ASCO Daily News – Details, episodes &amp; analysis

Dr. Arturo Loaiza-Bonilla

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)

How AI Can Improve Patient Identification and Recruitment for Clinical Trials

jeudi 15 août 2024 • Duration 18:20

Dr. Shaalan Beg and Dr. Arturo Loaiza-Bonilla discuss the potential of artificial intelligence to assist with patient recruitment and clinical trial matching using real-world data and next-generation sequencing results.

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 an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center in Dallas and senior advisor for clinical research at the National Cancer Institute. On today's episode, we will be discussing the promise of artificial intelligence to improve patient recruitment in clinical trials and advanced clinical research. Joining me for this discussion is Dr. Arturo Loaiza-Bonilla, the medical director of oncology research at Capital Health in Philadelphia. He's also the co-founder and chief medical officer at Massive Bio, an AI-driven platform that matches patients with clinical trials and novel therapies.

Our full disclosures are available in the transcript of this episode.

Arturo, it's great to have you on the podcast today.

Dr. Arturo Loaiza-Bonilla: Thanks so much, Shaalan. It's great to be here and talking to you today.

Dr. Shaalan Beg: So we're all familiar with the limitations and inefficiencies in patient recruitment for clinical trials, but there are exciting new technologies that are addressing these challenges. Your group developed a first-in-class, AI-enabled matching system that's designed to automate and expedite processes using real-world data and integrating next-generation sequencing results into the algorithm. You presented work at the ASCO Annual Meeting this year where you showed the benefits of AI and NGS in clinical trial matching and you reported about a twofold increase in potential patient eligibility for trials. Can you tell us more about this study?

Dr. Arturo Loaiza-Bonilla: Absolutely. And this is just part of the work that we have seen over the last several years, trying to overcome challenges that are coming because of all these, as you mentioned, inefficiencies and limitations, particularly in the manual patient trial matching. This is very time consuming, as all of us know; many of those in the audience as well experience it on a daily basis, and it’s resource intensive. It takes specialized folks who are able to understand the nuances in oncology, and it takes, on average, even for the most experienced research coordinator or principal investigator oncologist, 25 minutes per trial. Not only on top of that, but in compound there's a lack of comprehensive genomic testing, NGS, and that complicates the process in terms of inability to know what patients are eligible for, and it can delay also the process even further.

So, to address those issues, we at Massive Bio are working with other institutions, and we're part of this … called the Precision Cancer Consortium, which is a combination of 7 of the top 20 top pharma companies in oncology, and we got them together. And let's say, okay, the only way to show something that is going to work at scale is people have to remove their silos and barriers and work as a collaborative approach. If we're going to be able to get folks tested more often and in more patients, assess for clinical trials, at least as an option, we need to understand further the data. And after a bunch of efforts that happened, and you're also seeing those efforts in CancerX and other things that we're working on together, but what we realize here is using an AI-enabled matching system to basically automate and expedite the process using what we call real-world data, which is basically data from patients that are actually currently being treated, and integrating any NGS results and comparing that to what we can potentially do manually. The idea was to do multi-trial matching, because if we do it for one study, yeah, it will be interesting, but it will not show the potential applicability in the real world.

So with all that background, the tool itself, just to give you the punchline of it, was proven highly effective in terms of efficiency. We were able to increase the number of potential matches, and not only that, but reducing the time to the matching. So basically, instead of spending 25 minutes, it could be done in a matter of seconds. And when you compound all that across multiple clinical trials, in this case, it was several sponsors coming together, we were able to reduce the manual effort of seeing patients and testing for clinical trials to basically 1 hour when it would have otherwise taken a ridiculous amount of time. And it was quantified as 19,500 hours of manual work, compared to 1 hour done by the system to uniquely match a cohort of about 5,600 patients that came into the platform. And this was across 23 trials. Now imagine if we can do it for the 14,000 clinical trials currently in clinicaltrials.gov.

So for us, this kind of was an eye-opening situation that if we can increase not only the efficiency but find even more trials by integrating comprehensive genomic testing, which in this case was a twofold increase in eligibility for clinical trials, that gives us not only the opportunity for optimized processes using AI but also a call to action that there is still a lot of under-genotyping. And I know American Cancer Society and ASCO and many others are working hard on getting that into fruition, but we need to have systems that remind us that certain patients are not tested yet and that can improve not only real patients, but the R&D and the process of innovation in the future.

Dr. Shaalan Beg: Yeah, it's always an important reminder that even some of the highest impact IT solutions or AI solutions are most effective if they can be integrated into our normal clinical processes and into the normal workflow that we have in our clinics to help clinicians do their work quickly and more efficiently.

Can you talk about how, over the last few years, the availability of NGS data in our electronic medical record (EMR) has evolved and whether that's evolving for the better? And what are some next steps in terms of making that data available at EMR so that such solutions can then pull that data out and do clinical trial matching?

Dr. Arturo Loaiza-Bonilla: Yes. So one of the things that we have seen over the last couple of years is because of the applicability of the 21st Century Cures Act, there is less “information blocking,” which is patients not being able to access their information in real time. Now, with the appearance of health exchanges, with patient-centric approaches, which is something that many innovators, including ours, are trying to apply, it's really becoming more relevant. So it's not only helping us to find the patients when they really need to get tested, but also is giving us the opportunity to put those patients into the right treatment pathway when found.

Something that's still a challenge and I think we can work by being more collaborative once again – is my dream – is having these pre-screening hubs where no matter where you are in your cancer journey, you just go into that funnel and then are able to see, “Okay, you are in the second-line setting for non-small cell lung cancer, EGFR-mutated. Now, do you have a meta amplification, then you go for this study or this trial. Oh, you haven't been tested yet. You should get tested. You're a pancreas cancer patient who is KRAS wild type; well, there is a significant chance that you may have a biomarker because that's where most patients are enriched for.”

So having that opportunity to at scale, just for the whole country, to get those patients access to that information, I think is crucial for the future of oncology. And I think you working at the NCI, more than most, know how the impact of that can help for those underrepresented patients to get more access to better treatment options and whatnot. And we can activate clinical trials as well in new models, decentralized models, adjusting time models, all those things can be leveraged by using biomarker testing in real time. Identification when the patient really needs a trial option or a medication option, because the data is telling us when to activate that in real time.

Dr. Shaalan Beg: And identifying the patient for a potential clinical trial is one challenge. In oncology, given a lot of our trials, we are looking to enroll people at a specific time in their disease journey. So we call it first-line or second-line or third-line, becomes the next challenge. So just knowing someone has mutation number 1, 2, or 3 isn't enough to say they would be eligible for a second-line BRAF X, Y and Z mutation at a given trial. I've heard you talk a lot about this last-mile navigation for people once you've identified that they may be a soft match for a clinical trial. Can you talk about what you've seen in the ecosystem being developed on how AI is helping both clinics and patients navigate this last mile from the time they're identified for a clinical trial to the time they actually receive cycle 1, day 1?

Dr. Arturo Loaiza-Bonilla: Yeah, absolutely. And that is such a critical point because, as you know, we have helped tons of patients getting trial options in thousands of cases. But even my own patients, I give them a report for trial options and they're like, “Okay, I still need help.” And we have been talking with ASCO, with the American Cancer Society, and many other very good teams, and what we see as an opportunity in technology here is leveraging those cancer journeys to know when the patient really has the opportunity to enroll in a trial, because this is a very dynamic environment. Not only the patient's condition changes because their cancer progresses, the hemoglobin changes, the cancer moves from one place to the other, and there's nuances in between, but also new medications are coming up, studies open and close, sites open and close.

So having this information as a hub, as what we call a command center, is the key to make this happen. And we can use the same tools that we use for Uber or for Instacart or whichever thing you want to do; it's already the same concept. When you need groceries, you don't need groceries every day. But Amazon gives you a ding that’s like, “Well, I think you may be running out of milk,” because they already know how often you buy it, or just having the data behind the scenes of how typically these, in this case, patient journeys, may manifest based on the biomarker. So let's say a smoldering multiple myeloma is not the same across. One patient with biomarkers that make them very high risk, the risk of progressing to a multiple myeloma, first-line treatment-eligible patient is going to be much different than someone who has better risk cytogenetics. So using that tool to optimize the cancer journeys of those patients and being able to notify them in real time of new trial options, and also knowing when the patient really has that disease progression so there's a time of activation for trial matching again, the same way you get a credit score for buying a house, then you know exactly what options are in front of you at that very moment. And that is the last-mile component, which is going to be key.

What we have seen that we feel is important to invest on, and we have invested heavily on it, is that until the patient doesn't sign the consent form for the clinical trial, that patient is completely unknown to most people. The site doesn't know them because they haven't been there, and they may be there, but they don't know about the options sometimes. But no one's going to invest in getting that patient to the finish line. There's a lot of support for patients on trials, but not before they enroll on trials. And we feel that this is a big opportunity to really exponentially grow the chances of patients enrolling in trials if we support them all the way from the very time they get diagnosed with cancer in any setting. And we can help that patient on a very unique journey to find the trial options using technology. So it's very feasible. We see it once again in many other equally complex tasks, so why not do it in oncology when we have all the bonafides across wanting to do this.

Dr. Shaalan Beg: Can you give examples of where you are seeing it done outside of oncology that's a model that one can replicate?

Dr. Arturo Loaiza-Bonilla: I mean, oncology is the toughest use case to crack. You have experiences with DCTs in the past and all that. So the big opportunities are for patients, for example, in psychiatry, when they need certain counseling and help. We see that also in medical devices, when people have diabetes and they really need a device specifically for that unique situation, or also for patients with cardiovascular risk that they can in real time get access to novel therapeutics. And that's how they have been able to enroll so quickly. And all these GLP-1 inhibitors, all those models are really almost completely decentralized nowadays in something that we can extrapolate for oncology once we have aligned the ecosystem to make it see them. This is something that we can really revolutionize care while we manage all the complex variables that typically come with oncology uses.

Dr. Shaalan Beg: I would imagine while you translate those learnings from outside of oncology into oncology, a lot of those processes will be human and AI combination activities. And as you learn more and more, the human component becomes a smaller fraction, and the technology and the AI becomes more of a component. Are you seeing a similar transition in the clinical trial matching space as well?

Dr. Arturo Loaiza-Bonilla: Yes. So that's why people say humans are going to be replaced. They're not. Patients still want to see a human face that they recognize, they trust. Even family members of mine want to hear from me, even if they are in the top place in the world. What we can change with technology are those things that are typically just friction points. In this case, information gathering, collecting records, getting the data structured in a way that we can use it for matching effectively, knowing in real time when the patient progresses, so we can really give them the chances of knowing what's available in real time. And collecting the information from all these other stakeholders. Like, is the site open? Is the budget approved for that place? Is the insurance allowing the specific … do they have e-consent? Those things can be fully automated because they're just burdensome. They're not helping anyone. And we can really make it decentralized for e-consent, for just getting a screening. They don't need to be screened at the site for something that they're going to receive standard of care. We can really change that, and that's something that we're seeing in the space that is changing, and hopefully we can translate it fully in oncology once we are getting the word out. And I think this is a good opportunity to do so.

Dr. Shaalan Beg: You talked about your dream scenario for clinical trial matching. When you think about your dream scenario as a practicing oncologist, what are the AI tools that you are most excited about making their way into the clinic, either wishful thinking or practically?

Dr. Arturo Loaiza-Bonilla: I typically get feedback from all over the place on doing this, and I also have my own thoughts. But I always come to this for a reason. We all became physicians and oncologists because we like being physicians. We like to talk to patients. We want to spend the time. I tell folks in my clinic, I will see a thousand patients all the time as long as I don't have to do notes, as long as I don't have to place orders. But of course, they will have to hire 1,000 people ancillary to do all the stuff that we do.

If we can go back and spend all that time that we use on alert fatigue, on clicking, on gathering things, fighting insurance, and really helping align those incentives with clinical trials and biomarker testing and really making it a mankind or a humankind situation where we're all in this really together to solve the problem, which is cancer, that will be my dream come true. So I don't have to do anything that is clerical, that is not really helping me, but I want to use that AI to liberate me from that and also use the data that is generated for better insights.

I think that I know my subject of expertise, but there's so many things happening all the time that it is hard to keep up, no matter how smart you are. If the tool can give me insights that I didn't even know, then leverage that as a CME or a board certification, that would be a dream come true. Of course, I'm just dreaming here, but it's feasible. Many of these ideas, as I mentioned, they're not new. The key thing is getting them done. The innovative part is getting stuff done, because I'm sure there's a gazillion people who have the same ideas as I did, but they just don't know whom to talk to or who is going to make it happen in reality. And that's my call to action to people: Let's work together and make this happen.

Dr. Shaalan Beg: Well, Arturo, thanks a lot for sharing your insights with us today on the ASCO Daily News Podcast.

Dr. Arturo Loaiza-Bonilla: Well, thank you so much for the time and looking forward to having more exchanges and conversations and seeing everyone in the field.

Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find a link to the studies discussed today in the transcript of this episode. And 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

@DrBonillaOnc

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Disclosures: 

Dr. Arturo Loaiza-Bonilla:

Leadership: Massive Bio

Stock and Other Ownership Interests: Massive Bio

Consulting or Advisory Role: Massive Bio, Bayer, PSI, BrightInsight, Cardinal Health, Pfizer, Eisai, AstraZeneca, Regeneron, Verily, Medscape

Speakers’ Bureau: Guardant Health, Bayer, Amgen, Ipsen, AstraZeneca/Daiichi Sankyo, Natera

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

ASCO24: Transforming the Lung Cancer Treatment Landscape

vendredi 21 juin 2024 • Duration 33:17

Drs. Vamsi Velcheti and Nathan Pennell discuss novel approaches and key studies in lung cancer that were showcased at the 2024 ASCO Annual Meeting, including the Plenary abstracts LAURA and ADRIATIC.

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 the Perlmutter Cancer Center at NYU Langone Health. Today, I'm joined by Dr. Nate Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and the vice chair of clinical research at the Taussig Cancer Center in Cleveland Clinic. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Today, we will be discussing practice-changing abstracts and the exciting advances in lung cancer that were featured at the ASCO 2024 Annual Meeting.

You'll find our full disclosures in the transcript of the episode.

Nate, we're delighted to have you back on the podcast today. Thanks for being here. It was an exciting Annual Meeting with a lot of important updates in lung cancer.

Dr. Nate Pennell: Thanks, Vamsi. I'm glad to be back. And yes, it was a huge year for lung. So I'm glad that we got a chance to discuss all of these late-breaking abstracts that we didn't get to talk about during the prelim podcast.

Dr. Vamsi Velcheti: Let's dive in. Nate, it was wonderful to see all the exciting data, and one of the abstracts in the Plenary Session caught my attention, LBA3. In this study, the investigators did a comparative large-scale effectiveness trial of early palliative care delivered via telehealth versus in-person among patients with advanced non-small cell lung cancer. And the study is very promising. Could you tell us a little bit more about the study and your take-home messages?

Dr. Nate Pennell: Yes, I think this was a very important study. So just to put things in perspective, it's now been more than a decade since Dr. Jennifer Temel and her group at Massachusetts General Hospital did a randomized study that showed that early interventions with palliative medicine consultation in patients with advanced non-small cell lung cancer significantly improves quality of life and in her initial study, perhaps even overall survival. And since then, there have been numerous studies that have basically reproduced this effect, showing that getting palliative medicine involved in people with advanced cancer, multiple different cancer types, really, has benefits.

The difficulty in applying this has been that palliative care-trained specialists are few and far between, and many people simply don't have easy access to palliative medicine-trained physicians and providers. So with that in mind, Dr. Temel and her group designed a randomized study called the REACH PC trial, where 1,250 patients were randomized with advanced non-small cell lung cancer to either in-person palliative medicine visits which is sort of the standard, or one in-person assessment followed by monthly telemedicine video visits with palliative medicine. Primary endpoint was essentially to show that it was equivalent in terms of quality of life and patient satisfaction. And what was exciting about this was that it absolutely was. I mean, pretty much across the board in all the metrics that were measured, the quality-of-life, the patient satisfaction, the anxiety and depression scores, all were equivalent between doing telemedicine visits and in-person visits. And this hopefully will now extend the ability to get this kind of benefit to a much larger group of people who don't have to geographically be located near a palliative medicine program.

Dr. Vamsi Velcheti: Yeah, I think it's a great abstract, Nate and I actually was very impressed by the ASCO committee for selecting this for the Plenary. We typically don't see supportive care studies highlighted in such a way at ASCO. This really highlights the need for true interdisciplinary care for our patients. And as you said, this study will clearly address that unmet need in terms of providing access to palliative care for a lot of patients who otherwise wouldn't have access. I'm really glad to see those results.

Dr. Nate Pennell: It was. And that really went along with Dr. Schuchter’s theme this year of bringing care to patients incorporating supportive care. So I agree with you.

Now, moving to some of the other exciting abstracts in the Plenary Session. So we were talking about how this was a big year for lung cancer. There were actually 3 lung cancer studies in the Plenary Session at the Annual Meeting. And let's move on to the second one, LBA4, the LAURA study. This was the first phase 3 study to assess osimertinib, an EGFR tyrosine kinase inhibitor, in patients with EGFR mutant, unresectable stage III non-small cell lung cancer. What are your takeaways from this study?

Dr. Vamsi Velcheti: This is certainly an exciting study, and all of us in the lung community have been kind of eagerly awaiting the results of the study. As you know, for stage III non-small cell lung cancer patients who are unresectable, the standard of care has been really established by the PACIFIC study with the consolidation durvalumab after definitive concurrent chemoradiation. The problem with that study is it doesn't really answer the question of the role of immunotherapy in patients who are never-smokers, and especially in patients who are EGFR positive tumors, where the role of immunotherapy in a metastatic setting has always been questioned. And in fact, there have been several studies as you know, in patients with EGFR mutation positive metastatic lung cancer where immunotherapy has not been that effective. In fact, in the subgroup analysis in the PACIFIC study, patients with EGFR mutation did not really benefit from adding immunotherapy.

So this is an interesting study where they looked at patients with locally advanced, unresectable stage III patients and they randomized the patients 2:1 to osimertinib versus placebo following concurrent or sequential tumor radiation. The primary endpoint for the study was progression free survival, and a total of 216 patients were enrolled and 143 patients received a study treatment, which is osimertinib, and 73 received placebo. And 80% of the patients on the placebo arm crossed over to getting treatment at the time of progression.

So most of us in the lung cancer community were kind of suspecting this would be a positive trial for PFS. But however, I think the magnitude of the difference was truly remarkable. The median PFS in the osimertinib arm was 39.1 months and placebo was 5.6 months and the hazard ratio of 0.16. So it was a pretty striking difference in terms of DFS benefit with the osimertinib consolidation following chemoradiation. So it was truly a positive study for the primary endpoint and the benefit was seen across all the subgroups and the safety was no unexpected safety signals other than a slight increase in the radiation pneumonitis rates in patients receiving osimertinib and other GI and skin tox were kind of as expected. In my opinion, it's truly practice changing and I think patients with EGFR mutation should not be getting immunotherapy consolidation post chemoradiation.

Dr. Nate Pennell: I completely agree with you. I think that this really just continues the understanding of the use of osimertinib in EGFR-mutant lung cancer in earlier stages of disease. We know from the ADAURA trial, presented twice in the Plenary at the ASCO Annual Meeting, that for IB, stage II and resectable IIIA, that you prolong progression free or disease free survival. So this is a very similar, comparable situation, but at an even higher risk population or the unresectable stage III patients. I think that the most discussion about this was the fact that the osimertinib is indefinite and that it is distinct from the adjuvant setting where it's being given for three years and then stopped. But I think all of us had some pause when we saw that after three years, especially in the stage III patients from ADAURA, that there were clearly an increase in recurrences after stopping the drug, suggesting that there are patients who are not cured with a time limited treatment, or at least with 3 years of treatment.

The other thing that is sobering from the study, and was pointed out by the discussant, Dr. Lecia Sequist, is if you look at the two-year disease-free survival in the placebo arm, it was only 13%, meaning almost no one was really cured with chemo radiation alone. And that really suggests that this is not that different from a very early stage IV population where indefinite treatment really is the standard of care. I wonder whether you think that's a reasonable approach.

Dr. Vamsi Velcheti: I completely agree with you, Nate, and I don't think we cure a majority of our patients with stage III, and less so in patients who have EGFR-mutant, stage III locally advanced. As you just pointed out, I think very few patients actually make it that far along. And I think there's a very high rate of CNS micrometastatic disease or just systemic micrometastatic disease in this population that an effective systemic therapy of osimertinib can potentially have long term outcomes. But again, we perhaps don't cure a vast majority of them. I think that the next wave of studies should incorporate ctDNA and MRD-based assays to potentially identify those patients who could potentially go off osimertinib at some point. But, again, outside of a trial, I would not be doing that. But I think it's definitely an important question to ask to identify de-escalation strategies with osimertinib. And even immunotherapy for that matter, I think we all know that not all patients really require years and years of immunotherapy. They're still trying to figure out how to use immunotherapy in these post-surgical settings, using the MRD to de-escalate adjuvant therapies. So I think we have to have some sort of strategy here. But outside of a clinical trial, I will not be using those assays here to cite treatments, but certainly an important question to ask.

Moving on to the other exciting late-breaking abstracts, LBA5, the ADRIATIC study. This is another study which was also in the plenary session. This study was designed to address this question of consolidation immunotherapy, post chemo radiation for limited-stage small cell cancer, the treatment arms being durvalumab tremelimumab, and durvalumab observation. So what do you think about the study? This study also received a lot of applause and a lot of attention at the ASCO meeting.

Dr. Nate Pennell: It was. It was remarkable to be there and actually watch this study as well as the LAURA study live, because when the disease free survival curves and in the ADRIATIC study, the overall survival curves were shown, the speakers were both interrupted by standing ovation of applause just because there was a recognition that the treatment was changing kind of before our eyes. I thought that was really neat. So in this case, I think this is truly a historic study, not necessarily because it's going to necessarily be an earth shakingly positive study. I mean, it was clearly a positive study, but more simply because of the disease in which it was done, and that is limited-stage small cell lung cancer. We really have not had a change in the way we've treated limited-stage small cell lung cancer, probably 25 years. Maybe the last significant advances in that were the advent of concurrent chemotherapy and radiation and then the use of PCI with a very modest improvement in survival. Both of those, I would say, are still relatively modest advances.

In this case, the addition of immunotherapy, which we know helps patients with small cell lung cancer - it's of course the standard of care in combination chemotherapy for extensive stage small cell lung cancer - in this case, patients who completed concurrent chemo radiation were then randomized to either placebo or durvalumab, as well as the third arm of durvalumab tremelimumab, which is not yet been recorded, and co primary endpoints were overall survival and progression free survival. And extraordinarily, there was an improvement in overall survival seen at the first analysis, with a median overall survival of 55.9 months compared to 33.4 months, hazard ratio of 0.73. So highly clinically and statistically significant, that translates at three years to a difference in overall survival of 56.5%, compared to 47.6%, or almost 10% improvement in survival at three years.

There was also a nearly identical improvement in progression-free survival, also with a hazard ratio of 0.76, suggesting that there's a modest number of patients who benefit. But it seems to be a clear improvement with the curves plateauing out. In my opinion, this is very comparable to what we saw with the PACIFIC study in stage III, unresectable non-small cell lung cancer, which immediately changed practice back when that first was reported. And I expect that this will change practice pretty much immediately for small cell as well.

Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think it's an exciting advance in patients with limited-stage small cell lung cancer. For sure, it's practice-changing, and I think the results were exciting.

So one thing that really intrigued me was in the extensive-stage setting, the benefit was very mediocre with one-to-two month overall survival benefit in both the PACIFIC and in IMpower trial. Here we are seeing almost two-year of median OS benefit. I was kind of puzzled by that, and I thought it may have to do with patients receiving radiation. And we've seen that with the PACIFIC, and makes you wonder if both the CASPIAN and the IMpower studies actually did not allow consolidation thoracic radiation. Hypothetically, if they had allowed consolidation thoracic radiation, perhaps we would have seen better outcomes. Any thoughts on that?

Dr. Nate Pennell: We've been trying to prove that radiation and immunotherapy somehow go together better for a long time. Going back to the first description of the abscopal effect, and I'm not sure if I necessarily believe that to be the case, but in this setting where we truly are trying to cure people rather than merely prolong their survival, maybe this is the situation where it truly is more beneficial. I think what we're seeing is something very similar to what we're seen in PACIFIC, where in the stage IV setting, some people have long term survival with immunotherapy, but it's relatively modest. But perhaps in the curative setting, you're seeing more of an impact. Certainly, looking at these curves, we'll have to see with another couple of years to follow up. But a three-year survival of 56% is pretty extraordinary, and I look forward to seeing if this really maintains over the next couple of years follow up.

Moving beyond the Plenary, there were actually lots of really exciting presentations, even outside the Plenary section. One that I think probably got at least as much attention as the ones that we've already discussed today was actually an update of an old trial that's been presented for several prior years. And I'm curious to get your take on why you thought this was such a remarkable study. And we're talking about the LBA8503, which was the 5-year update from the CROWN study, which looked at previously untreated ALK-positive advanced non-small cell in cancer patients randomly assigned to lorlatinib, the third generation ALK inhibitor, versus crizotinib, the first generation ALK inhibitor. What was so exciting about this study, and why were people talking about it?

Dr. Vamsi Velcheti: Yeah, I agree, Nate. We've seen the data in the past, right? Like on the CROWN data, just first like a quick recap. This is the CROWN study, like the phase 3 study of third generation ALK inhibitor lorlatinib. So global randomized phase 3 study in patients with metastatic disease randomized to lorlatinib versus crizotinib, which is a controller. So the primary endpoint was PFS, and we've seen the results in the past of the CROWN readout quoted, with a positive study and the lorlatinib received FDA approval in the frontline setting. But the current study that was presented at the ASCO annual meeting is a kind of a postdoc analysis of five years. The endpoint for the study with central review stopped at three years, and this is actually a follow up beyond that last readout. Interestingly, in this study, when they looked at the median PFS at five years, the lorlatinib arm did not reach a median PFS even at five years and the hazard ratio is 0.19, which is kind of phenomenal in some ways. At 5 years, the majority of the patients were still on the drug. So that's quite incredible. And the benefit was more profound in patients with brain mets with a hazard ratio of 0.08. And again, speaking to the importance of brain penetrant, small molecule inhibitors, and target therapy, the safety profile, there were no additional safety signals noted in the study. We kind of know about the side effects of lorlatinib already from previous studies readouts. No unusual long-term toxicities.

I should note though, about 40% of patients did have CNS, AEs grade 1, 2 CNS toxicities on the lorlatinib arm. And the other interesting thing that was also reported in the trial was dose reduction of lorlatinib did not have an impact on the PFS, which is interesting in my opinion. They also did some subgroup analysis, biomarker testing, biomarker populations. Patients who had P53 cooperation did much better with lorlatinib versus crizotinib. So overall, the other thing that they also had shown on the trial was the resistance mechanisms that were seen with lorlatinib were very different than what we are used to seeing with the earlier generation ALK inhibitors. The majority of the patients who develop resistance have bypass mechanisms and alterations in MAP kinase pathway PI3K/MTOR/PTEN pathway, suggesting that lorlatinib is a very potent ALK inhibitor and on target ALK mutations don’t happen as frequently as we see with the earlier generation ALK inhibitors.

So I think this really begs the question, should we offer lorlatinib to all our patients with metastatic ALK-positive tumors? I think looking at the long-term data, it's quite tempting to say ‘yes’, but I think at the same time we have to take into consideration patient safety tolerability. And again, the competitor arm here is crizotinib. So lorlatinib suddenly seems to be, again, cross trial comparisons, but I think the long-term outcomes here are really phenomenal. But at the same time, I think we’ve got to kind of think about patient because these patients are on these drugs for years, they have to live with all the toxicities. And I think the patient preferences and safety profile matters in terms of what drug we recommend to patients.

Dr. Nate Pennell: I completely agree with you. I think the right answer, is that this has to be an individual discussion with patients. The results are incredibly exciting. I mean, the two-year progression free survival was 70%, and the five-year, three years later is still 60%. Only 10% of people are failing over the subsequent three years. And the line is pretty flat. And as you said, even with brain metastases, the median survival is in reach. It's really extraordinary. Moreover, while we do talk about the significant toxicities of lorlatinib, I thought it was really interesting that only 5% of people were supposedly discontinued the drug because of treatment related AEs, which meant that with dose reduction and management, it seems as though most patients were able to continue on the drug, even though they, as you mentioned, were taking it for several years.

That being said, all of us who've had experience with the second-generation drugs like alectinib and brigatinib, compared to the third-generation drug lorlatinib, can speak to the challenges of some of the unique toxicities that go along with it. I don't think this is going to be a drug for everyone, but I do think it is now worth bringing it up and discussing it with the patients most of the time now. And I do think that there will be many people for whom this is going to be a good choice, which is exciting.

Dr. Vamsi Velcheti: Absolutely, completely agree. And I think there are newer ALK inhibitors in clinical development which have cleaner and better safety profiles. So we'll have to kind of wait and see how those pan out.

Moving on to the other exciting abstract, LBA8509, the KRYSTAL-12 study. LBA8509 is a phase 3 study looking at adagrasib versus docetaxel in patients with previously treated advanced metastatic non-small cell cancer with KRASG12C mutation. Nate, there's been a lot of hype around this trial. You've seen the data. Do you think it's practice-changing? How does it differentiate with the other drug that's already FDA approved, sotorasib?

Dr. Nate Pennell: Yeah, this is an interesting one. I think we've all been very excited in recent years about the identification of KRASG12C mutations as targetable mutations. We know that this represents about half of KRAS mutations in patients with non-small cell lung cancer, adenocarcinoma, and there are two FDA-approved drugs. Sotorasib was the first and adagrasib shortly thereafter. We already had seen the CodeBreaK 200 study, which was a phase 3 study of sotorasib versus docetaxel that did modestly prolong progression free survival compared to docetaxel, although did not seem to necessarily translate to an improvement in overall survival. And so now, coming on the heels of that study, the KRYSTAL-12 study compared adagrasib, also the KRASG12C inhibitor versus docetaxel and those with previously treated non-small cell with KRASG12C. And it did significantly improve progression free survival with a hazard ratio of 0.58. Although when you look at the median numbers, the median PFS was only 5.5 months with the adagrasib arm compared to 3.8 months with docetaxel. So while it is a significant and potentially clinically significant difference, it is still, I would say a modest improvement.

And there were some pretty broad improvements across all the different subgroups, including those with brain metastases. It did improve response rate significantly. So 32% response rate without adagrasib, compared to only 9% with docetaxel. It's about what you would expect with chemotherapy. And very importantly, in this patient population, there was activity in the brain with an intracranial overall response rate among those who had measurable brain metastases of 40%. So certainly important and probably that would distinguish it from drugs like docetaxel, which we don't expect to have a lot of intracranial toxicity. There is certainly a pattern of side effects that go along with that adagrasib, so it does cause especially GI toxicity, like diarrhea, nausea, vomiting, transaminitis. All of these were actually, at least numerically, somewhat higher in the adagrasib arm than in docetaxel, a lot more hematologic toxicity with the docetaxel. But overall, the number of serious adverse events were actually pretty well matched between the two groups. So it wasn't really a home run in terms of favorable toxicity with that adagrasib.

So the question is: “In the absence of any data yet on overall survival, should this change practice?” And I'm not sure it's going to change practice, because I do think that based on the accelerated approval, most physicians are already offering the G12C inhibitors like sotorasib and adagrasib, probably more often than chemotherapy, I think based on perceived improvement in side effects and higher response rates, modestly longer progression-free survival, so I think most people think that represents a modest improvement over chemotherapy. And so I think that will continue. It will be very interesting, however, when the overall survival report is out, if it is not significantly better, what the FDA is going to do when they look at these drugs.

Dr. Vamsi Velcheti: Thanks so much. Very well summarized. And I do agree they look more similar than dissimilar. I think CodeBreaK-200 and the KRYSTAL-12, they kind of are very identical. I should say, though I was a little surprised with the toxicity profile of adagrasib. It seemed, I mean, not significantly, but definitely seemed worse than the earlier readouts that we've seen. The GI tox especially seems much worse on this trial. I'm kind of curious why, but if I recall correctly, I think 5% of the patients had grade 3 diarrhea. A significant proportion of patients had grade 3 nausea and vomiting. And the other complicating thing here is you can't use a lot of the antiemetics because of the QT issues. So that's another problem. But I think it's more comparable to sotorasib, in my opinion.

Dr. Nate Pennell: While this is exciting, I like to think of this as the early days of EGFR, when we were using gefitinib and erlotinib. They were certainly advances, but we now have drugs that are much more effective and long lasting in these patients. And I think that the first-generation inhibitors like sotorasib and adagrasib, while they certainly benefit patients, now is just the beginning. There's a lot of research going on, and we're not going to talk about some of the other abstracts presented, but some of the next generation G12C inhibitors, for example, olomorasib, which did have also in the same session, a presentation in combination with pembrolizumab that had a very impressive response rate with potentially fewer side effects, may end up replacing the first generation drugs when they get a little bit farther along.

And then moving on to another one, which I think potentially could change practice. I am curious to hear your take on it, was the LBA8505, which was the PALOMA-3 study. This was interesting in that it compared two different versions of the same drug. So amivantamab, the bispecific, EGFR and MET, which is already approved for EGFR exon 20 non-small cell lung cancer, in this case, in more typical EGFR-mutated non-small cell lung cancer in combination with osimertinib with the intravenous amivantamab, compared to the subcutaneous formulation of amivantamab. Why would this be an important study?

Dr. Vamsi Velcheti: I found this study really interesting as well, Nate. And as you know, amivantamab has been FDA approved for patients with exon 20 mutation. And also, we've had, like two positive readouts in patients with classical EGFR mutations. One, the MARIPOSA study in the frontline setting and the MARIPOSA-2, in the second-line post osimertinib setting. For those studies, the intravenous amivantamab was used as a treatment arm, and the intravenous amivantamab had a lot of baggage to go along with it, like the infusion reactions and VTEs and other classic EGFR related toxicity, skin toxicities. So the idea behind developing the subcutaneous formulation of amivantamab was mainly to reduce the burden of infusion, infusion time and most importantly, the infusion related reactions associated with IV formulation.

In a smaller phase 2 study, the PALOMA study, they had looked at various dosing schemas like, subcutaneous formulation, and they found that the infusion related reactions were very, very low with the subcutaneous formulation. So that led to the design of this current study that was presented, the PALOMA-3 study. This was for patients who had classical EGFR mutations like exon 19, L858R. The patients were randomized 1:1 to subcutaneous amivantamab with lazertinib versus IV amivantamab plus lazertinib. The endpoints for the study, it's a non-inferiority study with co primary endpoints of C trough and C2 AUC, Cycle 2 AUC. They were looking at those pharmacological endpoints to kind of demonstrate comparability to the IV formulation. So in this study, they looked at these pharmacokinetic endpoints and they were essentially identical. Both subcutaneous and IV formulations were compatible. And in terms of clinical efficacy as well, the response rate was identical, no significant differences. Duration of response was also identical. The PFS also was comparable to the IV formulation. In fact, numerically, the subcutaneous arm was a little better, though not significant. But it appears like, you know, the overall clinical and pharmacological profile of the subcutaneous amivantamab was comparable. And most interestingly, the AE profile, the skin toxicity was not much different. However, the infusion reactions were substantially lower, 13% with the subcutaneous amivantamab and 66% with IV amivantamab. And also, interestingly, the VTE rates were lower with the subcutaneous version of amivantamab. There was still a substantial proportion of patients, especially those who didn't have prophylactic anticoagulation. 17% of the patients with the subcutaneous amivantamab had VTE versus 26% with IV amivantamab. With prophylaxis, which is lower in both IV and subcutaneous, but still subcutaneous formulation at a lower 7% versus 12% with the IV amivantamab.

So overall, I think this is an interesting study, and also the authors had actually presented some interesting data on administration time. I've never seen this before. Patients reported convenience using a modified score of patient convenience, essentially like patients having to spend a lot of time in the infusion site and convenience of the patient getting the treatment. And it turns out, and no surprise, that subcutaneous amivantamab was found to be more convenient for patients.

So, Nate, I want to ask you your take on this. In a lot of our busy infusion centers, the time it takes for those patients to get the infusion does matter, right? And I think in our clinic where we are kind of fully booked for the infusion, I think having the patients come in and leave in 15, 20 minutes, I think it adds a lot of value to the cancer center operation.

Dr. Nate Pennell: Oh, I completely agree. I think the efficacy results were reassuring. I think the infusion related reaction difference, I think is a huge difference. I mean, I have given a fair amount of amivantamab, and I would say the published IRR rate of 66%, 67% I would say, is maybe even underestimates how many patients get some kind of reaction from that, although it really is a first dose phenomenon. And I think that taking that down to 13% is a tremendous advance. I think fusion share time is not trivial as we get busier and busier. I know our cancer center is also very full and it becomes challenging to schedule people, and being able to do a five-minute treatment versus a five-hour treatment makes a big difference for patients.

It's interesting, there was one slide that was presented from an efficacy standpoint. I'm curious about your take on this. They showed that the overall survival was actually better in the subcu amivantamab arm, hazard ratio of 0.62. Now, this was only an exploratory endpoint. They sort of talk about perhaps some rationale for why this might be the case. But at the very least, I think we can be reassured that it's not less effective to give it and does seem to be more tolerable and so I would expect that this hopefully will be fairly widely adopted.

Dr. Vamsi Velcheti: Yeah, I agree. I think this is a welcome change. Like, I think the infusion reactions and the resources it takes to get patients through treatments. I think it's definitely a win-win for patients and also the providers.

And with that, we come to the conclusion of the podcast. Nate, thank you so much for the fantastic insights today. Our listeners will find all the abstracts discussed today in the transcripts of the episode. Thank you so much for joining us today, Dr. Pennell.

Dr. Nate Pennell: Oh, thanks for inviting me. It's always fun to talk about all these exciting advances for our patients.

Dr. Vamsi Velcheti: Thanks to our listeners for your time today. You will find links to all the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.

Disclaimer:

Find out more about today’s speakers:

Follow ASCO on social media:  

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

ESOPEC and Other Key GI Studies at ASCO24

jeudi 20 juin 2024 • Duration 17:39

Dr. Shaalan Beg highlights practice-changing studies in GI cancers featured at the 2024 ASCO Annual Meeting, including the ESOPEC trial in esophageal adenocarcinoma and durable responses to PD-1 blockade alone in mismatch repair-deficient locally advanced rectal cancer.

TRANSCRIPT

Geraldine Carroll: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Shaalan Beg, an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center. Dr. Beg will be discussing practice- changing abstracts and other key advances in GI oncology that were presented at the 2024 ASCO Annual Meeting. His full disclosures are available in the transcript of this episode.

Dr. Beg, thanks for being on the podcast today.

Dr. Shaalan Beg: Thank you for having me.

Geraldine Carroll: Let's begin with LBA1, the ESOPEC trial. This was featured in the Plenary Session, and this study compared two treatment strategies for locally advanced esophageal adenocarcinoma that could be treated with surgery. The strategies include the CROSS protocol, which consisted of chemoradiotherapy before surgery, and the FLOT protocol of chemotherapy before and after surgery. Can you tell us about this practice-changing study, Dr. Beg?

Dr. Shaalan Beg: Yes. According to this study, perioperative chemotherapy with FLOT was better than neoadjuvant therapy with chemoradiation and carbo-taxol for people with adenocarcinoma of the esophagus. There were 438 patients enrolled on this phase 3 study. R0 resection rates were fairly similar across both groups. The PCR rates were a little higher on the FLOT group. But when you look at the median overall survival difference, 66 months in the FLOT group versus 37 months in the CROSS group, 3-year survival was 57% versus 50% favoring FLOT therapy as well.

So a couple of caveats on this clinical trial, because the first thing to note is that the standard treatment for this disease has evolved because we now don't only give CROSS chemoradiation, we also give immunotherapy after the completion of chemoradiation for this group of patients. And in this study, since it predated that standard of care, patients did not receive immunotherapy. But having said that, the take home for me here is that chemotherapy is better than chemoradiation for this group of patients, recognizing the fact that 1) they only enrolled adenocarcinoma patients, and 2) patients with high T stage were not included. So the folks with high T stage would be those who we would expect would benefit from the radiation aspect. So my take home here is that more chemotherapy is better in the perioperative space. Radiation should be considered for individuals who need more local control. But in general, I think we're going to see us moving more towards chemotherapy-based regimens with FLOT for this group of patients.

Geraldine Carroll: Great. So moving on to rectal cancer, in LBA3512, investigators reported durable, complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. Can you tell us more about the promising durable responses that occurred in this trial?

Dr. Shaalan Beg: On first glance, seeing that immunotherapy has good activity in patients with mismatched repair deficient rectal cancer isn't really headline breaking news anymore. We've known about this activity for this group of patients for many years. Earlier at ASCO, the investigators presented early results of this compound for people receiving six months of dostarlimab therapy for people with mismatched repair deficient, locally advanced rectal cancer, and showed that they had a very high complete response rate. At that time, it generated a lot of interest and there was a lot of curiosity on whether these outcomes will be sustained. We don't know other characteristics of their biologic status and whether this was some sort of reflection of the patients who are selected or not.

So here in this presentation at ASCO 2024, they did come back to present follow-up data for people with mismatch repair deficient colorectal cancer, having received 6 months of dostarlimab. Forty-seven patients had been enrolled, and the 41 patients who had achieved a clinical complete response continued to have disease control with no distant metastases. So that's very compelling information. There were no additional serious adverse events greater than grade 2 that they saw, and they did follow circulating tumor DNA, and those did normalize even before they had their colonoscopy to examine their tumors.

So, again, we're continuing to see very encouraging data of immunotherapy, and the response rate with dostarlimab seems to be very interesting for this disease, and it will be interesting to see how this pans out in larger studies and how this translates into the use of dostarlimab across other diseases where other checkpoint inhibitors are currently being used.

Geraldine Carroll: Absolutely. So, moving on to LBA3501. The COLLISION trial looked at surgery versus thermal ablation for small cell colorectal liver metastases. This was an international, multicenter, phase 3, randomized, controlled trial. How will this study change clinical practice?

Dr. Shaalan Beg: Kudos to the investigators here. They looked to understand the difference in outcome in treating people with colorectal cancer with liver only metastases. These clinical trials are extremely difficult to design. They're very difficult to enroll on because of the multidisciplinary aspect of the interventions and patient and provider biases as well. So on this clinical trial, the investigators enrolled people with resectable colorectal cancer, liver metastases so they did not have any metastases outside the liver. Patients were required to have 10 or less known metastases that were less than 3 cm in size. There were other allowances for larger tumors as well. And after an expert panel review, patients were randomized to either resection or ablation. It was up to the physicians whether they performed these laparoscopically or openly or percutaneously, depending on the biology of the patient and the anatomical presentation.

There was a predefined stopping rule at the half-time for this clinical trial, which showed a benefit in the experimental arm of ablation compared to standard of care. The overall survival was not compromised. Progression-free survival was not compromised with local therapy. But there were differences in morbidity and mortality, as we would expect, one being a surgical procedure and the other being ablation, where, according to this study, of the 140 or so patients who received either treatment, 2.1% of people who underwent resection died within 90 days of surgery. The AE rate was 56% in the resection sample compared to 19% in ablation, and the 90-day mortality for ablation was 0.7%. So less morbidity, improved mortality, reduced adverse events with ablation versus surgical resection without compromising local control and overall survival.

And I think for practice here in the United States, this does provide very interesting data for us to take back to the clinic for lesions that are relatively small and could generally be addressed by both surgery and ablation. Historically, there are various non biologic factors that could go into deciding whether someone should have surgery or ablation, and it could be based on who the physician is, who's seeing the patient, what the practice patterns in a specific organization are, and where their expertise lie. But here we're seeing that ablation for the small lesions is a very effective tool with very good local control rates, and again, in this selected group of patients with liver only metastases. And I think it is going to make tumor board discussions very interesting with data backing ablation for these lesions.

Geraldine Carroll: Well, let's move onto the MOUNTAINER study. This study created some buzz in the colorectal cancer space. That's Abstract 3509. Can you tell us about the final results of this phase 2 study of tucatinib and trastuzumab in HER2-positive metastatic CRC? What are your thoughts on this treatment option, which seems to be well tolerated?

Dr. Shaalan Beg: So, HER2 overexpression or amplification occurs in about 3 to 5% of patients with metastatic colorectal cancer and up to 10% of people who have a RAS/RAF wild type disease. On the previous episodes of the podcast we have covered precision targeted therapy in colorectal cancer, focusing on c-MET, focusing on BRAF, and here we have updated results targeting HER2 for colorectal cancer. And the results of the MOUNTAINEER study have been out for a while. This is a phase 2 study looking at combining tucatinib which is a highly selective HER2 directed TKI with trastuzumab, the monoclonal antibody for HER2 targeting. And what they found on this study is the confirmed overall response rate was 38%. Duration of response was 12 months, overall survival was 24 months and these are the results that have been already released and now we have an additional 16 months of follow up and these results continue to hold on. PFS and overall survival gains were held, which makes it a very interesting option for people with colorectal cancer. You mentioned the tolerability aspect and side effects. I think it's important to know the spectrum of side effects for this disease may be a little different than other TKIs. There's hypertension, but there's also the risk of diarrhea, back pain and pyrexia, with the most common grade 3 treatment related adverse event was an increase in AST level seen in 10% of people of grade 3 and above.

So where does that really leave us? There is a confirmatory randomized first-line trial of tucatinib and trastuzumab in the first line setting, which is currently ongoing. So we'll stay tuned to see where that leads us. And with the HER2 space right now for colorectal cancer with the development of antibody drug conjugates, we may have more than one option for this group of patients once those trials read out.

Geraldine Carroll: Excellent. Well, moving on to LBA4008, that's the CheckMate-9DW trial. This trial reported first results looking at nivolumab plus ipilimumab versus sorafenib or lenvatinib as first-line treatment for advanced hepatocellular carcinoma. Can you tell us about this trial? Will there be a potential new standard of care in advanced HCC?

Dr. Shaalan Beg: When we think about patients with advanced HCC, the only treatment option that they had for about a decade and a half were just oral track tyrosine kinase inhibitors that had modest to moderate clinical activity. Since then, we've seen that combination therapy is better than TKI therapy, and the combination therapy has taken two different forms. One is a combination of checkpoint inhibitor and antiangiogenic therapy, such as in the combination of atezolizumab and bevacizumab. The other is a combination of dual checkpoint inhibitor therapy. Here we are talking about the results of nivolumab and ipilimumab. Previously, we've talked about the combination of durva and tremi for the treatment of patients with HCC.

So in this study, nivo was given for the first 4 cycles, nivo and ipi were given together, nivo 1 mg per kg, and IPI 3 mgs per kg every 3 weeks for 4 cycles. And then the CTLA-4 inhibitor ipilimumab was stopped. And this was followed by monotherapy nivolumab every 4 weeks until disease progression or up to 2 years. And it was compared to dealers' choice, lenvatinib or sorafenib. The median overall survival of nivo-ipi was 23 months versus 20 months with lenvatinib-sorafenib. The 24-month overall survival was 49% with ipi-nivo versus 39%. And the overall response rate with nivo-ipi was 36% compared to 13%. So again, significantly improved clinical activity.

And when we talk about immunotherapy combinations, the question that comes to mind is how well is this tolerated? There's a lot of work and iteration that took place in figuring out what the right combination strategy of ipi and nivo should be, because some of the earlier studies did demonstrate fairly high adverse events in this group of patients. So on this study, we saw that grade 3 or 4 treatment related adverse events were seen in 41% of people who received nivo-ipi and 42% if they received lenvatinib or sorafenib. So, certainly a high proportion of treatment related adverse events, but probably also reflective of the disease population, which is being tested, because those numbers were fairly similar in the control arm as well.

So we've known that nivo-ipi is active in HCC. There is an approval in the second-line space, so it remains to be seen if this data helps propel nivo-ipi to the first-line space so we end up with another combination regimen for patients with advanced hepatocellular carcinoma.

Geraldine Carroll: Excellent. Well, before we wrap up the podcast, I'd like to ask you about LBA3511. In this study, investigators looked at total neoadjuvant treatment with long course radiotherapy versus concurrent chemoradiotherapy in local advanced rectal cancer with high risk factors. So this was a multicenter, randomized, open label, phase 3 trial. What are your key takeaways here?

Dr. Shaalan Beg: Key takeaway here is that total neoadjuvant therapy was better than the conventional chemoradiation followed by chemo. So this clinical trial enrolled people with T4a/b resectable disease with clinical N2 stage, and they were randomized, as you mentioned, to receiving chemoradiation with radiation capecitabine followed by surgery, and then CAPOX or capecitabine versus chemo, short-course radiation, and additional chemotherapy followed by surgery.

And when we compare both arms, the total neoadjuvant therapy led to improved disease-free survival, improved PCR rates compared to standard concurrent neoadjuvant chemo radiotherapy in this group of patients. The two arms were fairly well-balanced. The number of T4 lesions was a little higher in the chemoradiation group. There were 49% in the chemo radiation group versus 46% had clinically T4 disease, but the nodal status was fairly similar. We should keep in mind that the other baseline characteristics were fairly well balanced.

And when we look at the outcomes, the disease-free survival probability at 36 months was 76% in the total neoadjuvant group compared to 67% with chemoradiation. And the metastasis free survival in total neoadjuvant therapy was 81% versus 73%. So a fairly compelling difference between the two arms, which did translate into an overall survival of 89% versus 88% in the two groups. So definitely higher disease-free survival and metastasis free survival, no difference on the overall survival with these groups. And it talks about the importance of intensifying chemotherapy upfront in this group of patients who can have a fairly high burden of disease and may struggle with receiving chemotherapy postoperatively.

Geraldine Carroll: Excellent. Well, thank you, Dr. Beg, for sharing your fantastic insights with us on these key studies from the 2024 ASCO Annual Meeting. It's certainly a very exciting time in GI oncology.

Dr. Shaalan Beg: Absolutely. Thank you for bringing these studies out, because I think a lot of these are practice-changing and can start impacting the clinical care that we're giving our patients right now.

Geraldine Carroll: 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 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. 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

Follow ASCO on social media: 

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

Immunotherapy at ASCO24: NADINA and Other Key Studies

mercredi 19 juin 2024 • Duration 34:51

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in the neoadjuvant immunotherapy space that were presented at the 2024 ASCO Annual Meeting, including promising outcomes in high-risk melanoma from the NADINA trial, as well as other new treatment options for patients with advanced cancers.

TRANSCRIPT

Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I am an associate professor of medicine and the clinical director of the Melanoma Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I am delighted to have my colleague and friend Dr. Jason Luke on the podcast today to discuss key late-breaking abstracts and advances in immunotherapy that were presented at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the associate director of clinical research, and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center.

You will find our full disclosures in the transcript of this episode.

Jason, it's always a pleasure to hear your insights on the key trials in these spaces and to have you back as a guest on this podcast that highlights some of the work, especially advances, that were just presented.

Dr. Jason Luke: Well, thanks very much for the invitation. I always love joining the podcast.

Dr. Diwakar Davar: We'll start very quickly by talking about some advances and really interesting things that happened both in the context of melanoma but also in immunotherapy in general. And we'll start with what I think was certainly one highlight for me, which was LBA2, the late-breaking abstract on the NADINA trial. It was featured in the Plenary Session, and in this abstract, Dr. Christian Blank and colleagues reported on the results of this phase 3 trial of neoadjuvant ipi-nivo. This is the flipped dose of ipi1/nivo3 versus adjuvant nivolumab in PD-1 naive, macroscopic, resectable, high-risk stage 3 melanoma.

By way of background, neoadjuvant immunotherapy for those listening is an area of increasing interest for drug developers and development for both approved and novel agents. Neoadjuvant immunotherapy has been studied with multiple approved agents, including PD-1 monotherapy, PD-1 LAG-3, PD-1 CTLA-4, T-VEC, as well as investigational agents and multiple randomized and non-randomized studies. The benchmark pathologic response rates with these agents range from 17% PCR with PD-1 monotherapy, 45% to 55% PCR with PD-1 CTLA-4 combination therapy, and slightly higher 57% PCR with PD-1 LAG-3 has recently reported by Dr. Rodabe Amaria from MD Anderson. However, as we embark on phase 3 comparisons for various neoadjuvant compared to adjuvant immunotherapy trials and combinations, we're increasingly moving towards event-free survival as the primary endpoint for neoadjuvant versus adjuvant studies. And this was most recently studied in the context of SWOG S1801, a study that was led by Dr. Sapna Patel.

So, Jason, before we start on NADINA, can you briefly summarize the SWOG S1801 trial and the event-free survival statistic reported by Dr. Patel and her colleagues?

Dr. Jason Luke: Well, absolutely. And these data were reported at ESMO about two years ago and then in the New England Journal last year. The S1801 study answered a very simple question: What would happen if you took three of the doses of standard adjuvant therapy with pembrolizumab and moved them prior to surgery? And on a high level, the study is as simple as that. And many of us were somewhat skeptical of this trial design because we thought that just moving the doses earlier may not actually have a major impact.

In the study, you alluded to the event-free survival statistic, and that alludes to what was considered an event. And so, without reading all of it, there were several different aspects that were included in terms of time, based on the date of randomization until the first of a series of events, such as disease progression, toxicity from treatment, if the patient was unable to go to surgery or had surgical complications, or if they had delay in starting the adjuvant therapy due to toxicity, and obviously, recurrence of melanoma or death from any cause. In that context, merely moving the 3 doses of pembrolizumab to the neoadjuvant setting saw an improvement in this two-year event free survival to 72% for the neoadjuvant therapy compared to 49% for the adjuvant therapy. That was quite an outstanding change. And again, noting the power of neoadjuvant treatment, really dictating the impact of anti PD-1, again, just with 3 doses moving from adjuvant into the neoadjuvant setting, and I think all of us were somewhat surprised to see that magnitude of a benefit. But it set up the current study very well, where we now look at combination therapy.

Dr. Diwakar Davar: So let's move on to the phase 3 NADINA trial. Do you want to perhaps discuss the study design, particularly focusing on the EFS primary endpoint and maybe also touching on the different schedules? So, SWOG S1801 was a neoadjuvant study of 3 cycles of pembrolizumab and how did that compare and contrast to the neoadjuvant combination that was studied in NADINA?

Dr. Jason Luke: Well, as you alluded to, NADINA investigated the regimen of nivolumab plus ipilimumab and compared that against adjuvant therapy with nivolumab alone. So, in the study, as you alluded, the dose and schedule of the two drugs used was nivolumab at 3 milligrams per kilogram, and ipilimumab with 1 milligram per kilogram. That was based on a series of signal finding and safety studies that had been previously done by the same group of authors identifying that as the optimal treatment regimen. And it's worth noting that's slightly different than the labeled indication that's generally used for those same drugs for metastatic melanoma, albeit that the NCCN also endorses this schedule. So, in the trial, 423 patients were randomized, 1:1 to receive either neoadjuvant therapy with those 2 doses of nivolumab plus ipilimumab as compared with standard adjuvant therapy with nivolumab following surgery.

Now, one interesting tweak was that there was an adaptive nature to the study, meaning that patients had a fiducial placed at the index lymph node, and after the neoadjuvant therapy in that arm, that lymph node was removed. And if the patient had a major pathological response, they did not go on to receive the adjuvant portion of the treatment. So it was adaptive because those patients who did very well to the neoadjuvant did not require the adjuvant portion. And in those patients who did not achieve a major pathological response, they could go on to have the adjuvant therapy. And that also included the BRAF therapy for those whose tumors were BRAF mutants.

It's also worth pointing out that the definition of event free survival was slightly different than in the S1801 study that was alluded to just a second ago. And here, EFS was defined from the date of randomization until progression due to melanoma or due to treatment. So that's slightly different than the definition in the S1801 trial. So, a somewhat complicated study, but I really applaud the authors because I think this study does mirror what we would likely be doing in actual clinical practice.

Dr. Diwakar Davar: So, just to briefly summarize the efficacy, and then to get your comments on this, the path response, the PCR rate was 47%. The major pathologic response rate, which is the proportion of patients with between 0% to 1/10% of residual viable tumors, was about 12%. And for a major pathologic response rate of 0% to 10% of 59%. And then the rest of the patients had either pathologic partial response, which was 10% to 50%, or pathologic non response or 50% or greater residual viable tumor, all assessed using central pathology grades. The one year RFS was 95% in the FDR patient population versus 76% in the pathologic partial response patient population, 57% in the pathologic non response patient population. So how do you view these results? Can you context the FDR rates and the EFS rates from NADINA relative to nivo-rela and also potentially SWOG 1801?

Dr. Jason Luke: Well, I think these are very exciting results. I think that for those of us that have been following the field closely, they're actually not especially surprising because they mirror several studies that have come before them. When we put them in context with other studies, we see that these rates of major pathological response are consistent with what we've seen in phase 2 studies. They're relatively similar. Or I should say that the results from nivolumab and relatlimab, which was also pursued in a phase 2 study of somewhat similar design, are somewhat similar to this. So, combination immunotherapy does look to deliver a higher major pathological response than pembrolizumab alone, as was known in S1801. Which of course, the caveat being is these are cross control comparisons that we need to be careful about. So I think all of these are active regimens, and I think adding a second agent does appear to enhance the major pathologic response rates. When we look at the event free survival, we see something similar, which is that numerically it looks to be that combination immunotherapy delivers a higher event free survival rate. And that looks to be rather meaningful given the difference in the hazard ratios that were observed between these various studies. And here in the NADINA study, we see that 0.3 hazard ratio for EFS is just extremely impressive.

So the abstract then, from ourselves, out of these specific studies, what does this mean more broadly in the real world, where patients exist and the rest of the landscape for clinical trials? I think we can't take enough time to stop for a second and just think about what a revolution we've come forward in with immune checkpoint blockade and melanoma. When I started my career, now, more than 15 years ago, melanoma was the cancer that made cancer bad. And now here we say, in the highest risk of perioperative patients, we can deliver 2 doses of nivolumab and ipilimumab, and essentially half of the patients then don't need to go on, and more than half the patients don't need to go on to have a full surgery and don't need adjuvant therapy. And from what we could tell of a very, very low risk of every heavy recurrence of melanoma. Of course, there's the other half of patients where we still need to do better, but these are just fantastic results and I think highly meaningful for patients.

In the context of ongoing clinical trials, another abstract that was presented during the meeting was the update to the individualized neoantigen therapy, or V940 with pembrolizumab or against pembrolizumab alone. That's the KEYNOTE-942 study. In that study, they presented updated data at two and a half years for relapse free survival, noting a 75% rate without relapse. So those results are also highly intriguing. And these are in a similar population of very high risk patients. And so I think most of us believe that neoadjuvant therapy with this study in NADINA is now confirmed as the priority approach for patients who present with high-risk stage 3 disease. So that would be bulky disease picked up on a scan or palpable in a clinic. I think essentially all of us now believe patients should get preoperative immunotherapy. We can debate which approach to take, and it may vary by an individual patient's ability to tolerate toxicity, because, of course, multi agent immunotherapy does have increased toxicity relative to anti PD-1 alone. But we'll have to wait now for the full phase 3 results from the V940 individualized neoantigen therapy. And if those come forward, that will be an extremely attractive approach to think about for patients who did not achieve a major pathological response to neoadjuvant therapy, as well as of course to the other populations of patients with melanoma where we otherwise currently give adjuvant therapy stage 2B all the way through stage 4 resected. It’s an amazing time to think about perioperative therapy in melanoma.

Dr. Diwakar Davar: So this is clearly outstanding data, outstanding news. Congratulations to the investigators for really doing what is an investigative initiated trial conducted across multiple continents with a huge sample size. So this clearly appears to be, at this point in time at least, a de facto standard. But is this going to be FDA-approved, guideline-approved, or is it possible in your mind?

Dr. Jason Luke: Well, that's an interesting question. This study was not designed with the intent to necessarily try to register this treatment regimen with the FDA. One would have to take a step back and say, with how powerful these data appear, it sort of seemed like it would be too bad if that doesn't happen. But all the same, I think the community and those of us who participate in guideline recommendations are fully supportive of this. So, I think we will see this move into compendium listings that support insurance approval, I think, very, very quickly. So, whether or not this actually becomes formally FDA approved or is in the guidelines, I think this should become the standard approach that is considered for patients, again presenting with high-risk stage 3 disease.

Dr. Diwakar Davar: Fantastic. So now we're going to go in and talk about a slightly different drug, but also from the melanoma context, and that is the safety and efficacy of RP1 with nivolumab in the context of patients with melanoma who are PD-1 failures. So, this is Abstract 9517. And in this abstract, our academic colleagues essentially talked about these data, and we'll start by describing what RP1 is. RP1 essentially is a HSV-1 based oncolytic immunotherapy. And RP1 expresses GM-CSF as well as a fusogenic protein, GALV-GP-R-. And in this abstract, Dr. Michael Wong from MD Anderson and colleagues are reporting the results of IGNYTE, which is a phase I trial of intratumoral RP1 co-administered with systemic nivolumab in patients with advanced metastatic treatment refractory cutaneous melanoma. And the data presented in this abstract represents data from a registration directed, abbreviated as RD, registration directed cohort of RP1 plus nivolumab in PD-1 refractory melanoma. So, let's start with the description of the cohort.

Dr. Jason Luke: Right. So, in this study, there were a total of 156 patients who were presented, and that included an initial safety and dose finding group of 16, as well as the RD cohort, as you noted, of 140 patients. And it's important to point out that this was a cohort that was selected for a very strict definition of progression on anti PD-1, or a combination immunotherapy as their immediately prior treatment. So, all of the patients in the cohort had exposure to anti PD-1, and 46% of them had anti PD-1 plus anti CTLA4, nivolumab and ipilimumab as their immediately prior therapy. This was also a group of relatively high-risk patients when one considers stage. So, within the stage 4 population, the entry here included 51% who had stage M1B, C, and D melanoma. And that is worth pointing out because this is an injectable therapy. So, trials like this in the past have tended to be biased towards earlier stage, unresectable or metastatic melanoma, meaning stage 3B, 3C, 3D and then stage 4m1a. Again, to emphasize the point here, these were pretreated patients who had a strict definition of anti PD-1 resistance, and over half of them, in fact, had high-risk visceral metastatic disease.

In that context, it's very interesting to observe that the overall response rate was described in the total population, as 31%, and that included 12% who achieved complete response. And so, again, to make sure it's clear, we're talking about a treatment where the oncolytic virus is injected into one or multiple sites of recurrent disease, and then the patients administer nivolumab as per standard. And so, I think these data are quite intriguing. Again, such a high- risk population and their maturity now, with a follow-up of over a year, I think, makes this look to be a very interesting treatment option.

Dr. Diwakar Davar: I guess on that topic of mature follow-up, it probably would be important for us to inform our audience that the top line data for the primary analysis was actually just released, I think, earlier today, and wherein the central confirmed objective response rate was 34% by modified RECIST and 33% by RECIST, clearly indicating that these responses, as you noted, very treatment refractory patient population, these responses were clearly very durable. So, you mentioned that there were responses seen in uninjected visceral lesions, responses seen in both PD-1 and PD-1 CTLA-4 refractory patients. Can you talk a little bit about the response rate in these high-risk subgroups, the uninjected visceral lesions, the patients who had both combination checkpoint and epidural refractory response rate by primary PD-1 resistance.

Dr. Jason Luke: Sure. You know, I think, again, to emphasize this point in the study, we saw that there were responses in the non-injected lesions, and I think it's really important to emphasize that. Some have referred to this as a putative abscopal like effect, similar to what is described in radiation. But it implies that local treatment with the oncolytic virus is triggering a systemic immune response. In the higher risk patient population, we'll note that whereas the overall response rate in PD-1 refractory patients was 34%, in the combination of PD-1 and CTLA-4 refractory patients, the response rate was 26%. So, [this is] still very good. And when we looked at that split by stage, as I alluded to before, in the population of patients that had, what you might call earlier unresectable diseases, so 3B through 4A, the response rate was 38%, and in the stage 4 M1b through M1d, it was 25%. So slightly lower, but still very good. And that would be as expected, because, of course, the patients with visceral metastatic disease have more advanced disease, but those response rates look quite good. Again, looking at the combination refractory population as well as the more high-risk disease.

Dr. Diwakar Davar: So, clearly, these are very promising data and exciting times for multiple investigators in the field and the company, Replimune, as well. So, what are the next steps? I believe that a registration trial is planned, essentially, looking at this with the goal of trying to get this combination registered. Can you tell us a little bit about IGNYTE-3, the trial design, the control arm, and what you foresee this trial doing over the next couple of years?

Dr. Jason Luke: So, as this agent has been maturing, it's worth pointing out that the company that makes this molecule, called RP1, but I guess now we'll have to get used to this name vusolimogene oderparepvec as the actual scientific term, they have been having ongoing discussions with the FDA, and there is the potential that this agent could come forward on an accelerated path prior to the results being released from a phase 3 trial. That being said, the phase 3 confirmatory study, which is called the IGNYTE-3 study, is in the process of being launched now. And that's a study investigating this molecule in combination with nivolumab, as was alluded to earlier, and a randomized phase 3 design, where that combination is compared with a physician's choice, essentially a chemotherapy-based option.

In that study, it will be 400 patients with stage 3B through stage 4; patients will have progressed on anti PD-1, either as a combination or in sequence, and then come on the study to be randomized to either vusolimogene oderparepvec plus nivolumab versus that physician's choice. And the physician's choice includes chemotherapy agents, but also nivolumab plus relatlimab as another option, or an anti PD-1 monotherapy, if that's deemed to be a reasonable option by the treating investigator. And the primary endpoint of that study is overall survival. And unfortunately, in this highly refractory patient population, that's something that may not take long to identify with key secondary endpoints of progression free survival, as well as overall response rate. I'm quite enthusiastic about this study, given these data, which have now been centrally confirmed as you alluded to before. I think this is a very exciting area of investigation and really crossing my fingers that this may be perhaps the first locally administered therapy which does appear to have a systemic impact that can hold up in phase 3.

Dr. Diwakar Davar: Very, very, very exciting results. And I guess it's worthwhile pointing out that this company also has got, I think, multiple studies planned with both RP1 and cutaneous squamous cell carcinoma in a solid organ transplant patient population where single agent activity has already been reported by Dr. Migden at prior meetings, as well as a novel trial of potentially RP2 metastatic uveal melanoma.

So we'll now pivot to Abstract 6014. So, 6014 is a drug by a company known as Merus. Essentially, it's a very novel agent. Merus essentially is a company that is specialized in making bicyclics and tricyclics. And these are not bicycles or tricycles, but rather drugs that essentially are bispecific antibodies. And Merus essentially has come up with petosemtamab. I think we're going to have to figure out better names for all of these drugs at some point. But petosemtamab, or MCLA-158, essentially is a bicyclic, targeting both EGFR as well as LGR-5. So EGR-5, of course, is a known oncogenic driver in multiple tumor types, squamous, including non small cell lung cancer, cutaneous squamous cell carcinoma, but also head and neck squamous cell carcinoma. And LGR-5 essentially is leucine-rich repeat-containing G-protein coupled receptor 5, but it's a receptor in cancer stem cells and certainly highly expressed in head neck squam. And MCLA-158, or petosemtamab is a IgG one bispecific with ADCC-activity because of IgG1 backbone co-targeting EGFR and LGR5. Merus had earlier results that evaluated petosemtamab monotherapy. They defined the RP2D and second- and third-line head and neck blastoma patients with a respectable response rate of 37% investigator-assessed ORR with six months median DoR, and this was published by Ezra Cohen about a year or so ago.

In this abstract, Dr. Fayette and colleagues report on the results of the MCLA-158-CL01 trial, which is a trial of pembrolizumab plus petosemtamab in one front line head and neck squamous cell population. So maybe let's start with the description of the cohort. And it is a small trial, but we'll be able, I think, to dig into a little bit about why this might be exciting.

Dr. Jason Luke: Yes. So, as alluded to, it's not the biggest trial as yet, but there were 26 patients with anti PD-1 treatment naive head and neck squamous cell carcinoma. And all the patients in the study did receive, as you alluded to, pembrolizumab plus petosemtamab. Based on the label for pembrolizumab, all the patients in this study were PDL-1 positive. So that's one point that it’s worth pointing out to make sure that that's understood. This is the population of patients who would be expected to benefit from pembrolizumab in the first place. Now, in the abstract, they reported out only 10 response evaluable patients, but they updated that in the actual slides of presentation at the meeting. So among 24 patients that were alluded to, 67% were described as having had a response, although some of those were yet to be confirmed responses. And when it was evaluated by PDL-1 status, there didn't seem to be a clear enrichment of response in the PD-1 positive more than 20% group, as compared to the 1-19% group. That isn't especially surprising because that was a trend that one would see, presumably with pembrolizumab alone. But overall, I think these data are pretty exciting in terms of a preliminary study.

Dr. Diwakar Davar: You know, you mentioned that the objective response rate was high, almost 60-something%. The prognosis of these patients is generally poor. The OS is typically thought of as between 6-15 months. And based on KEYNOTE-048, which was led by Dr. Burtness and colleagues, the standard of care in the setting is pembrolizumab +/- platinum based chemotherapy regimens. Allowing for the fact that we only have 10 patients here, how do you think these results stack up against KEYNOTE-048? And you made a very important point earlier, which was, by definition, pembro is on label only for the CPS. So PDL-1 score, at least in head and neck squamous cell carcinoma CPS and not TPS. But in the CPS 1% or greater patient population, where pembro is on label, how do these results stack up against the KEYNOTE-048 results.

Dr. Jason Luke: Right. KEYNOTE-048 is considered the seminal study that dictates frontline treatment in head and neck cancer. And before we dive into this too far, we do want to acknowledge that here we're comparing 26 patients versus a phase 3 trial. So, we're not trying to get too far ahead of ourselves, but this is just a preliminary comparison. But in KEYNOTE-048, as you alluded to, two regimens were superior to chemotherapy. One was the pembrolizumab monotherapy, as well as pembrolizumab plus chemotherapy. So again, the study overall survival, of course, was much higher, the PDL-1 positive subgroup, which is what dictated the unlabeled use of this. But response to pembro monotherapy in that population of patients is still modest. We're talking about upwards of 20-30%. So, if you compare that to, again, preliminary evidence here from this trial of only 24 patients, that response rate of 60% seems extremely high. And so even if that were to come down somewhat in a larger data series of patients, that still looks to be quite promising as a treatment regimen, that might eventually even be chemotherapy sparing for this population of patients. I think this raises a lot of eyebrows that perhaps this dual targeting approach, EGFR and LDR-5, may bring something really important to the field that evolves it.

Dr. Diwakar Davar: So, what are the next steps for petosemtamab? You mentioned that the activity was interesting. Are we going to see a larger trial? Any thoughts on where things are going to go?

Dr. Jason Luke: Well, based on the phase 2 data of petosemtamab alone, even without pembrolizumab, the molecule had already been given fast track designation by FDA, which means allowing for greater communication between the drug sponsor in the FDA and designing a seminal study design. One would assume that this trial will be rapidly expanded quite greatly, perhaps to 100 or 200 patients, to try to flush out what the real response rate is in a more meaningful number of patients. But I think these data will probably also trigger the design and probably near-term evaluation or expedited acceleration of a phase III clinical trial design that would potentially validate this against the current standard of care. So, I'm pretty excited. I think we'll see a lot more about this agent in the relatively near future.

Dr. Diwakar Davar: So, finally, we'll pivot to the last abstract that we're going to talk about, which is Abstract 2504. It's a relatively interesting target, CCR8 monoclonal antibody. But this is the efficacy and safety of LM-108, and LM-108 is an anti CCR8 monoclonal antibody that is being developed by LaNova Medicine. And the results that are described, actually a pool set of results of combinations of LM-108 with anti PD-1, two separate anti PD-1, in patients with gastric cancer, mostly done ex-U.S., which is interesting because of this patient population, and it's a pool result of several, 3 phase 1 and 2 studies.

LM-108 is an Fc-optimized anti CCR8 monoclonal antibody that selectively depletes tumor infiltrating Tregs. The abstract reported a pooled analysis of three phase 1, 2 trials with 3 different NCT numbers that all evaluated the efficacy of LM-108 and anti PD-1 in patients with gastric cancer. So, let's start with the description of the cohort. Maybe, Jason, you can tell us a little bit about before you start, as you describe the cohort, sort of what we know, editorially speaking, about the difficulty with which Tregs depletion has been tried and obviously failed up until now in the tumor microenvironment.

Dr. Jason Luke: Right. I think that's a really interesting comment. And so, for decades, in fact, targeting regulatory T-cell to alleviate immune exclusion in the tumor microenvironment has been of interest in immuno-oncology. And in preclinical mouse models, it seems quite clear that such an approach can deliver therapeutic efficacy. However, by contrast, in human clinical trials, various different Treg depleting strategies have been attempted, and there's really little to no evidence that depleting Tregs from human tumors actually can deliver therapeutic responses. And by that we're referring to CD-25 antibodies. The drug ipilimumab, the CTLA-4 antibody, was punitively described as a Tregs depleter preclinically, but that doesn't seem to be the case in patients. And so, in that background, this is quite an eye raiser that an anti CCR8 antibody could be driving this effect. Now, before we talk about the results of this trial, I will point out, however, that given the Fc-optimization, it's entirely possible that the Tregs are being depleted by this mechanism, but that more could also be going on. Because Fc gamma RII binding by this antibody that could be nonspecific also has the potential to trigger immune responses in the tumor microenvironment, probably mediated by myeloid cells. So I think more to come on this. If this turns out to be the first meaningful Tregs depletor that leads to therapeutic efficacy, that would be very interesting. But it's also possible this drug could have multiple mechanisms.

So, having said all of that, in the clinical trial, which was a pooled analysis, like you mentioned, of LM-108 in combination with anti PD-1 of a couple different flavors, there were 48 patients treated either with LM-108, with pembrolizumab, or with toripalimab, which is another anti PD-1 antibody. On the drug combination was, generally speaking, pretty well tolerated, noting grade 3 treatment related adverse events in the range of 38%, which is somewhat expected given combination immunotherapy. We talked about nivolumab and ipilimumab before, which, of course, gives even higher rates of immune-related adverse events, with the most common toxicities being anemia, lipase elevations, rash, ALC decrease; albeit, quite manageable.

Dr. Diwakar Davar: So, what about the objective response rate? Can you contextualize the efficacy? And as you do that, maybe we'll think about what you'd expect in the context of, say, gastric cancer, especially in patients who've never really had a prior checkpoint inhibitor before. What do you think about the ORR? What do you think about the relative efficacy of this combination?

Dr. Jason Luke: Well, so, in the study, they described overall response rate in the 36 patients as 36% and described immediate progression for survival of about 6.5 months. And so that was among patients who were treatment naive. And in second-line patients, they actually described an even higher response rate, although it was only 11 patients, but they're at 64%. And so, I think those data look to be somewhat interesting. When I was actually scrutinizing the actual data presented, it was of some interest to note that the quality of responses seemed to be about as good on the lower dose of LM-108, so 3 milligrams per kilogram as compared to 10 milligrams per kilogram. I think there's definitely more to learn here to try to optimize the dose and to fully understand what the overall efficacy of this treatment combination would be.

I would emphasize that in this disease, I think novel treatment strategies are certainly warranted. While anti PD-1 with chemotherapy has moved the needle in terms of standard of care treatment, it's really only a minor subset of patients who derive durable long-term benefit like we normally associate with immune checkpoint blockade. I think these are preliminary data. They're very intriguing.

You alluded to earlier that this population of patients was an Asian data set, and it is well known that the efficacy of chemotherapy and immunotherapy does appear to be somewhat enhanced in Asian populations, and that goes to distributions of metastasis and tumor microenvironment effects, etc. Very difficult to try to tease any of that out in this abstract, other than to look at these data and suggest that this is pretty interesting, both from a novel therapeutic approach, we talked about the Tregs consideration, but also straight up on the efficacy because I think if these data could hold up in a larger number of patients, and particularly in a western population of patients, I think it would be very intriguing.

Dr. Diwakar Davar: Certainly, ASCO 2024 had a lot of interesting data, including data from targeted agents, the LAURA trial, ADCs. But just focusing on the immune therapy subset, we certainly saw a lot of great advances in patients who were treated with neoadjuvant as well as relapse refractory disease in the context of RP1 and then a couple of newer agents such as this petosemtamab as well as LM-108. And of course, we cannot forget to highlight the extended DMFS data from the pembro vaccine study from KEYNOTE-942.

Jason, as always, thank you for taking a little bit of time out of your extremely busy schedule to come and give us insights as to how these agents are impacting the landscape. We really value your input and so thank you very much.

Dr. Jason Luke: Thank you for the opportunity.

Dr. Diwakar Davar: And thank you to our listeners for your time today. You will find the links to all the abstracts that we discussed 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 podcasts. So, thank you.

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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.

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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

Day 4: Top Takeaways From ASCO24

lundi 3 juin 2024 • Duration 10:57

Dr. John Sweetenham shares highlights from Day 4 of the 2024 ASCO Annual Meeting, including exciting new data from the IMROZ trial in multiple myeloma, adjuvant therapy for triple-negative breast cancer in A-BRAVE, and the front-line treatment of advanced renal cell carcinoma in JAVELIN Renal-101.

TRANSCRIPT

Dr. John Sweetenham: I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my top takeaways on selected abstracts from Day 4 of the 2024 ASCO Annual Meeting.

Today's selection features 3 randomized prospective trials in the first-line treatment of multiple myeloma, adjuvant therapy for triple negative breast cancer, and the frontline treatment of advanced renal cell carcinoma, all of which provide important new data.

My full disclosures are available in the transcript of this episode.

The first of today's abstracts is number 7500. This abstract, presented by Dr. Thierry Facon from the Department of Hematology at the University of Lille in France, describes the results of the IMROZ study. This was a multicenter phase 3 study comparing a current standard first-line regimen for transplant ineligible patients with myeloma VRd with the same combination plus an additional agent, isatuximab.

The combination of bortezomib, lenalidomide and dexamethasone, known as VRd, is currently a standard first-line regimen for patients with multiple myeloma, both transplant eligible and ineligible. Previous phase 3 studies have shown that the addition of an anti-CD38 antibody to triplet regimens improves outcomes in newly diagnosed patients. Based on early phase clinical trial data showing promising response rates with isatuximab, the IMROZ study was conducted to compare isatuximab VRd with VRd alone in patients who were either ineligible for transplant or had no immediate indication for transplant.

IMROZ was a global study conducted in 21 countries that involved 446 patients randomly assigned 3:2 to induction therapy with Isa-VRd followed by continuous Isa-Rd or induction therapy with VRd followed by Rd alone. The rate of complete response or better was approximately 75% with Isa-VRd compared with 64% with VRd alone. Very good partial response or better was achieved in 89% of patients with Isa-VRd, compared with around 83% of those with VRd alone. With a median follow-up at 5 years, Isa-VRd followed by Isa-Rd had reduced the risk of progression or death by 40.4% compared with VRd alone. The 60-month progression-free survival rate was 63% for Isa-VRd compared with around 45% with VRd alone, and the progression-free survival benefit was maintained in most of the analyzed subgroups. Minimal residual disease negativity was also measured in this study in both the intent to treat population and those patients who achieved a complete response. For example, in the intent to treat population, the MRD negative rate was 58% with Isa-VRd compared with around 43% with VRd alone.

There were also higher rates of sustained MRD negativity for 12 months or longer among patients assigned to Isa-VRd compared with VRd alone, reflecting deeper responses in the Isa-VRd arm. Although overall survival data is still immature, data from an interim analysis showed a favorable trend in the Isa-VRd arm with 22.4% risk reduction compared with VRd alone. There was little additional toxicity from the inclusion of isatuximab with the VRd regimen and the quality-of-life data were comparable and stable in both arms of the study. The investigators concluded that although overall survival data are immature, there is a trend in favor of Isa-VRd and this, combined with the favorable response, toxicity and progression-free survival data, establish isatuximab VRd as a potential new standard of care for newly diagnosed multiple myeloma patients not eligible for transplant. There was some discussion regarding the potential use of this regimen in patients over 80 years of age since the upper age limit was capped in IMROZ at 80 years. Although there are concerns for tolerance of the 4-drug regimen in the older patient group, it seems likely that this will be adopted, especially for those with good performance status and without major comorbidities.

Next up is LBA500. This abstract reports results of the A-BRAVE trial. This trial, presented by Dr. Pier Franco Conte from the University of Padova, Italy, was a phase 3 randomized trial to assess the efficacy of the immune checkpoint inhibitor avelumab in 2 groups of patients: those with early triple negative breast cancer, with residual disease after neoadjuvant chemotherapy; and those at high risk after primary surgery and adjuvant chemotherapy. As Dr. Conte explained in the introduction to this trial, there is a fairly compelling rationale for the use of checkpoint inhibitors in triple negative breast cancer. The disease has been shown to be more immunogenic than the other breast cancer types with immune biomarkers such as TILs and PDL-1 expression associated with better prognosis, added to which, data in metastatic breast cancer show a correlation between PDL-1 expression and checkpoint inhibitor response. In the A-BRAVE study, 477 high risk patients who had completed local, regional, and systemic treatment with curative intent were stratified according to adjuvant or post neoadjuvant status and randomized 1:1 to receive avelumab at 2-week intervals for 52 weeks or to observation only.

Results of the study showed a non-statistically significant improvement in three-year disease-free survival in the overall intent to treat population at 5.1% and in the post neoadjuvant patients at 6.2%. Overall survival was a secondary endpoint in this trial. The results show a significant improvement in overall survival of 8.1% in the intent-to-treat population and a very similar improvement in the post-neoadjuvant patients. The authors reported good tolerance of avelumab, although in total almost 30% discontinued treatment at some point. In their conclusion, the investigators state that the 34% reduction in the risk of death suggests a potential role for avelumab in early triple negative breast cancer patients at high risk after primary surgery or with invasive disease after neoadjuvant chemotherapy. Correlative studies are planned on tumor plasma and feces in this study. These are interesting and somewhat tantalizing results, suggesting a real effect from avelumab. Although confounded somewhat by the sample size, it will be important to see how these results mature with further follow-up.

Today's third selected abstract is number 4508 reporting the final analysis of the JAVELIN Renal 101 phase 3 trial in patients with advanced renal cell carcinoma. This study compared the combination of axitinib plus avelumab with sunitinib in this patient group. The trial included 886 patients, of whom around 61% of those in the combination group and around 65% of those in the monotherapy group were PDL-1 positive. In the initial analysis from the JAVELIN Renal 101 study, after at least 6 months of follow-up, avelumab and axitinib significantly improved progression-free survival over sunitinib in patients with PDL-1 positive tumors and in the overall population with advanced renal cell carcinoma. In the fall cohort, the median progression-free survival with the combination was 13.8 months compared with only 8.4 months with sunitinib, and based on those results, the combination received FDA approval as a first-line treatment for patients with advanced renal cell carcinoma in May of 2019. The progression-free survival observed in the initial analysis was confirmed with a new long-term analysis in the overall population. Median progression-free survival with avelumab and axitinib was 13.9 months compared with only 8.5 months with sunitinib and the median duration of response with the combination was 19.4 months versus 14.5 months with sunitinib. However, no difference in overall survival was seen. At 60 months, the overall survival in the combination group was 38.8% and 36.2% with sunitinib. In patients who were PDL-1 positive at 60 months, overall survival with a combination was 37.1% compared with 33.4% with sunitinib.

Despite the sustained difference in progression-free survival seen with this combination, the discussant at this session pointed out that most oncologists are unlikely to recommend a combination which has not been shown to improve overall survival when published studies have reported on 4 combinations which do positively impact overall survival in this patient group. Despite the good tolerance of this regimen, it seems unlikely to be a preferred frontline regimen in advanced renal carcinoma moving forward.

That concludes today's report. Thanks for listening and we hope you have enjoyed listening to our top takeaways from ASCO24. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review and subscribe wherever you get your podcasts.

Disclaimer:

Follow ASCO on social media:

Disclosures:

Dr. John Sweetenham:

Consulting or Advisory Role: EMA Wellness

Day 3: Top Takeaways From ASCO24

dimanche 2 juin 2024 • Duration 11:57

Dr. John Sweetenham shares highlights from Day 3 of the 2024 ASCO Annual Meeting, including selected studies on the treatment of cancer cachexia, surgical approaches in advanced ovarian cancer, and advanced colorectal cancer with liver metastases.

TRANSCRIPT

Dr. John Sweetenham: I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my top takeaways on selected abstracts from Day 3 of the 2024 ASCO Annual Meeting.

Today's selection features studies addressing the treatment of cancer cachexia and 2 studies of surgical approaches to the treatment of advanced ovarian cancer and of advanced colorectal cancer with liver metastases.

My full disclosures are available in the transcript of this episode.

Cachexia affects up to 80% of patients with advanced cancer and is thought to be directly responsible for 30% of cancer deaths, according to the National Cancer Institute. Despite these statistics, the condition remains understudied and there is no standard treatment. Current guidelines recommend dietary counseling and low-dose olanzapine or short courses of corticosteroids or progesterone analogues can be used to promote weight gain. However, the guidelines mainly point to evidence gaps. No drug therapy could be strongly endorsed to improve patient outcomes and no recommendations could be made regarding exercise.

Dr. Tora Solheim from the Cancer Clinic at St. Olavs Hospital in Trondheim, Norway, today reported results from the MENAC trial in LBA12007, which tested an intervention that combined treatment with nonsteroidal anti-inflammatory medication ibuprofen, home-based exercise to improve endurance and muscle strength, nutritional counseling, and supplements containing omega-3 fatty acids, which, based on previous research, may enhance muscle mass in patients with cancer cachexia. This trial enrolled 212 patients with stage III or IV lung or pancreatic cancer from 17 sites in 5 countries. All patients were receiving palliative chemotherapy and either had cachexia or were at high risk of developing it. Half were randomly assigned to the intervention and half to standard care. For the exercise components of the intervention, patients were encouraged to engage in aerobic activity such as walking, swimming, or even household chores at least twice a week. They were also encouraged to perform strengthening exercises such as half squats, bicep curls, and knee lifts 3 times per week.

Over 6 weeks, the trial found average body weight stabilized in the intervention group compared with a loss of 1 kg in the standard care group, but there were no differences between the two groups and the secondary endpoints of muscle mass and daily step count as measured by ActiGraph. Dr. Solheim pointed out that 6 to 8 weeks may be too early to observe any anabolic effects on muscle mass or function, but that this timeframe was chosen, she said, because previous studies, including her team’s own feasibility study had encountered high dropout rates among similar patient groups after 6 to 8 weeks.

Although these are interesting data, I think they also pose many questions: Is maintaining 1 kg of body weight a meaningful endpoint? Did the patients report any improvement in other symptoms? How was at-home exercise monitored for compliance? Did we know whether the patients were fulfilling adequate amounts of exercise? And there are many more questions. I think the investigators should be congratulated for demonstrating the feasibility of conducting a randomized trial in this challenging patient group, and this will hopefully provide a basis for future studies exploring new interventions.

In LBA5505, Dr. Jean-Marc Classe presented data from the CARACO study, a randomized trial evaluating the use of retroperitoneal lymph node dissection in patients undergoing primary surgery or interval cytoreductive surgery after neoadjuvant chemotherapy for advanced epithelial ovarian cancer.

To provide some context, an earlier study, the phase 3 LION trial, assessed the role of RPLD in patients with advanced ovarian cancer with complete resection and normal lymph nodes after primary surgery. In this trial, RPLD provided no significant improvement in overall or progression-free survival and was associated with a significant increase in serious postoperative complications and 60-day mortality. In recent years, the use of neoadjuvant chemotherapy and interval surgery has increased significantly in the U.S. and Europe, and it was unknown whether RPLD could have a benefit among these patients. The CARACO trial was undertaken to answer this question, enrolling patients treated with either primary surgery or neoadjuvant chemotherapy and interval surgery to reflect a real-world population. The multicenter trial enrolled 379 patients with FIGO stage III-IVA epithelial ovarian cancer with no suspicious retroperitoneal lymph nodes in whom optimal surgery was achievable with primary surgery or with interval cytoreductive surgery after neoadjuvant chemotherapy with residual tumor at less than 1 cm. Patients were randomly assigned to surgery with or without retroperitoneal lymph node dissection. Patients receiving primary surgery accounted for about 26% of the no RPL arm and 21% of the RPL arm. The primary endpoint was progression free survival, and secondary endpoints included overall survival, safety, surgical outcomes, and quality of life.

Although the trial initially planned to enroll 450 patients, enrollment slowed after the presentation of the results of the Lyon trial, leading to a premature closing of this trial to enrollment with 379 patients. The median age of enrolled patients was 64 - 65 years and 87% had serous or endometrioid carcinoma. Surgery was performed with no residual tumor in around 86% of the patients in the no RPL arm and 88% of patients in the RPL arm. Importantly, the median duration of surgery was 240 minutes in those with no RPL versus 300 minutes in the RPL arm, representing an additional hour for those who underwent retroperitoneal lymph node dissection. Severe morbidity within 30 days of surgery was significantly improved in the no RPL arm compared with the RPL arm as assessed by rates of transfusion or blood loss, re-intervention, and urinary injury. In an intent to treat analysis, there was no significant difference in progression-free survival in patients who did or did not receive retroperitoneal lymph node dissection. The respective median progression-free survivals were 14.8 and 18.6 months. Median overall survival was 48.9 months and 58.8 months, respectively, and on subgroup analysis, no benefit for retroperitoneal lymph node dissection was observed.

Although the results of this study are slightly confounded by the failure to reach their target accrual, the data shows strong evidence that these patients can be spared the additional surgery and subsequent surgical complications without compromising progression free or overall survival. Dr. Classe and his colleagues hope to determine whether retroperitoneal lymph node dissection is useful in patients with suspicious nodes.

The third selected abstract today is 3500, which describes a remarkable prospective study of chemotherapy plus liver transplantation versus chemotherapy alone in patients with unresectable colorectal cancer liver metastases. The results of the so-called TRANSMET study were presented by Dr. Adam from Villejuif, France, on behalf of a study group including centers from France, Belgium, and Italy. In the introduction to the study, the presenter pointed out that liver resection is currently the optimal treatment for liver metastases from colorectal cancer and offers the potential for long-term survival and even cure. But resection is only possible in 10% to 20% of patients. And although cytoreductive chemotherapy may convert some patients to a resectable status, this is relatively rare. The current standard of care is the use of chemotherapy, which may prolong survival but is not curative. Liver transplantation has been used in this context since the 2000s with apparent improvements in outcome, but TRANSMET is the first randomized trial to assess the benefit of adding liver transplantation to chemotherapy in this patient group.

The TRANSMET study evenly randomized 94 patients to either undergo chemotherapy and liver transplantation or only chemotherapy. The patients were highly selective in terms of age, performance status, resection of primary tumor, months of tumor control, previous line of therapy, and tumor markers. It's noteworthy that of the 157 patients eventually considered, 63 failed to meet the demanding eligibility criteria on the review of the trial committee. The 5-year overall survival rate in the intent to treat analysis was 57% in the chemotherapy plus liver transplant cohort and 13% in the chemotherapy-alone arm. Progression-free survival was 17.4 versus 6.4 months, respectively. 28 of the 38 transplanted patients suffered relapses, 15 of which were in the lungs. Surgical resection and/or radio ablation were used in many of these patients. The authors concluded that liver transplantation is an option which should be considered in this highly selective patient group and that the outcomes reported here are comparable to outcomes for liver transplantation and other conditions. Understandably, this is a small study in a highly selective group, and it's difficult to know where this will gain traction. With a shortage of organs for donation, prioritization of this small patient group may be challenging.

That concludes today's report. Join me again tomorrow to hear more top takeaways from ASCO24. If you value the insights that you hear on the ASCO Daily News Podcast, please remember 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.

Follow ASCO on social media:

Disclosures:

Dr. John Sweetenham:

Consulting or Advisory Role: EMA Wellness

Day 2: Top Takeaways From ASCO24

samedi 1 juin 2024 • Duration 10:15

Dr. John Sweetenham shares highlights from Day 2 of the 2024 ASCO Annual Meeting, including potentially practice-changing results in advanced Hodgkin lymphoma, intriguing data on the effect of metformin on active surveillance for prostate cancer, and the potential of AI to improve patient outreach and adherence to medical appointments.

TRANSCRIPT

Dr. John Sweetenham: I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my top takeaways on selected abstracts from Day 2 of the 2024 ASCO Annual Meeting.

Today's selection features potentially practice-changing results for patients with advanced stage Hodgkin lymphoma, results from a large trial testing the effects of metformin in patients on active surveillance for their prostate cancer, and early results giving insights into the benefits that artificial intelligence may bring to address disparities in cancer care.

My full disclosures are available in the transcript of this episode.

The first of today's abstracts is LBA7000, which reports the results from a large international randomized trial in patients with advanced Hodgkin lymphoma, presented by Dr. Peter Borchmann from the German Hodgkin Study Group. Since Hodgkin lymphoma typically affects adults in their 20s and 30s, the focus of clinical trials in recent years has been on achieving high rates of disease control while at the same time reducing the potential for short-term and long-term toxicities associated with classical chemotherapy and radiation therapy regimens. Particular emphasis has been given to reducing risk for secondary malignancy and impaired reproductive function in long-term survivors.

Building on the back of previous studies from this group, the escalated BEACOPP regimen was modified to reduce the overall duration of treatment and the potential for toxicity by incorporating novel agents, including brentuximab vedotin. This novel regimen, known as BrECADD, was compared with escalated BEACOPP in a randomized trial, HD21. Patients received 4 or 6 cycles of therapy based on the response of their disease to the first 2 cycles assessed by interim PET scan. 1,482 patients were randomized, 740 to escalated BEACOPP and 742 to BrECADD, with median follow-up at 48 months. The 4-year progression-free survival was 94.3% with BrECADD, compared with 90.9% for escalated BEACOPP, with a hazard ratio of 0.66. These results are particularly noteworthy since 64% of patients on the BrECADD arm had a negative PET scan after 2 cycles of therapy and therefore received a total of just 4 cycles, reducing their risk of toxicity.

On that note, lower rates of treatment related toxicity were observed with BrECADD. Specifically, hematologic toxicity and peripheral sensory neuropathy were less frequently seen. Female reproductive toxicity was lower with BrECADD, with more than 95% of women having normal FSH levels after 1 year on BrECADD, compared with 73% on escalated BEACOPP. Dr. Borchmann also noted that recovery of male reproductive function was improved with BrECADD, although details were not provided. These are impressive data, although no overall survival difference was observed. This is not surprising in view of the effective salvage therapies available to patients whose disease relapses after first-line therapy.

The authors conclude that these results are unprecedented for the first-line treatment of Hodgkin lymphoma and that the BrECADD regimen should be considered as a new standard of care option. Although these results are likely to change practice in some parts of the world, particularly in Europe, it's less clear whether they will impact current treatments in the United States, where modifications to the ABVD regimen, including the addition of brentuximab vedotin and more recently nivolumab, have been the subject of recent randomized trials. That said, these data add to the increasing evidence that cure of advanced Hodgkin lymphoma is possible in most patients, and that concerns over short- and long-term toxicities of therapy for this young group of patients are being addressed using several strategies.

The next abstract, LBA5002 reports the results of a Canadian study investigating the use of metformin to slow or prevent progression in patients with low-risk prostate cancer on active surveillance. Professor Anthony Joshua pointed out in his presentation that there are extensive epidemiologic, biologic, and clinical data suggesting that metformin may affect the progression of low-risk prostate cancer, but this has not previously been evaluated in the context of a randomized controlled trial. The MAST study – or Metformin Active Surveillance Trial – was designed to prospectively evaluate the use of metformin in patients with low-risk prostate cancer eligible for active surveillance. Patients were eligible for the trial if they had been diagnosed within the previous 12 months, had low-risk prostate cancer, defined as a Gleason score of less than 6 in less than one-third of cores involved and less than 50% of any 1 core plus having a PSA of less than 10. These patients were randomized to either active surveillance plus placebo or active surveillance plus metformin at an initial dose of 850 milligrams daily for 1 month, followed by 850 milligrams twice daily for 35 months. Evaluations including prostate biopsies were performed at baseline, then at 18 and 36 months. 405 patients were randomized 1:1 and were well matched for patient characteristics and risk factors. Pathologic and therapeutic progression were the major endpoints of the study.

The overall results of the study showed that the use of metformin in this population had no effect on pathologic or treatment progression. Although not a planned analysis, there was a signal that the use of metformin may accelerate progression in certain patients, including those with a high BMI. This study shows definitively that metformin should not be used in low-risk, localized prostate cancer patients who are eligible for active surveillance. There are many unanswered questions about its use in other situations in prostate cancer and in low-risk patients who also have diabetes.

The final selection for today is Abstract 100. In this presentation, Dr. Alyson Moadel from Montefiore Einstein Comprehensive Cancer Centre in New York City described an artificial intelligence platform which showed potential to improve patient outreach and adherence to medical appointments. In underserved communities of color, barriers to colorectal cancer screening can contribute to disparities due to late-stage diagnosis and poor outcomes. Despite active outreach by skilled patient navigators at this center, which serves an ethnically minoritized and disadvantaged population, 59% of patients either canceled or did not show for their colonoscopy appointments in 2022. While patient navigator reengagement efforts led to 21% eventually completing colonoscopy, 1,500 patients did not undergo potentially lifesaving colon cancer screening that year. The study used MyEleanor, a virtual patient navigator that engages in personalized AI conversation, to target 2,400 patients who had not attended their colonoscopy appointment in 2022 to 2023. MyEleanor called patients to discuss rescheduling, assessed barriers to uptake, offered live transfers to clinical staff to reschedule, and provided procedure preparation reminder calls.

During the study, 57% of patients engaged with MyEleanor, with 58% of this group or 33% overall accepting the live transfer. The rate of completed colonoscopies for patients who did not show for their initial appointment nearly doubled from 10% to 19% after the initiation of MyEleanor. Overall patient volume increased by 36%. Nearly one-third of the patients reported at least 2 barriers to screening. Top barriers included lack of perceived need, time, medical mistrust, concerns about findings, and cost. The investigators plan to extend these studies to explore the impact of this tool on patient preparation adherence, staff burden, and revenue. As data emerge on the potential applications of AI in the cancer care ecosystem, it's exciting to see how tools such as this have the potential to improve rates of prevention and early detection and address cancer care disparities.

Join me again tomorrow to hear more top takeaways from ASCO24. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.

Disclaimer:

Follow ASCO on social media: 

Disclosures:

Dr. John Sweetenham:

Consulting or Advisory Role: EMA Wellness

Day 1: Top Takeaways From ASCO24

vendredi 31 mai 2024 • Duration 10:35

In the first episode of a special daily series during the 2024 ASCO Annual Meeting, Dr. John Sweetenham shares highlights from Day 1, including exciting data on the CROWN trial in NSCLC, the ASC4First study in chronic myeloid leukemia, and the effects of high-deductible health plans on cancer survivorship.

TRANSCRIPT

Dr. John Sweetenham: I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. I'm delighted to bring you a special series of daily episodes from the 2024 ASCO Annual Meeting and to share my top takeaways on selected abstracts.

Today, I'll be reviewing exciting new data in chronic myeloid leukemia, remarkable outcomes for patients with ALK-positive non-small cell lung cancer, and a compelling study on the effects of high deductible health plans on cancer survivorship.

My disclosures are available in the transcript of this episode.

LBA6500, the ASC4FIRST trial, is a phase 3 combination of asciminib with the current standard of care tyrosine kinase inhibitors, those being imatinib, nilotinib, dasatinib and bosutinib for the first line treatment of patients with chronic myeloid leukemia. The data from this large multinational study, conducted in 29 countries, were presented by Dr. Timothy Hughes from the Royal Adelaide Hospital in Australia. Some patients with chronic phase CML respond well to tyrosine kinase inhibitor therapy, and about one-third may eventually be able to stop therapy and will remain in remission, the so-called treatment free remission or TFR. Unfortunately, almost half of patients eventually need to change therapy due to resistance and intolerance, and most patients will need to remain on therapy for many years, possibly for life.

Asciminib is the first BCR-ABL1 inhibitor to specifically target the ABL myristate pocket or STAMP and was designed to be highly potent but also highly specific, thus minimizing side effects and toxicity. In this large trial, which is the first randomized head-to-head comparison of asciminib with other tyrosine kinase inhibitors, 405 patients were randomized 1:1 to receive either asciminib at a dose of 80 milligrams daily or another investigator-selected TKI. The groups were well balanced for all patient characteristics, including ELTS risk. The primary objectives of the study were to compare the major molecular response rate at 48 weeks with an additional analysis for the patients who received imatinib as the investigator-selected TKI. With median follow-up at 16.3 months for patients receiving asciminib and 15.7 months for those receiving the other TKIs, the 48-week MMR rates were 68% for asciminib compared with 49% for the other investigators-selected TKIs.

The rates of MR4 after 48 weeks, a deep molecular response which is a prerequisite to be considered for treatment free remission, were 39% for asciminib compared to 21% for the investigator-selected TKI. Tolerability and safety were excellent for asciminib, with only 5% discontinued due to toxicity compared to 10% for the other TKI arm. Frequently observed toxicities with asciminib included thrombocytopenia and neutropenia. The investigators concluded that asciminib is the only agent to show a statistically significant improvement in efficacy and toxicity in this patient group when compared with all other TKIs, and that asciminib has the potential to become the preferred standard of care for the first line treatment of CML. Follow-up on the study continues, but there is no question that these are exciting and probably practice-changing results.

The next exciting study, LBA8503, was presented by Dr. Benjamin Solomon from the Peter MacCallum Cancer Centre in Melbourne, Australia. This presentation was an update of the CROWN study for patients with previously untreated advanced ALK-positive non-small cell lung cancer. Lorlatinib is a third-generation brain-penetrating ALK inhibitor which was compared with crizotinib in the CROWN-3 study. This phase 3 study enrolled 296 patients randomly assigned to lorlatinib 100 milligrams once daily or crizotinib 250 milligrams twice daily. The interim results showed a 72% reduction in the risk for progression or death with lorlatinib compared with crizotinib and formed the basis for the March 2021 FDA approval of the drug for metastatic ALK positive non-small cell lung cancer. A subsequent post hoc analysis at three years showed continued progression free survival benefit with lorlatinib compared with crizotinib.

Earlier today, Dr. Solomon presented a further post hoc analysis of the study at 60.2 months of median follow-up. Among the entire patient population, the median PFS was not reached with lorlatinib compared with 9.1 months with crizotinib. At 60 months, the PFS rate was 60% with lorlatinib compared with only 8% with crizotinib. The PSF benefits with lorlatinib were seen across all patient subgroups. The improved control of central nervous system metastatic disease, which was observed in the earlier reports, has been confirmed in this recent analysis. Among those patients with baseline brain metastases, the median PFS with lorlatinib was not yet reached compared with six months with crizotinib. More than half of patients with baseline brain metastases were progression free at 60 months.

But the benefit of lorlatinib is certainly not confined to patients with brain metastases. Lorlatinib also significantly improved progression-free survival among patients without metastases. At 60 months, 63% of patients without baseline brain metastases assigned to lorlatinib were progression free, compared with only 10% of those assigned crizotinib. These are remarkable results. As Dr. Solomon stated in his conclusion, 60% of patients on lorlatinib are still progression free and 92% are progression free in the brain. No new safety signals were seen and the improved efficacy over crizotinib was seen across all risk groups. These results are unprecedented in patients with ALK-positive non-small cell lung cancer.

Concerning data were presented today by Dr. Justin Barnes from Washington University. Dr. Barnes presented results from a retrospective study in Abstract 11005 which showed whether a patient with cancer has high-deductible health insurance can play a role in their survival. Although previous studies have shown care disparities for those with high-deductible plans, this report focuses specifically on effects on survival and concludes that cancer survivors with high-deductible health plans had a greater risk of mortality both overall and from cancer. High-deductible insurance was defined as costing between $1,200 and $1,350 annually for individual insurance, or between $2,400 and $2,700 annually for a family plan. Investigators used data from the U.S. National Center for Health Statistics National Health Interview Survey and linked them to files from the National Death Index to determine mortality rates. Included were more than 147,000 respondents aged between 18 and 84 years who did not have Medicaid. Among these individuals, 5.9% were cancer survivors. The concern for cancer survivors with these plans is that in addition to recurrence that could require costly treatments, there might be issues related to survivorship. Investigators found that overall survival was worse for those with a cancer diagnosis coupled with high-deductible health insurance, with a hazard ratio of nearly 1.5.

But when the researchers reviewed data from the general population without a history of cancer, they didn't find any association between high-deductible health insurance and outcomes. According to Dr. Barnes, the leading hypothesis is that patients with cancer who have a high-deductible plan delay workup for a potential new or recurrent cancer diagnosis or postpone or avoid other care. The results also indicated that survival among certain subgroups, such as non-Hispanic white patients, patients with higher incomes, and patients with at least a college or high school education, was worse for those with a high-deductible health plan, not the groups who are typically impacted by care disparities. It is possible that these individuals are more likely to select high-deductible health plans and that having these plans might counteract what might otherwise be adequate access to care.

A key take-home from this analysis is that cancer patients and survivors, whatever their racial, ethnic, or socioeconomic status, should have access to health plans with low deductibles and should be informed of the potential risks of their long-term health and survival when covered by high-deductible plans.

Join me again tomorrow to hear more top takeaways from ASCO24. If you value the insights that you hear on the ASCO Daily News Podcast, please remember 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 ASCO on social media:

Disclosures:

Dr. John Sweetenham:

Consulting or Advisory Role: EMA Wellness

Key Abstracts in GU Cancers at ASCO24

samedi 25 mai 2024 • Duration 26:04

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% regardless of the treatment arm. Furthermore, ctDNA 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.

Find out more about today’s speakers:

Dr. Neeraj Agarwal

@neerajaiims

Dr. Jeanny Aragon-Ching

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