additional checkpoint inhibitor did not appear to improve outcomes. But as you alluded to multiple reasons, but we don't know how it's going to shake out. Next, Abstract 9507 and this is a very interesting trial known as the MATISSE trial. So, in the context of cutaneous squamous cell carcinoma, cutaneous squamous cell carcinoma is a relatively not uncommon cancer, primarily seen in older cancer patients, particularly a little bit more common in men. And in this setting, we've got checkpoint inhibitor therapy that is FDA-approved, at least two of which are FDA-approved right now, pembrolizumab and cemiplamab both were approved in the advanced cancer setting. And we do know that because of the extraordinarily high tumor mutation burden associated with cutaneous squamous cell carcinoma, checkpoint inhibitor therapy has got a very dramatic effect. Response rates are between 35% to 42% with pembrolizumab and 40% to 50% with cemiplamab, depending on whether or not one looks at the relapsed metastatic or the locally advanced patient populations.  And interestingly, much like we've seen with melanoma, we have migrated the use of this therapy early in the lines of patients, particularly in the setting of perioperative therapy. So, Jason, how would you contextualize the results of the MATISSE trial in relation to the existing and known data from several of our colleagues regarding the role of what checkpoint inhibitor therapy is doing in terms of organ preservation?  Dr. Jason Luke: Yeah, and I think this is an area of tremendous excitement. And as you were alluding to, the activity of anti-PD-1 really was transformative in this disease, which really can be a disfiguring and locally destructive disease. And with that activity for unresectable disease, last year, near the end of the year, there was a first report of a large neo-adjuvant clinical trial in cutaneous squamous which showed really outstanding results in terms of improving surgery and pathologic complete response using anti-PD-1 in that setting. And for this trial, this was a trial done in Europe; they took a similar tact of trying to think about giving anti-PD-1 or anti-PD-1 with anti-CTLA-4 with ipilimumab in that neoadjuvant period to see whether or not they could reduce the use of extensive surgery and/or radiation therapy.  The short version is they were able to do that. And so they described 40% of patients with single-agent anti-PD-1 and 53% of patients who received a combination having major pathologic response to treatment. And this was so much so that 10 of the patients who had pathologic responses actually withdrew their consent to go on to have surgery because they decided that they had had such a good effect of the immunotherapy, they weren't willing to put themselves through what was going to be a very difficult surgery. And I think that speaks to the upside potential of these checkpoint immunotherapy approaches in certain settings, specifically here in cutaneous squamous cell carcinoma. Moreover, they describe clinical response in neoadjuvant setting as 50% for PD-1 monotherapy and 61% for the combination and I really think that this is really ready for prime time.  With the study published in the New England Journal last year and these data now, I really think the field needs to start moving towards the use of perioperative anti-PD-1 with or without ipilimumab as a standard approach. And I think it's the case that even the NCCN and ASCO and various guideline societies are going to start acknowledging that this ought to be considered for most patients who are facing difficult surgical operations for continuous squamous cell carcinoma. Dr. Diwakar Davar: So, Jason, you bring up a fascinating point, which is the appearance of this in guidelines. So this is undoubtedly extraordinarily good data. It's confirmatory, the pathologic response rates in many ways paradoxically low. You'd expect something about 50% or so. But the reason it's low is because 10% of patients who actually benefited didn't undergo surgery. So really the degree of benefit is tremendous. It's about 50% to 60%. So the fascinating thing in the setting that we'd have is if one is going to try to get the drug FDA-approved, what we now have is the conventional setting in which one needs a definitive endpoint. And at least we know that pathological response rate is not a definitive endpoint in the context of melanoma or, for that matter, cutaneous squamous cell carcinoma. The only setting in which it is a regulatory endpoint is a non-small cell lung cancer or triple-negative breast cancer. But recently there’s been some very exciting data from another PD-1 inhibitor called dostarlimab in a trial done by your former colleague Dr. Luis Diaz when he demonstrated a dramatic result of dostarlimab in the context of perioperative rectal cancer where it is micro-satellite high wherein the standard of care is typically very disfiguring abdominal perineal resection.    So in the context of some of our listeners who might be thinking a little bit about how this pertains to regulatory approval, what are your thoughts about the paradigm of avoiding highly disfiguring surgery relating to what was seen in the rectal cancer discussion to what we’re now seeing with perioperative therapy in the context of cutaneous squamous cell carcinoma?  Dr. Jason Luke: I think it's a very important question. And the easy out for diseases that have a pattern of progression that is metastasis is to use event-free survival which can include both the pre-surgical and the post-surgical period in terms of looking for whether or not the cancer comes back. And that works for diseases potentially like lung cancer, like you said, maybe melanoma. In cutaneous squamous cell carcinoma, however, that's not probably going to work because this tends to be a locally invasive and less of a metastatic disease. So here then, we really need to have sort of organization across patient advocacy, dermatology, medical oncology to come up with what the most appropriate considerations are going to be for evaluating that long-term benefit because I think we need a tangible result that we can show the FDA. Everyone is really impressed by these results, and I think that next step is to craft this into a way that we have a measurable output that we can then go to them with and say bless this so that all of our patients can get this kind of treatment. Dr. Diwakar Davar: Really great discussion, Jason. And I think this is going to be an area of particular interest going forward, given both the number of trials that have been conducted in this space and also the role of the very interesting regulatory paradigm that has now been set initially at least with the rectal cancer that is microsatellite high and now potentially we will see with cutaneous squamous cell carcinoma.   And so the final abstract that we have selected for you is Abstract 9511. And this is a trial that was conducted by a mutual colleague, Dr. Ryan Sullivan, and his colleagues. And it's essentially a trial of looking at targeted therapy with or without navitoclax in BRAF mutant melanoma patients. And part of the reason to highlight this, it's very interesting preclinical data supporting the addition of navitoclax, b but also a great example of an early trial that came through the CTEP portfolio. And so Jason, can you tell us about why this is exciting and how we might contextualize the addition of navitoclax to the targeted therapy backbone?   Dr. Jason Luke: Sure. So listeners will be quite aware of targeting mutant BRAF as a therapeutic strategy across oncology that was really initially pioneered in melanoma with the development of vemurafenib as the first selective BRAF inhibitor. But the field, of course, moved eventually to BRAF and MEK combinations across essentially all settings. We know that dabrafenib and trametinib are now approved pan-cancer for anywhere we find a BRAF V600e mutation. In the context of melanoma, looking at mechanisms of resistance, we observed that they were quite heterogeneous with reactivation of elements of the mitogen-activated protein kinase pathway, the MAPK pathway. But also there were metabolic changes in the cancer cells themselves which could drive resistance and were downstream of some of those reactivation signaling points. So one of those is the induction of anti-apoptotic machinery in the cell. So activation of BCL-2 or Bcl-xL to try to save those melanoma cells when they were under stress by blockade with BRAF and MEK inhibitors. And that observation was made now about a decade ago or more. And that raised the possibility that repurposing a drug that was being used actually in the chemo malignancy space might be useful in augmenting targeted therapy. And that's where we come in with the navitoclax as a BH3-mimetic that can actually knock down those antiapoptotic proteins, BCL-2 Bcl-xL. And so that was the context for this initially phase I clinical trial of combining navitoclax with the dabrafenib and trametinib.  And those data supported the safety of doing that and moved to this study, which was a randomized phase 2 study of that triplet regiment versus the dabrafenib and trametinib alone. And so this study started quite a long time ago, before the sort of initiation or widespread use of anti-PD-1 antibodies. And so it had to kind of undergo some various iterations throughout its course but eventually has now read out. And it had two primary endpoints, with one being focused on improving the complete response rate for targeted therapy because that's been associated with long-term outcomes as well as to look at the maximum tumor shrinkage of patients within this trial and of course to look at other endpoints like response rate, progression-free survival, et cetera.  About half the patients who participated in the trial had prior immune checkpoint blockade and they were actually distributed evenly across the two arms. So we think that probably won't impact on the outcomes. And what was observed in the clinical trial was that in fact, the triplet did improve the complete response rate for targeted therapy. So navitoclax plus dabrafenib and trametinib had a complete response rate of 20% versus dabrafenib and trametinib alone being at 15%. Both of them had an overall response rate in the 80% range, with slightly higher for the triplet at 84% versus 80% for the double-edged standard therapy. There was also a suggestion that there may be a disproportionate benefit for the triplet actually in patients with smaller baseline tumors. And we know that the efficacy of targeted therapy is more pronounced in the lower-volume disease state.   And so overall, when we look at this without really adding much toxicity, I think this is an intriguing place to look at further drug development. BRAF and MEK inhibition has been a backbone therapy in Melanoma for a long time, but we really haven't been able to move past it or augment it in any real way because of the heterogeneity of treatment resistance. And here, by going after metabolic changes, we perhaps might have the opportunity to enhance our targeted therapy somewhat further. And so we'll look forward to further results investigating this regimen in subsequent clinical trials. Dr. Diwakar Davar: Fantastic discussion, Jason. So these are all great insights. As you've heard, we've now discussed a couple of key abstracts covering major topics that will be presented, major themes of the malignancy space at ASCO 2023, including the addition of a lactate inhibitor to checkpoint in both a randomized large phase 3 trial and a smaller phase 2 trial, the context of targeted-therapy in melanoma making another forerun in the post-3c setting. And two very interesting studies I have looked at, checkpoint inhibitor therapy in the context of cutaneous squamous cell carcinoma and Merkel cell carcinoma, addressing themes that are of huge importance going forward, including the role of perioperative therapy in squam and the addition of a CTLA-4 inhibitor in Merkel. These oral abstracts are all going to be presented at the 2023 ASCO Annual Meeting. We look forward to seeing you there.  So, thank you Jason for taking the time to join us and for highlighting these important advances in immunotherapy. And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Thank you for your attention. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers: Dr. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Diwakar Davar:  Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:  Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio
5/25/202328 minutes, 57 seconds
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ASCO23: COMMANDS, CAPTIVATE, and Key Studies in Hematologic Malignancies

Dr. John Sweetenham and Dr. Marc Braunstein discuss the role of maintenance therapy in high-risk multiple myeloma, advances in myelodysplastic syndromes in the COMMANDS study, the promise of bispecific antibodies in the pivotal EPCORE NHL-1 in relapsed/refractory large B-cell lymphoma, and improving outcomes for patients with chronic lymphocytic leukemia in the CAPTIVATE trial.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. My guest today is Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center. Today, we'll be discussing key posters and oral abstracts highlighting advances in hematologic malignancies that will be featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.  Dr. John Sweetenham: So, Marc, thanks for returning to us and coming to join us on the podcast today. Dr. Marc Braunstein: Thanks for inviting me back. Dr. John Sweetenham: I'd like to start out with Abstract 8001. This is a study which is addressing the role of maintenance therapy in patients with high-risk multiple myeloma. Could you take us through this study and the key take-home points that you think are the most important ones? Dr. Marc Braunstein: Sure, absolutely. So, the first abstract that we're going to discuss is an oral abstract being presented by Dr. Nooka regarding maintenance therapy in high-risk multiple myeloma patients. Outcomes of patients with multiple myeloma are clearly improving, yet those with high-risk cytogenetic abnormalities, which represent about 10-20% of all multiple myeloma, tend to have poorer survival, and worst among these are those with what's called ultra-high-risk or double-hit multiple myeloma who have more than 1 high-risk cytogenetic abnormality. So, this study looked at maintenance therapy following stem cell transplantation in 26 high-risk patients, about 59% of whom had double hit disease, representing very high-risk disease. This was a phase II study looking at using carfilzomib, pomalidomide, and dexamethasone in high-risk multiple myeloma patients who achieved at least a partial remission following stem cell transplant. There were 26 patients enrolled. The median age was 60. Of note, about 59% of patients were Black, which is important because these patients tend to be historically underrepresented in studies. And what they found was that at study entry, about 24% of patients were in a complete remission or better, and that deepened to 79% while on the study. And the median time to best response was 2 months, which is fairly brisk. With a median follow-up of about 26 months, the 36-month progression-free survival was 63%, and the overall survival was 72%, which is impressive, again in the context of patients who have very high-risk disease. So, although it remains to be determined what the optimal regimen or duration of maintenance should be in multiple myeloma, clearly, combination therapy is effective and should be used in patients who have high-risk or ultra-high-risk multiple myeloma. Dr. John Sweetenham: Great. Thanks, Marc. So, as you say, I mean, clearly the take-home message is around the effectiveness of this type of maintenance therapy. I just have a couple of quick follow-up questions for you. The first of those is, where do you see this going next? I mean, in your opinion, what would be the next logical study with this combination or similar combinations? And then secondly, what do you see on the horizon for those patients with very high-risk myeloma, particularly the double-hit population that you just mentioned? Dr. Marc Braunstein: It's a paradigm in multiple myeloma that combination therapy tends to be more effective as long as we're able to manage the adverse events that come with additional combinations. And we've been able to succeed in that regard with quadruplet regimens, even now that we have monoclonal antibodies that tend to be better tolerated and more targeted in nature. In terms of maintenance therapy, single-agent lenalidomide has been the long-standing agent of use for the majority of patients. But we now understand that the combination of an immunomodulator like lenalidomide and a proteasome inhibitor like bortezomib or carfilzomib is more effective for patients with higher risk disease.   We also have data from various upfront studies of quadruplet regimens, such as the FORTE study, which looked at carfilzomib and lenalidomide maintenance after transplant that shows that we can improve progression-free survival in all comers with multiple myeloma following transplants. So, I think down the road we're going to be looking at more use of combination therapies and maintenance. And as far as for high-risk patients, whether that's going to be using monoclonal antibodies in maintenance or combination proteasome inhibitors and immunomodulators or even other immunotherapies like bispecific antibodies as maintenance in the future remains to be determined, but clearly, for high-risk patients, we should be using combination therapies. Dr. John Sweetenham: Thanks, Marc. Let's change gears a little now and take a look at Abstract 7003, which addresses patients with myelodysplastic syndrome. This study addresses the efficacy and safety results from a study of luspatercept versus epoetin alfa in low-risk myelodysplastic syndrome. I wonder if you could describe this study and the results to us and maybe also for the benefit of our listeners, just mention quickly the mechanism of action of the experimental agent here.  Dr. Marc Braunstein: This is an oral abstract being presented by Dr. Garcia-Manero looking at a phase 3 study, as you mentioned, called the COMMANDS study, and this is looking at an agent called luspatercept in patients with low-risk myelodysplastic syndrome (MDS). So, patients with MDS can have inferior quality of life and survival when they become transfusion dependent. An earlier study called the MEDALIST study, which was published in the New England Journal of Medicine in 2020, randomized low-risk or intermediate-risk patients with MDS who were refractory or unlikely to respond to erythropoietin stimulating agents to either luspatercept, which is an agent that binds to TGF-beta family members and helps stimulate erythropoiesis. Patients were randomized in the MEDALIST study to luspatercept or placebo. And that study showed that luspatercept could improve a degree of anemia and lead to transfusion independence in certain patients. So, the COMMANDS study is a randomized controlled study that randomized 354 patients with low-risk MDS who were transfusion dependent and naive to an erythropoietin stimulating agent to receive either luspatercept or the erythropoietin stimulating agent erythropoietin alfa with the primary endpoint of transfusion independence at some time between 12 to 24 weeks. So, patients were randomized 1:1 to receive either luspatercept or epoetin alfa, and the primary endpoint again was transfusion independence. So, 354 patients were randomized in the study and the median treatment durations were 42 weeks of luspatercept and 27 weeks of epoetin alfa. And transfusion independence occurred in greater quantity in the patients who got luspatercept. For example, in the patients who received luspatercept at 8 weeks, transfusion independence was achieved in 74 versus 51% in the epoetin alfa group. So, in terms of treatment-related adverse events, they were fairly similar between the groups and consistent with the classes -  they were reported in 30% in the luspatercept group and 17% in the erythropoietin group, with no difference in patients who progressed to acute myeloid leukemia.  So, I think when it comes to MDS in low-risk patients, it's really important to preserve their quality of life by limiting their transfusion burden. And I think this study demonstrates that luspatercept continues to be an important part of the management in these low-risk patients. And whether or not you would start a patient with low-risk transfusion-dependent MDS on an erythropoietin stimulating agent or luspatercept is really addressed by this study showing that you can achieve greater rates of improvement in anemia and transfusion independence with luspatercept.  Dr. John Sweetenham: Great. Thanks, Marc. A really interesting study. And I do have one question for you about this study, which I think will make it clear to you that I am an expert neither in myelodysplastic syndrome nor in erythropoiesis. But my question is based on the mechanism of action. Is there any rationale for combining these 2 agents in future studies?  Dr. Marc Braunstein: Yes, it would potentially make sense to use 2 synergistic mechanisms to improve erythropoiesis. We would have to see what the potential for adverse events are. I think epoetin alfa tends to be a fairly low burden in terms of its side effect profile. Luspatercept can have some potentially dose-limiting side effects, such as GI side effects, but you can make dose adjustments to both of these medications. So we may need to find the correct doses of either of them in combination. But from a theoretical standpoint, it makes sense that these could potentially be synergistic, especially in patients who are likely to respond to erythropoietin by having a baseline lower erythropoietin level. Dr. John Sweetenham: Okay, let's move on in another change of gear now. And for the rest of the podcast, we're going to be talking about some studies in lymphoid malignancy, beginning with Abstract 7535, which is a follow-up of the phase 2 CAPTIVATE study which now has significantly extended follow-up from the original report. So Marc, can you walk us through this study and the outcomes to date? Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Barr and it is looking at CLL, which is a field that is really moving away from chemotherapy for newly diagnosed patients, thanks to the development of novel targeted agents. The CLL14 trial, which was published in the New England Journal of Medicine in 2019, showed that fixed-duration venetoclax plus obinutuzumab improved progression-free survival and rates of negativity of minimal residual disease, or MRD, when compared to chlorambucil and obinutuzumab. So building on the success of that study, combining a monoclonal antibody and a BCL2 inhibitor, the CAPTIVATE study is a phase II study, which examines venetoclax with ibrutinib, the BTK inhibitor, and previously untreated CLL. So it's kind of combining 2of the novel targeted therapies in a fixed duration, similar to what was done in the CLL14 study where patients received 1 year of therapy and then stopped treatment.   So in the CAPTIVATE study, 154 patients were enrolled. This was a phase 2 study that included about 56% of higher-risk patients who had unmutated IGHV, and the median time on the study was 50 months, with a CR rate of 58% at a 4-year follow-up and an overall response rate of 96%, which is quite high, especially considering that more than half of patients had high-risk disease. The progression-free survival was 79% and the overall survival rate was 98% at 4 years. And when they looked at patients who had undetectable minimal residual disease, the 4-year overall survival rate was 100%, which also suggests that MRD can help serve as a predictive marker of longer-term survival. So I think we have to also consider what the side effects are of combining these 2 agents and the most common adverse events were hematologic, which is expected based on what we know about the 2 classes. So I think the implication of the study is that giving 2 oral agents for a fixed period of treatment for 12 cycles is a rational approach that may spare patients indefinite therapy and can lead to positive outcomes, including in patients who have high-risk features with CLL.  Dr. John Sweetenham: Yeah, the other interesting observation that was made in the abstract, which I found to be really encouraging, was the fact that a number of these patients apparently have been re-treated successfully upon progression with ibrutinib again, which seems to be somewhat reassuring as well.  Dr. Marc Braunstein: That's right. There were 4 patients who started re-treatment in the study and perhaps we'll see the outcomes of that small subgroup are at the poster presentation. But I think when we discuss fixed-duration treatment, it also opens the door to potentially re-challenging patients when they relapse. We know that when we stop single-agent BTK inhibitors, which are historically given indefinitely in patients with CLL, those patients who stop, many will relapse, but you can potentially re-challenge them with the BTK inhibitor. So this study with the CAPTIVATE trial gives us some liberty to discontinue therapy, but also considering re-challenging upon relapse.   Dr. John Sweetenham: Yeah, absolutely. Moving on to aggressive B-cell lymphoma, now, the next abstract I'd like to discuss with you is Abstract 7525. I find this one particularly interesting as the continued excitement around CAR T cell therapy for relapsed aggressive lymphoma remains high at the moment. It's intriguing that t cell-engaging antibodies also have been reported, at least, to have remarkable activity in this set of diseases. So can you take us through Abstract 7525 and what they're reporting?  Dr. Marc Braunstein: Absolutely. Bispecific antibodies represent an emerging field in multiple hematologic malignancies, and this is a class of antibodies that bind to both the tumor cell as well as T-cells, and activate T-cell immunity against the tumor cell. So epcoritamab is a bispecific antibody that binds to CD3, which is expressed on T cells, and CD20, which is expressed on B cells. And Thieblemont et al published results in the Journal of Clinical Oncology last year in a phase I/2 study that looked at epcoritamab in patients with diffuse large B cell lymphoma following 2 prior lines of therapy, and this was given subcutaneously until progression of disease. In that study, at a median follow-up of about 11 months, the overall response rate was 63% with 39% complete remissions.   So the EPCORE NHL-1 study, which is being presented at this year's ASCO meeting, is presenting the updated results of that study looking at patients with diffuse large B cell lymphoma that includes a small population as well of patients with high-grade B cell lymphomas and primary mediastinal B cell lymphomas who had at least 2 prior lines of therapy. In this presentation, 157 patients were included in this study, and 61% had primary refractory disease, and actually, 39% had prior CAR T-cell therapy, of whom 75% progressed within 6 months. So these were patients who were not only refractory to treatment but also had prior T-cell therapy.   So at a median follow-up of 20 months, the overall response rate was 63% and the complete response rate was again about 39%, and the median duration of complete remission was 21 months. In terms of overall survival, the median was about 19 months, which is substantial for this group of patients who really wouldn't be expected to respond very well to conventional therapies.   As we know, T-cell-engaging therapies, such as these bispecific antibodies or CAR T-cells have the potential risk for certain immune-related adverse events, including cytokine release syndrome or icons, and a neurologic syndrome related to the therapy. And it's worth noting that the CRS in this study was predominantly low-grade. There were only 3% of patients who had grade III CRS, and 9 patients, or 6% had grade I to II icons. I think that also reflects how we're better managing those side effects and intervening earlier. So I think the results are impressive from the standpoint of the population studied, who were quite refractory to treatment and show relatively high rates of response. In fact, the median overall survival was not reached in the overall population.   So I think what we take away from this abstract is that bispecific antibodies are going to play a vital role in the relapse-refractory setting for large cell lymphoma and may also offer an alternative to patients who aren't necessarily fit for CAR T-cell therapy, which plays a vital role in patients who are both refractory to first-line therapy or relapse-refractory to subsequent disease. So these are very encouraging results, and I'm sure we'll see randomized data as well in the future, further supporting the use of bispecific antibodies like epcoritamab.  Dr. John Sweetenham: Yeah, I agree. Thanks, Marc. I think that's a great summary. And it's particularly exciting to me that the investigators were able to achieve this kind of level of response and progression-free survival with a subcutaneous treatment. It's really quite remarkable and really exciting to see that.  We're going to wind up with our final abstract today, which is looking at the utilization of circulating tumor DNA in, again, in patients with aggressive B cell lymphoma. This is Abstract 7523, so maybe you could walk us through this one, Marc.  Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Herrera looking at a, I guess you could call it a biomarker in the blood using circulating tumor DNA in patients with newly diagnosed diffuse large B cell lymphoma in the POLARIX study. So the results of the phase 3 POLARIX study were published last year in the New England Journal of Medicine and showed improvement in progression-free survival with the addition of these anti-CD79b antibody polatuzumab to standard R-CHOP chemotherapy compared to R-CHOP alone. And this study actually led to the approval of first-line treatment that includes polatuzumab.   In the abstract being presented by Dr. Herrera, the investigators looked at the value of circulating tumor DNA as a potential marker to serve as a guide for prognosis and predicting longer-term responses, particularly when the blood is cleared of circulating tumor DNA. So the study involved 654 patients who had ctDNA results both at baseline and then with longitudinal assessment, and they used an assay called the CAPP-Seq assay to assess circulating tumor DNA and assess for its clearance. In the study, undetectable circulating tumor DNA was achieved in 57% of patients who got the polatuzumab R-CHP combination and 59% of the patients who got R-CHOP by cycle 5 and then 6% in the polatuzumab group at 67% in the R-CHOP group.  So the rates of circulating tumor DNA clearance were similar between the 2 arms. But what's notable is that patients in the polatuzumab arm who achieved a complete response at the end of treatment plus cleared their circulating tumor DNA had superior progression-free and overall survival compared to patients who achieved a CR but retained circulating tumor DNA in their blood.   And this has implications because it might help gauge, for example, if patients may need additional cycles to clear the circulating tumor DNA, although we still need more data to answer whether that's necessary or not. And it may help serve as a predictive marker for longer-term remission, particularly in patients who perhaps have higher risk factors at baseline. So I don't think this is necessarily ready for primetime to use in clinical practice, but it is intriguing to know that we could finally have a tumor-specific biomarker in the blood to help monitor patients and potentially predict their longer-term remissions.  Dr. John Sweetenham: Thanks, Marc. I agree. Great summary, and obviously there's still something to learn about the kinetics of the response and so on. And also, I suppose it raises the question of whether those patients who still have detectable levels should be switched at the end of therapy to some kind of preemptive second-line therapy. And these are obviously all questions for the future, but it's going to be very interesting to watch this space, I think, and see how this story develops. Dr. Marc Braunstein: Absolutely. And my colleagues in the solid tumor space are already using circulating tumor DNA, for example, in colon cancer, to help with surveillance. So perhaps this could be a tool to use to predict relapse also in patients who are on surveillance after their treatment. But again, as you alluded to, we need more data to address that.  Dr. John Sweetenham: Well, thanks so much, Marc, for sharing your insights with us today on a really interesting set of abstracts coming up at the June meeting. And thanks for joining us on the ASCO Daily News Podcast. Dr. Marc Braunstein: Thank you for inviting me.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in a transcript of this episode. Join us again after the annual meeting for key takeaways on the late-breaking abstracts and other key advances from the ASCO Annual Meeting. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:  Dr. John Sweetenham Dr. Marc Braunstein @docbraunstein   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. John Sweetenham:Consulting or Advisory Role: EMA Wellness Dr. Marc Braunstein:Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp Speakers’ Bureau: Janssen OncologyResearch Funding (Institution): Janssen, Celgene/BMS
5/25/202323 minutes, 38 seconds
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ASCO23: Novel Approaches in RCC, mUC, and Prostate Cancer

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss the CLEAR study in renal cell carcinoma, a new exploratory analysis combining the TheraP and VISION trials in metastatic urothelial cancer, and compelling advances in prostate cancer and across GU oncology in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host for the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical director of the Genitourinary Cancers Program at the Inova Schar Cancer Institute in Virginia.   Today, we'll be discussing some key abstracts in GU oncology that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcript at asco.org\DNpod.   Jeanny, it's great to have you on the podcast today. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal, for having me. Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4502 regarding long-term updated results on the CLEAR study. The abstract reports the final, prespecified overall survival analysis of the CLEAR trial, a four-year follow-up of lenvatinib plus pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yes, I would be happy to. So, just as a reminder, the combination of lenvatinib and pembrolizumab was initially approved by the FDA in August 2021 for first-line treatment of adult patients with advanced renal cell carcinoma. So, this was based on significant benefits that were seen in progression-free survival, which was a primary endpoint, but also showed improvement in the overall response rates compared with sunitinib in first-line advanced renal cell carcinoma.   So this abstract reports on longer-term follow-up now at a median of 49.8 months, and PFS favored the combination lenvatinib and pembrolizumab compared to sunitinib across all MSKCC risk groups, and PFS benefit versus lenvatinib and pembro compared to sunitinib was maintained with a hazard ratio of 0.47. And even overall survival was also maintained with the combination with a hazard ratio of 0.79, and the overall survival favored the combination across all risk groups. If we look at the CR rate, it was 18.3% for the combination compared to 4.8% with sunitinib, unless patients in the combination arm received subsequent anticancer therapies, and that's intuitive. And the PFS2 was also longer with the combination at 43 months compared to 26 months. Now, it is important to note that grade III or more treatment-related adverse events did occur in about 74% of the patients in the combination of lenvatinib and pembro, compared to 60.3% in patients with sunitinib. Dr. Neeraj Agarwal: Jeanny, this is good news. So the main message from the abstract is that sustained results from this combination of lenvatinib plus pembrolizumab are being seen even after a longer follow-up of more than four years.  Dr. Jeanny Aragon-Ching: Yes, I agree. So now, moving on, Neeraj, to a different setting in the RCC space, let's look at Abstract 4519, which is titled “Efficacy of First-line Immunotherapy-based Regimens in Patients with Sarcomatoid and/or Rhabdoid Metastatic Non-Clear Cell RCC: Results from the IMDC,” which will be discussed by Dr. Chris Labaki. So, Neeraj, based on this abstract, can you tell us a little bit more about the impact of these adverse pathologic risk features in non-clear cell RCC?  Dr. Neeraj Agarwal: Of course. So, using real-world patient data, the IMDC investigators compared the outcomes of patients with metastatic non-clear cell RCC who were treated with immunotherapy-based combination regimens versus those who were treated with VEGF-TKIs alone. They also assessed the impact of sarcomatoid and rhabdoid features on response to IO-based combinations versus VEGF-TKIs. Of 103 patients with metastatic non-clear cell RCC who had rhabdoid or sarcomatoid features, 32% of patients were treated with immunotherapy-based combinations.   After adjusting for confounding factors, the authors show that those treated with a combination of two immune checkpoint inhibitors or an immune checkpoint inhibitor with a VEGF-TKI combination had significantly improved overall survival, which was not reached in the immunotherapy combination group versus seven months within the VEGF-TKI group. Time to treatment failure and objective responses were also prolonged, significantly higher, and better in the immunotherapy groups compared with patients who were treated with VEGF-TKIs alone. Interestingly, if you look at those 430 patients with metastatic non-clear cell RCC who did not have sarcomatoid or rhabdoid features, they didn't seem to benefit with immunotherapy-based combinations.  Dr. Jeanny Aragon-Ching: This is an exciting update, Neeraj. What are the key takeaways from this abstract? Dr. Neeraj Agarwal: So the main takeaway is if you see a patient with advanced non-clear cell RCC who has sarcomatoid and rhabdoid features, there appears to be a rather substantial and selective benefit with IO-based combinations. And in this context, I would like to highlight the ongoing SWOG 2200 trial also known as PAPMET2 trial, which is comparing the combination of cabozantinib plus atezolizumab. So immuno-therapy-based combinations versus cabozantinib alone in advanced papillary renal cell carcinoma setting. So this trial is being led by Dr. Benjamin Maughan and Dr. Monty Pal. And I like to encourage our listeners to consider referring their patients for involvement in this federally funded trial so that we can validate the data from this retrospective study in a prospective way. So, Jeanny, let’s now move on to another important disease type which is urothelial carcinoma. There is a very recent accelerated FDA approval of the drug combination of enfortumab vedotin and pembrolizumab for cisplatin-ineligible metastatic urothelial carcinoma patients. This is Abstract 4505, which is being presented by Dr. Shilpa Gupta and colleagues. Can you please tell us more about this update? Dr. Jeanny Aragon-Ching: Yeah, absolutely. So, as you mentioned, Neeraj, the FDA just granted accelerated approval in April 2023 for this combination of enfortumab vedotin or EV, which is and ADC, antibody drug conjugate against nectin-4 and the PD-1 inhibitor pembroluzimab. So it’s a combination for patients with locally advanced or metastatic urothelial carcinoma who are considered cisplatin ineligible. So this is nearly a four-year follow-up.   So as a reminder, this was a phase 1b/2 trial that included 45 patients and it had a primary endpoint of safety and tolerability although the key secondary endpoints included confirmed overall responses, duration of response, progression-free survival, and the resist criteria was investigated via investigator and BICRs which is in a blinded independent central review. Even overall survival was a key secondary endpoint.  So, the bottom line was the confirmed overall response by BICR was 73.3%, the disease control rate was about 84%, and the CR rate was 15.6% with a PFS of close to 13 months, and a 12-month overall survival rate of 83%. However, it is important to cite that there were treatment-related adverse events including skin reactions in 66%, neuropathy occurred in 62%, and ocular disorders in 40%. And there was a little bit of pneumonitis in close to 9%, colitis, and hypothyroidism, so there are side effects to watch out for.  Dr. Neeraj Agarwal: So, Jeanny this is great. What is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: So I think the most important thing is we now have a new combination of EV and pembro which shows very promising responses and survival in part which led to the FDA accelerated approval in the cisplatin-ineligible population of patients. However, we must note that the phase 3 trial of EV302 will ultimately establish which approach is really beneficial for all of our cisplatin-ineligible patients, either a carboplatin-based chemotherapy regimen or a non-platinum-based regimen such as EV and pembro. Dr. Neeraj Agarwal: Thanks Jeanny, would you like to discuss any other study in the bladder cancer space? Dr. Jeanny Aragon-Ching: Absolutely. I think Abstract 4508 from Dr. Seth Lerner and colleagues will be very relevant to our colleagues. This abstract is SWOG S1011, which is a phase 3 surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at the time of radical cystectomy for muscle-invasive bladder cancer.  Dr. Neeraj Agarwal: Yes. So this trial, as you said, is an important trial which randomized in a one-on-one fashion 618 patients with muscle-invasive bladder cancer undergoing radical cystectomy, and these patients were randomized to either standard lymph node dissection or an extended lymph node dissection. And standard lymph node dissection included, as we know, external and internal iliac and operative lymph node. The extended lymph node dissection included lymph nodes up to aortic bifurcation which included common iliac, presciatic, and presacral lymph nodes. At a median follow-up of approximately 6 years, there was no disease-free survival or overall survival benefit in patients undergoing an extended lymph node dissection compared to standard lymph node dissection. And extended lymph node dissection was also associated with greater morbidity and preoperative mortality. Dr. Jeanny Aragon-Ching: Very interesting data, Neeraj. So these results, I think, will be very useful for a lot of our surgical colleagues in both academia and the community who may still be inclined to perform extended lymphadenectomy during cystectomy. This study shows that it's actually not necessary. Dr. Neeraj Agarwal: Absolutely. So now let's move on to another disease type, which is very important - prostate cancer. There are several practice-informing abstracts that are worthwhile discussing. The first of these involves Abstract 5002, which looks at the impact of the PSA nadir as a prognostic factor after radiation therapy for localized prostate cancer, which will be presented by Dr. Praful Ravi and  colleagues. Jeannie, can you please tell us more about this abstract? Dr. Jeanny Aragon-Ching: Yeah, definitely. So this abstract, as you mentioned, Neeraj, is a prognostic impact of PSA nadir of more than or equal to 0.1 nanogram per ml within six months after completion of radiotherapy for localized prostate cancer - an individual patient data analysis of randomized trials from the ICECaP Collaborative. Basically, it refers to an attempt to evaluate early surrogate measures to predict for long term outcomes such as prostate cancer-specific survival, metastases-free survival, and overall survival. So they looked at a big registry from the ICECaP collaboration that included 10,415 patients across 16 randomized controlled trials. And those men underwent treatment for intermediate risk and high risk prostate cancer treated with either radiation therapy alone in about a quarter of patients, or they got RT with short-term ADT in about 58% of patients, and 17% of them got RT with long-term ADT.  So, after a median follow-up of ten years, what they found was, if you had a PSA nadir that is over or equal to 0.1 nanogram per ml within six months after completion of radiation therapy, it was associated with worse prostate cancer-specific survival, metastases-free survival, and overall survival. For instance, the five-year metastases-free survival for those who achieved a PSA nadir of less than 0.1 was 91% compared to those who did not, which was 79%. Therefore, they concluded that if you achieve a bad PSA of 0.1 or above within six months after you completed radiation, you had worse outcomes.  Dr. Neeraj Agarwal: Jeanny, what is the key takeaway message from this study? Dr. Jeanny Aragon-Ching: The key takeaway from this ICECaP analysis is that this information would be very important to augment a signal-seeking endpoint, especially for clinical trial development, so that we can develop further strategies to de-escalate for those who don't need systemic intensification or therapy intensification versus escalation for those who really do. Dr. Neeraj Agarwal: So, my radiation oncology colleagues need to watch out for those patients who do not achieve a PSA of less than 0.1 nanogram per ml within the first six months of finishing radiation therapy. Very interesting data.  Dr. Jeanny Aragon-Ching: Yes, absolutely. So. Neeraj another important abstract for our fellow clinicians, switching gears a little bit now, is Abstract 5011, which is titled “Do Bone Scans Overstage Disease Compared to PSMA PET?” This was an international, multicenter retrospective study with blinded, independent readers. Can you tell us more about this abstract? Dr. Neeraj Agarwal: Yes, a relatively small retrospective study, but still pertinent to our practice. So I'll summarize it. This study by Dr. Wolfgang Fendler and colleagues evaluated the ability of bone scans to detect osseous metastasis using PSMA PET scan as a reference standard. So in this multicenter retrospective study, 167 patients were included, of which 77 patients were at the initial staging of prostate cancer, 60 had biochemical recurrence after definitive therapy, and 30 patients had CRPC or castor-resistant disease.  These patients had been imaged with a bone scan and a PSMA PET scan within 100 days. And in all patients, the positive predictive value, negative predictive value and specificity for bone scan were evaluated at different time points. They had bone scan and PSMA PET scan and both were compared. And what they found was interesting. All these three values - positive predictive value, negative predictive value, and specificity for bone scan were 0.73, 0.82 and 0.82 in all patients, and in initial staging, it was even lower at 0.43 and 0.94 and 0.80.  So, without getting into too much detail regarding these numbers, I want to highlight the most important part of the study, that at the initial staging, 57% patients who had a positive bone scan had false positive bone scans. The interreader agreement for bone disease was actually moderate for bone scans and quite substantial for the PSMA PET scan.  Dr. Jeanny Aragon-Ching: So, Neeraj, what do you think is the key takeaway message here for our audience?   Dr. Neeraj Agarwal: The key takeaway message is that positive predictive value of bone scan was low in prostate cancer patients at initial staging, with the majority of positive bone scans being false positive. This suggests that a large proportion of patients which we consider to have low-volume metastatic disease by bone scan actually have localized disease. So in the newly diagnosed patients with prostate cancer, patients should ideally have a PSMA PET scan to rule out metastatic disease.   So, let's move on to another abstract I would like to discuss, which has important implications in treatment, especially now that lutetium 177 is approved, but frankly not available widely. Dr. Jeanny Aragon-Ching: Yeah, that's actually very timely. So the abstract you're referring to is 5045, which is being presented by Dr. Yu Yang Sun and colleagues entitled “Effects of Lutetium PSMA 617 on Overall Survival in TheraP Versus VISION Randomized Trials: An Exploratory Analysis.” So, Neeraj, can you tell us more about the relevance of this exploratory analysis? Dr. Neeraj Agarwal: Definitely. In this abstract, Dr. Yang Sun and colleagues assess the effect of lutetium PSMA on overall survival in two different trials, TheraP and VISION trials. So, just for our listeners' recollection, the phase 2 TheraP trial compared lutetium PSMA and cabazitaxel in patients with mCRPC who had progression on docetaxel and had significant PSMA avidity on gallium PSMA pet scan, which was defined as a minimum uptake of SUV max of 20 at least one site of disease and SUV max of more than 10 at all sites of measurable disease.  In this trial, 20 of 101 patients in the cabazitaxel arm crossed over to lutetium PSMA, and 32 of 99 patients in the lutetium PSMA arm crossed over to cabazitaxel. In the VISION trial, patients with mCRPC who previously progressed on at least one ARPI and one taxane-based therapy and had a positive gallium PSMA scan, and here, positivity was not stringently pre-specified as it was done in the context of TheraP trial. So, positive gallium pet scans were randomly assigned in two to one fashion to receive either lutetium PSMA plus best supportive care or standard of care versus standard of care.  And I'd like to highlight that the standard of care comprised ARPIs and bone protecting agents and these patients were not allowed to have cytotoxic chemotherapy such as cabazitaxel in the standard of care arm. Now, overall survival was similar in the lutetium PSMA group regardless of whether they got lutetium PSMA in the VISION trial or TheraP trial. There was no difference in overall survival with lutetium in the lutetium arms of VISION and TheraP trial with a hazard ratio of 0.92. And there was no difference in the overall survival between the lutetium PSMA and the cabazitaxel group in the TheraP trial if you use counterfactual analysis, assuming crossover had not occurred. So, quite interesting in my view. Dr. Jeanny Aragon-Ching: Yeah, thanks Neeraj for that wonderful synopsis and discussion. So, what is the key take home message then? Dr. Neeraj Agarwal: The main message in this new exploratory analysis, which combined both the TheraP and VISION trials, is that lutetium PSMA and cabazitaxel seem to be associated with similar overall survival benefit in these highly selected patients with PSMA positivity. Additionally, the difference in the observed effect of lutetium PSMA and overall survival in the TheraP and VISION trials may be actually better explained by the use of different treatments in the respective control arms of these trials. And these results, in my view, are quite pertinent for those patients and providers who do not have access to lutetium-177 therapy.  Let's go to another abstract that is currently relevant to our practice, given many patients with advanced prostate cancer who have concurrent diabetes; I'm talking about Abstract 5066. Jeanny, can you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Certainly, Neeraj. So this abstract will be presented by Dr. Amy Shaver and colleagues. So it's also very relevant, since many men who are diagnosed with prostate cancer frequently also have a concomitant diagnosis of type 2 diabetes mellitus. So, this was a SEER-Medicare population database analysis that looked at men who were treated with either abiraterone or enzalutamide and also had concomitant diagnosis of type 2 diabetes mellitus (DM). And they were identified using ICD-9 and ICD-10 codes and they were all tied in to acute care utilization. So they looked at CMS research data codes and ER hospitalization visits six months after treatment initiation was recorded. So all in all, they took a sample of 11,163 men, of whom close to 62% were treated with abiraterone and about 38% were treated with enzalutamide.  So, of these, about 27% of them had type 2 DM, of whom 59% received abiraterone and about 41% had enzalutamide. So, the bottom line is, compared to those without diabetes mellitus, those who had type 2 diabetes had worse acute care utilization, which was 43% higher than those who got abiraterone compared to enzalutamide, and also had higher overall mortality. Therefore, the bottom line is, having type 2 diabetes mellitus, unfortunately, portends worse outcomes in men with prostate cancer, so careful attention needs to be paid to those who are starting out already with such comorbidities. So Neeraj, any final thoughts you have regarding this abstract and overall before we wrap up on the podcast today?  Dr. Neeraj Agarwal: Absolutely. So it looks like, based on this very important pertinent Abstract 5066, which talks about the impact of diabetes on our patients, I think we need to be very watchful regarding the impact of diabetes on our patients who are being treated with abiraterone or enzalutamide, especially drugs which are known to make the metabolic syndrome and diabetes worse. I think close monitoring and close attention to control of diabetes is very important. So with that, I would urge the listeners to come and join us at the Annual Meeting, not only to celebrate these successes but also to help disseminate this cutting-edge data to practitioners and maximize the benefit to our patients across the globe.   And thank you to our listeners for joining us today. You will find links to the abstracts we discussed today on the transcript of this episode. Finally, if you value the insights that you hear on our ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:  Dr. Neeraj Agarwal @neerajaiims Dr. Jeanny Aragon-Ching Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching: Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant,  Exelixis, Speakers’ Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics.
5/25/202324 minutes, 49 seconds
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ASCO23: CodeBreak-101, NAPOLI-3, and Other Advances in GI Cancers

Dr. Shaalan Beg and Dr. Mohamed Salem discuss novel therapies in gastrointestinal cancers, including CAR T therapy and the CodeBreak-101 trial in mCRC, new advances in uHCC in the HIMALAYA trial, and an exciting update from the NAPOLI-3 trial in pancreatic cancer, ahead of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science 37 and an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center. My guest today is Dr. Mohamed Salem, a GI oncologist at the Levine Cancer Institute at Atrium Health. We'll be discussing key posters and oral abstracts in GI oncology that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Mohamed, thanks for coming on the podcast today.  Dr. Mohamed Salem: Thanks, Shaalan.  Dr. Shaalan Beg: There's some interesting studies in colorectal cancer that I'd like to get us started with today. Abstract 3547 is titled “A Phase I Dose-escalation Study of GCC19 CAR T: A Novel Coupled CAR Therapy for Patients with Metastatic Colorectal Cancer.” What are your thoughts on the study? Dr. Mohamed Salem: Actually, this was a very exciting study to see coming out in GI cancer, especially colorectal cancer. As you know, CAR T made its way to the treatment of lymphoma and other heme malignancies. In fact, we saw a fascinating response and outcome using that technique and that niche in the immunotherapy module. The challenge we had was that we could not replicate this in solid tumors until very recently. I'm sure you had the same thing in your clinic, too. A lot of patients with GI cancer or colorectal cancer come to you and say, "Okay, why can't I have CAR T?" And the response was, "We don't know if it's effective or if it's going to work yet." Here at our center, we had a phase 1 study, I think that was looking also at CAR T and solid tumors, particularly prostate cancer. So that I think was very exciting to see that technology is making its way to the solid tumor. I was very pleased to see this CAR T study coming out from the work of our Chinese colleagues looking into this in the CRC space.  Obviously, as you know, in colorectal cancer, we made a significant advancement, but I don't think we made enough advancement yet, and especially for refractory patients, patients with refractory disease who have underwent multiple lines of therapy. And this study actually addressed the need for those patients. So in this study, that was a phase I escalation dose, very much is we looked at about 13 patients who had metastatic CRC, they had at least two lines of therapy. So in what we say is a "refractory setting," unfortunately for those patients, we don't have large treatment options. And they used two doses, the first dose and the second dose that was a little bit higher. And the interesting part is that they were able to see very nice responses on this patient population. In the lower dose, I think the response was the PFS was about 1.9 months. But when they went up on the dose, actually the PFS was 6.3 months, which I think in the refractory setting is very meaningful.   And also the median overall survival for the first group was 13 months, which in the refractory setting is something we don't see often, and the higher dose was 18 months, which was even better. So there was a trend that higher doses are perhaps more effective or have better efficacies than lower doses, but also in terms of side effects, actually patients were relatively able to tolerate it well, and there were no surprising adverse events. So again, yes, that's 13 patients in total. So it's a very small study, but like everything else, the proof of concept sometimes is the first step and it's very important to see that data to suggest that this technology now can be utilized in solid tumors and CRC, especially now there is an unmet need for those patient populations. I'm sure you and I will see a lot of patients at the clinic with good progress status, and just looking for the next option, and I'm glad to see that. Hopefully, we can continue to build on that work.  Dr. Shaalan Beg: Another key abstract in colorectal cancer is Abstract 3513, the CodeBreak 101 study. This is a phase 1b safety efficacy trial of sotorasib plus panitumumab and chemotherapy with FOLFIRI for previously treated KRAS-G12C mutated colorectal cancer. And this is a really important study because even though KRAS-G12C represents a minority of KRAS mutated colorectal cancer, we know that this treatment can cause meaningful improvement in disease for other cancers like non-small cell lung cancer. And when sotorasib was tested as monotherapy in colorectal cancer, it saw an objective response rate of 9.7% that increased to 30% when added to panitumumab.   So in this trial, they took sotorasib plus panitumumab and added it to chemotherapy to see how it’s tolerated and what its effectiveness is going to look like. And they enrolled people who had more than one or more lines of prior therapy for metastatic disease. They treated 33 patients. The most common side effect was dermatologic, which is probably related to EGFR-based therapy, and they saw a confirmed overall response rate of 58%. Side effects are those that we look to expect with this specific regimen. I don't see any additional safety concerns here, but this can be a big step forward for KRAS-G12C-altered colorectal cancer. What do you think? Dr. Mohamed Salem: I totally agree. And again, it was very exciting to see that abstract and that result. I totally believe now, and I'm sure you would agree with me too, Shaalan, that we're moving from an era of one size fits all to a precision oncology and tailored treatment. And the fact now we have a treatment option for patients with a KRAS mutation is very exciting because before, we didn't have much that we can do about that mutation. So now it's not just a proof of concept. Now you're hitting that target with the chemotherapy and you're getting a 50% response rate. That’s something interesting also to see for this patient population and as you highlighted as safety also, and the adverse event was not high and patients were able to tolerate it, which makes it more doable for us to use it. Dr. Shaalan Beg: Yeah. And one of the challenges in the precision oncology space, which I'm sure you're experiencing in clinic as well, are the real-world applications of precision oncology and the drop-offs that happen that are preventing us from universal precision oncology - meaning the drop-offs that we see on eligible patients receiving the appropriate genomic testing, those who have genomic testing receiving the appropriate treatment. And we've seen a couple of fairly high-profile studies that are describing this in non-small cell lung cancer where the rates are not as encouraging as we would want it to be, which to me, as a physician, makes me worried that there are people out there who we don't know are carrying these mutations or have these mutations, and it hasn't been acted upon.   And related to that, there is an abstract at ASCO23, which is Abstract 3602, that looked at the real-world rates of FDA-approved targeted therapy and immunotherapy for people with metastatic colorectal cancer. They used the VA's National Precision Oncology Program data to study the prevalence of these mutations and how many of the folks ended up receiving the treatment that would be appropriate for those mutations. And this is a very exciting study. They looked at 908 metastatic colorectal cancer patients who underwent genomic profiling, 81% were colon and the rest were rectal. They found that 34% of patients harbored NRAS, KRAS, BRAF mutations, 9.6% were TMB-high, 7.7% had BRAF V600E, and 5.6% were MSI-high, which kind of puts the overall actionable variant prevalence in colon cancer at 47% and for rectal cancer at 44%.  And then they went down to see amongst those 424 eligible patients, how many ended up on appropriate therapy. And these were their numbers: for MSI-high 70%, TMB-high 47%, NRAS, KRAS, BRAF, wild-type 38%, BRAF V600E 17%. So nearly 30% of patients with MSI-high colorectal cancer did not receive immune checkpoint inhibitor therapy, and again, other aspects in terms of EGFR use, and I know that there are other challenges that may affect the use of EGFR inhibitors in colorectal cancer, but it really begs the point on aspects related to implementation science, on getting the testing and acting on those results. And I'm curious to what you're seeing that's being done on these initiatives nationally.  Dr. Mohamed Salem: I totally agree with you, Shaalan. This is a big problem we’re facing day in and day out because we struggle to find treatment options for our patients. And I think if we’re missing patient with targetable or actionable mutations and we’re not utilizing that, I don’t think that’s a good situation to be in. And I think that’s just a group effort. You have to work with the pathologist, you have to work with your team at the clinic. And as an oncologist treating this patient, we have to pay close attention to those markers. And frankly, just look for them. At least  the ones that you know are going to have therapeutic implications.  I do also think patient advocacy has a huge role here and huge opportunities that they can contribute. I am sure you are familiar with the pancreatic study that was published by our colleague Mike Pishvaian in Lancet a year or two ago. I think he named it the Know Your Tumor Type. I think that should be the way forward now, not just for pancreatic but for any cancer. Patients should ask their oncologists what my tumor is. Is it MSI-high, is it KRAS-G12C, is it BRAF? Because it will affect the treatment. I think it’s multi-layer and all of us should work in a cohesive manner to be able to not ever miss those markers which carry therapeutic potential.   Dr. Shaalan Beg: So moving on to hepatocellular carcinoma, Dr. George Lau and colleagues, they'll be sharing data from the phase 3 HIMALAYA study with hepatocellular carcinoma in the Annual Meeting that's Abstract 4004. And he looked at outcomes by occurrence of immune-related events for people who received tremelimumab and durvalumab. What are your thoughts on this study?  Dr. Mohamed Salem: This was a very interesting abstract to see. For a long time, we didn't have many treatment options in hepatocellular carcinoma. So, over the last two or three years now, I think we've made nice advancements in the therapeutic landscape. So, we have multiple options including immunotherapy which is very exciting for all of us to be able to utilize those powerful drugs in that disease. The question that comes out is who actually responds? Obviously, in HCC you don't have a lot of biomarkers like the immune therapy biomarkers like MSI-high and PDL-1, and TMB. It isn't really playing a huge role in HCC. So, as you know, the HIMALAYA study is a phase 3 study and examined the STRIDE regimen which is treme plus durva in the first line of patients with metastatic or unresectable HCC against sorafenib. And the outcome was in favor of the STRIDE regimen with improvement in OS response rate and duration of response and because of that, it became one of the standards of care for that disease. But Abstract 4004 is actually asking a very interesting question - whether immune-related adverse events can predict outcomes. Meaning like those patients who experience immune-related adverse events will likely do better compared to those patients who didn't experience immune-related adverse events or not. The idea of adverse events as a biomarker if you will, for efficacy is not new. I mean we saw that back in the renal carcinoma TKI, hypertension. People who had hypertension were more likely to have a better response. In the GI also there was some data suggesting that rash might be a biomarker in predicting response to EGFR. So the same question we’re applying here - immune-related adverse events can function as a biomarker for efficacy for the immune system.  And there are some data out there in other tumors that may be the case, but I think at least to my knowledge in the HCC or GI, this was the first study to address that question. So just to remind our audience that the HIMALAYA was a phase 3 study using the STRIDE regimen as a frontline for patients with hepatocellular carcinoma, either unresectable or metastatic disease. And they compared the STRIDE which is durva-treme compared to the standard of care at that time was sorafenib. The primary endpoint was overall survival and they had secondary endpoint duration of response, response rate, and obviously adverse event.  The study was positive, it met its primary endpoint and OS was in favor of the STRIDE regimen compared to sorafenib. But that part of the abstract now is focusing mainly on those patients who had immune therapy and whether that was a STRIDE regimen or the third arm that durva alone treatment. And they're looking at those patients who had immune-related adverse events, and those who didn't have immune-related adverse events. So basically four groups of patients, the patient who had a STRIDE regimen, about 139 patients had immune-related adverse events, and about 249 didn't have immune-related adverse events. For the cohort who had durva alone, about 64 patients had immune-related adverse events, almost 300 patients had no immune-related adverse events.  And it was very interesting that at least in the STRIDE arm, those patients who experienced immune-related adverse events, their outcome was better than those patients who did not have immune-related adverse events. It's the same trend seen on the durva alone arm, but I think the number was very small to make a statistical value out of it. But I think at least in the STRIDE arm there was a suggestive trend toward the outcome of those patients who experienced immune-related adverse events. So I think this is in a way very interesting because we're always wondering if we give the same dose at least in immunotherapy like for everyone.   What I was wondering is if it's too much, too little, or just right. It's hard to know for sure. But perhaps in my opinion and just me trying to understand why, in my theory, maybe that's just an indication of patients receiving enough drugs and effective drugs that will translate into efficacy. But at the same time, I also wanted to just put a word of caution here because we don't want to see side effects as a good thing. I think we want to make sure that us as oncologists treating these patients and patients also don't see like it's good to have a side effect. Side effects associated with especially those grade 3 or 4 can be associated with significant problems and decreased quality of life. So, definitely should be looking at those side effects and be careful interpreting those data. But I think that is very interesting and I will look for more work on that.   Dr. Shaalan Beg: Let's move on to pancreatic cancer. We heard the results of the NAPOLI-3 clinical trial at GI ASCO and this year in ASCO 2023 we will hear the results of Abstract 4006 by Dr. O'Reilly that are presenting results of the 12 and 18-month survival rates from the study that compared NALIRIFOX or nano-liposomal irinotecan, 5-fluoro/leucovorin, and oxaliplatin versus nab-paclitaxel/gemcitabine for newly diagnosed pancreatic cancer patients. I'm interested to hear what you think about that study. Dr. Mohamed Salem: Thank you, Shaalan. So this also is a very exciting abstract to see, and anyone who treats pancreatic cancer patients realizes that, unfortunately, even in 2023, we don't have a lot of treatment options. And yes, I think over the last decade we're now talking about second-line and third-line, but yet we still don't have a lot of treatment options. So, having more options is always good. But the question now is how do you sequence those chemotherapy options? Most of us obviously use FOLFIRINOX in the first line or gemcitabine and paclitaxel in the first line. Until very recently– because we didn’t have a head-to-head comparison– we couldn't tell patients for sure if one is better than the other. I think we had some assumptions, but it wasn't really proven. It was just a cross-trial comparison.  So, the fact is that now we have that phase 3 trial looking at liposomal irinotecan, 5-fluoro/leucovorin and the oxaliplatin comparing to nab-paclitaxel/gemcitabine. To me, that was actually very exciting because now, at least, I can see a triplet chemotherapy drug compared to a doublet chemotherapy drug. And as you mentioned, Shaalan, the first initial read was positive in favor of the triplet regimen compared to the doublet, which I think was an important message to give to our colleagues and all of us that if you can, obviously, the triplet comes with side effects, but if you can deliver the triplet, that's perhaps a better starting point for the treatment. But the study here, we're trying to get more read after more mature or more time-lapsing. So the initial study was initial read was positive. And I think this is good to see, too because it translates that even with a longer follow-up, we're still seeing the same benefit. So the OS rate in 12 months for the triplet was about 45% compared to 39.5% for the doublet, and the 18 months, a year and a half, was 26% compared to 19%. So, definitely, you can see an improvement in every single endpoint. OS in general was 11.1 months compared to 9.2 months, and PFS was also in favor of the triplet. So I think it's a message here to reinforce what we saw a few months ago in the initial presentation that, in fact, the triplet is associated with better