Powered by RND

ASCO Daily News

American Society of Clinical Oncology (ASCO)
ASCO Daily News
Último episódio

Episódios Disponíveis

5 de 114
  • What Is Precision Palliative Care? Rethinking a Care Delivery Problem
    Dr. Joseph McCollom and Dr. Ramy Sedhom discuss precision palliative care, a new strategy that aims to align palliative care delivery with patient and caregiver needs instead of diagnosis alone. TRANSCRIPT ADN Podcast Episode 8-22 Transcript: What Is Precision Palliative Care? Rethinking a Care Delivery Problem Dr. Joseph McCollom: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Joseph McCollom. I'm a GI medical oncologist and palliative oncologist at the Parkview Packnett Family Cancer Institute here in Fort Wayne, Indiana. So, the early benefits of palliative care for patients with cancer have been well documented, but there are challenges in terms of bandwidth to how do we provide this care, given the workforce shortages in the oncology field. So today, we'll be exploring a new opportunity known as precision palliative care, a strategy that aims to align care delivery with patient and caregiver needs and not just diagnosis alone. Joining me for this discussion is Dr. Ramy Sedhom. He is the medical director of oncology and palliative care at Penn Medicine Princeton Health and a clinical assistant professor of medicine at the University of Pennsylvania Perelman School of Medicine. Our full disclosures are available in the transcript of this episode.  Dr. Sedhom, it's great to have you on the podcast today. Thank you so much for being here. Dr. Ramy Sedhom: Thank you, Joe. It's a pleasure to be here and lucky me to be in conversation with a colleague and friend. Yes, many of us have heard about the benefits of early palliative care. Trials have shown better quality of life, reduced symptoms, and potentially even improved survival. But as we know, the reality is translating that evidence into practice, which is really, really challenging. So Joe, both you and I know that not every patient can see palliative care, or I'd even argue should see palliative care, but that also means there are still many people with real needs who still fall through the cracks. That's why I'm really excited about today's topic, which we'll be discussing, which is precision palliative care. It's a growing shift in mindset from what's this patient's diagnosis or what's this patient's prognosis, to what matters most for this person in front of me right now and what are their individual care needs. I think, Joe, it's very exciting because the field is moving from a blanket approach to one tailored to meet people where they actually are. Dr. Joseph McCollom: Absolutely, Ramy. And I think from the early days when palliative care was kind of being introduced and trying to distinguish itself, I think one of the first models that came to clinicians' eyes was Jennifer Temel's paper in The New England Journal of Medicine in 2010. And her colleagues had really looked at early palliative care integration for patients with advanced non–small cell lung cancer. And in that era – this is a pre-immunotherapy era, very early targeted therapy era – the overall prognosis for those patients are similar to the population I serve as a GI medical oncologist, pancreatic cancer today. Typically, median overall survival of a year or less. And so, a lot of her colleagues really wanted her to track overall survival alongside quality of life and depression scores as a result of that. And it really was a landmark publication because not only did it show an improvement of quality of life, but it actually showed an improvement of overall survival. And that was really, I think, revolutionary at the time. You know, a lot of folks had talked about if this was a drug, the FDA would approve it. We all in GI oncology laugh about erlotinib, which got an FDA approval for a 2-week overall survival advantage. And so, it really kind of set the stage for a lot of us in early career who had a passion in the integration of palliative care and oncology. And I think a lot of the subsequent ASCO, NCCN, COC, Commission on Cancer, guidelines followed through with that. But I think what we realized is now we're kind of sitting center stage, there's still a lot of resource issues that if we sent a referral to palliative care for every single patient diagnosed with even an advanced cancer, we would have a significant workforce shortage issue. And so, Ramy, I was wondering if you could talk a little bit about how do we help center in on who are the right patients that are going to have the greatest benefit from a palliative care specialist intervention? Dr. Ramy Sedhom: Thanks, Joe. Great question. So you mentioned Dr. Temel's landmark 2010 trial published in the New England Journal of Medicine. And it is still a game changer in our field. The results of her work showed not only improved quality of life and mood, but I think very surprisingly at the time, a survival benefit for patients with lung cancer who had received early palliative care. That work, of course, has helped shape national guidelines, as you've shared, and it also helped define early, as within 8 weeks of diagnosis. But unfortunately, there remains a disconnect. So in clinical practice, using diagnosis or stage as the only referral trigger doesn't really match the needs that we see show up. And I think unfortunately, the other part is that approach creates a supply demand mismatch. We end up either referring more patients than palliative care teams can handle, or at the opposite extreme, we end up referring no one at all. So, I actually just wanted to quickly give, for example, two real world contrasts. So one center that I actually have friends who work in, tried as a very good quality improvement incentive, auto-refer all patients with stage IV pancreas cancer to palliative care teams. And while very well intentioned, they saw very quickly that in a two-month period, they had 30 new referrals. And on the palliative care side, there were only 15 available new patient slots. On the other hand, something that I often see in practice, is a situation where, for example, consider the case of a 90-year-old with a low-grade B-cell lymphoma. On paper, low-risk disease, but unfortunately, when you look under the microscope, this gentleman is isolated, has symptoms from his bulky adenopathy, and feels very overwhelmed by many competing illnesses. This is someone who, of course, may benefit from palliative care, but probably doesn't check the box. And I think this is where the model of precision palliative care steps in. It's not really about when was someone diagnosed or what is the prognosis or time-based criteria of their cancer, but it's really fundamentally asking the question of who needs help, what kind of help do they need, and how urgently do we need to provide this help? And I think precision palliative care really mirrors the logic and the philosophy of precision oncology. So just like we've made strides trying to match therapies to tumor biology, we also need to have the same attention and the same precision to match support to symptoms, to context of a patient situation and their caregiver, and also to their personal goals. So I think instead of a blanket referral, we really need to tailor care, the right support at the right moment for the right person to the right care teams. And I think to be more precise, there's really four core elements to allow us to do this well. So first, we really need to implement systematic screening. Let's use what we already have. Many of our centers have patient reported outcomes. The Commission on Cancer motivates us to use distress screening tools. And the EHR is there, but we do very little to flag and to surface unmet care needs. We have seen amazing work from people like Dr. Ethan Bash, who is the pioneer on patient-reported outcomes, and Dr. Ravi Parikh, who used to be my colleague at Penn, now at Emory, who show that you could use structured data and machine learning to identify some of these patient needs in real time. The second piece is after a systematic screening, we really need to build very clear referral pathways. One very good example is what the supportive care team at MD Anderson has done, of course, led by Dr. Eduardo Brera and Dr. David Huey, where they have, for example, designed condition-specific triggers. Urgent referrals, for example, to palliative care for severe symptoms, where they talk about it like a rapid response team. They will see them within 72 hours of the flag. But at the same time, if the unmet need is a caregiver distress, perhaps the social work referral is the first part of the palliative care intervention that needs to be placed. And I think this helps create both clarity and consistency but also it pays attention to that provider and availability demand mismatch. Third, I really think we need to triage smartly. As mentioned in the prior example, not every patient needs every team member of the palliative care team. Some benefit most from the behavioral health intervention. Others might benefit from chaplaincy or the clinician for symptom management. And I think aligning intensity with complexity helps us use our teams wisely. Unfortunately, the greatest barrier in all of our health care systems is time and time availability. And I think this is one strategic approach that I have not yet seen used very wisely. And fourth, I really think we need to embrace interdisciplinary care and change our healthcare systems to focus more on value. So this isn't about more consults or RVUs. I think it's really about leveraging our team strengths. Palliative care teams or supportive care teams usually are multidisciplinary in their core. They often have psychologists, social workers, sometimes they have nurse navigators. And I think all of these are really part of that engine of whole person care. But unfortunately, we still are not set up in care delivery systems that unfortunately to this day still model fee for service where the clinician or the physician visit is the only quote unquote real value add. Hopefully as our healthcare systems focus more on delivery and on value, this might help really embrace the structure to bring through the precision palliative care approach. Dr. Joseph McCollom: No, I love those points. You know, we talk frequently in the interdisciplinary team about how a social worker can spend 5 minutes doing something that I could not as a physician spend an hour doing. But does every patient need every member every time? And how do we work as a unified body to deliver that dose of palliative care, specialized palliative care to those right patients and match them? And I think that perfect analogy is in oncology as a medical oncologist, frequently I'm running complex next-generation sequencing paneling on patients' tumors, trying to find out is there a genetic weakness? Is there a susceptibility to a targeted therapy or an immunotherapy so that I can match and do that precision oncology, right patient to the right drug? Similarly, we need to continue to analyze and find these innovative ways like you've talked about, PROs, EHR flags, machine learning tools, to find those right patients and match them to the right palliative care interdisciplinary team members for them. I know we both get to work in oncology spaces and palliative and supportive spaces in our clinical practice. Share a little bit, if you could, Ramy, about what that looks like for your practice. How do you find those right patients? And how do you then intervene with that right palliative oncology dose? Dr. Ramy Sedhom: So Joe, when I first started in this space as a junior faculty, one thing became immediately clear. I think if we rely solely on physicians to identify the patients for palliative care, we're unfortunately going to be very limited by what we individually, personally observe. And I think that's what reflects the reality that many patients have real needs that go unseen. So over the past few years, I've really worked with a lot of my colleagues to really work the health system to change that. The greatest partnership I've personally had has been working with our informatics team to build a real time EHR integrated dashboard that I think helps us give us a broader view of patient needs. What we really think of as the population health perspective. Our dashboard at Penn, for example, pulls in structured data like geriatric assessment results, PHQ-4 screens, patient reported outcomes, whether or not they've been hospitalized, whether or not these hospitalizations are frequent and recurrent. And I think it's allowed us to really move from a reactive approach to one that's more proactive. So let me give you a practical example. So we have embedded in our cancer care team, psycho-oncologists. They share the same clinic space, they're right down the hall. And we actually use this shared dashboard to review weekly trends in distress scores and patient reported outcomes. And oftentimes, if they see a spike in anxiety or worsening symptoms like depression, they'll reach out to me and say, “Hey, I noticed Mrs. Smith reported feeling very anxious today. Do you think it'd be helpful if I joined you for her visit?” And I think that's how we could really use data and teamwork to offer and maximize the right support at the right time. Like many of our other healthcare systems, we also have real-time alerts for hospitalizations. And I think like Dr. Temel’s most recent trial, which we'll discuss at some point, I'm sure, it's another key trigger for vulnerability. I think whenever someone's admitted or discharged, we try to coordinate with our palliative care colleagues to assess do they need follow-up and in what timeline. And we know that these are common triggers, progression of disease, hospitalizations, drops in quality-of-life. And it's actually surprisingly simple to implement once you set up the right care structures. And I think these systems don't just help patients, which is what I quickly learned. They also help us as clinicians too. Before we expanded our team, I often felt this weight, especially as someone dual trained in oncology and palliative medicine, as trying to be everything to everyone. I remember one patient in particular, a young woman with metastatic breast cancer who was scheduled for a routine pre-chemo visit with me. Unfortunately, on that day, she had a very dramatic change in function. We whisked her down to x-ray and it revealed a pretty large pathologic fracture in her femur. And suddenly what was scheduled as a 30-minute visit became a very complex conversation around prognosis, urgent need for surgery and many, many life changes. And when I looked at my Epic list, I had a full waiting room. And thankfully, because we have embedded palliative care in our team, I was able to bring in Dr. Collins, the physician who I work with closely, immediately. She spent the full hour with the patient while I was able to continue seeing other patients that morning. And I think that's what team-based care makes possible. It's not just more hands on deck but really optimizing the support the patient needs on each individual day. And I think last, we're also learning a lot from behavioral science. So many institutions like Penn, Stanford, Massachusetts General, they've experimented with a lot of really interesting prompts in the EHR. One of them, for example, is the concept of nodes or the concept of prompt questions. Like, do you think this patient would benefit from a supportive care referral? And I think these low-level nudges, in a sense, can actually really dramatically increase the uptake of palliative care because it makes what's relevant immediately salient and visible to the practicing physician. So I think the key, if I had to maybe finish off with a simple message: It's not flashy tech, it's not massive change against staffing, but it's having a local champion and it's working smarter. It's asking the questions of how can we do this better and setting up the systems to make them more sustainable. Dr. Joseph McCollom: I appreciate you talking about this because I think a lot of folks want to put the wheels on in some way and they don't know where to get started. And so I think some of the models that you've been able to create, being able to track patients, screen your population, find the right individuals, and then work within that team to be able to extend, I think when you have an embedded palliative care specialist in your clinic, they expand your practice as a medical oncologist. And so you can make that warm handoff. And that patient and that caregiver, when they view the experience, they don't view you as a medical oncologist, someone else as a palliative care specialist, they view that team approach. And they said, "The team, my cancer team took care of me." And I think we can really harness a lot of the innovative technological advancements in our EHR to be able to prompt us in this work. I know that Dr. Temel had kind of set the stage for early palliative care intervention, and you did mention her stepped palliative care trial. Where do you see some of the future opportunities as we continue to push the needle forward as oncologists and palliative care specialists? What do you see as being the next step? Dr. Ramy Sedhom: So for those who are not familiar with the stepped palliative care trial, again, work by Dr. Temel, I think it's really important to explain not just the study itself, but I think more importantly, what it's representing for the future of our field. First, I really want to acknowledge Dr. Temel, who is a trailblazer in palliative oncology. Her work has not only shaped how we think about timing and delivery, but really about the value of supportive care. And more importantly, I think for all the young trainees listening, she had shown that rigorous randomized trials in palliative care are possible and meaningful. And I think for me, one quick learning point is that you could be an oncologist and lead this impactful research. And she's inspired many and many of us. Now let's quickly transition to her study. So in this trial, the stepped palliative care trial, patients with advanced lung cancer were randomized into two groups. One group followed the model from her landmark 2010 New England Journal of Medicine paper, which was structured monthly palliative care visits, again, within eight weeks of diagnosis. The second group, which is in this study, the intervention or the stepped palliative care group, received a single early palliative care visit. Think of this as a meet and greet. And then care was actually stepped up. If one of three clinical triggers happened. One, a decline in patient reported quality of life as measured by PROs. Two, disease progression, or three, hospitalization. And the findings which were presented at ASCO 2024 were striking. Clinical outcomes, very similar between the two groups. And this included quality-of-life, end-of-life communication, and resource use. But I think the take-home point is that the number of palliative care visits in the stepped group was significantly lower. So in other words, same impact and fewer visits. This was a very elegant example of how we can model precision palliative care, right sizing patient care based on patient need. So where do we go from here? I think if we want this model to take root nationally, we really need to pull on three key levers: healthcare systems, healthcare payment, and healthcare culture. So from a system alignment, unfortunately, as mentioned too often, the solution to gaps in palliative care is we need more clinicians. And while yes, that's partly true, it's actually not the full picture. I think what we first need to do and what's more likely to be achieved is to develop systems that focus on building the infrastructure that maximizes the reach of our existing care teams. So this means investing in nurse navigation, real-time dashboards with patient-reported outcomes and EHR flags, and again, matching triage protocols where intensity matches complexity. And the goal, as mentioned, isn't to maximize consults, but to really maximize deployment of expertise based on need. The second piece is, of course, we need payment reform. So the stepped palliative care model only works when it allows continuous patient engagement. But unfortunately, current pay models don't reward or incentivize that. In fact, electronic PROs require a very high upfront financial investment and ongoing clinician time with little to no reimbursement. Imagine if we offered bundled payments or value-based incentives for teams that integrated PROs. Or imagine if we reimbursed palliative care based on impact or infrastructure instead of just fee-for-service volume. There is a lot of clear evidence that tele-palliative care is effective. In fact, it was the Plenary at ASCO 2024. Yet we're still battling these conversations around inconsistent reimbursement, and we're always waiting on whether or not telehealth waivers are gonna continue. So I think most importantly is we really need to recognize the broader scope of what palliative care offers, which is caregiver support, improving navigation, coordinating very complex transitions. To me, and what I've always prioritized as a champion at Penn, is that palliative care is not a nice to have, and neither are all of these infrastructures, but they're really essential to whole person care, and they need to be financially supported. And last, we really need a culture shift. We need to change from how palliative care is perceived, and it can't be something other. It can't be something outside of oncology, but it really needs to be embraced as this is part of cancer care itself. I often see hesitancy from many oncologists about introducing palliative care early. But it doesn't need to be a dramatic shift. I think small changes in language, how we introduce the palliative care team, and co-management models can really go a very long way in normalizing this part of patient care. And I'm particularly encouraged, Joe, by one particular innovation in this space, which is really the growth of many startups. And one startup, for example, is Thyme Care, where I've seen them working with many, many private practices across the country, alongside partnerships with payers to really build tech-enabled navigation that tries to basically maximize triage support with electronic PROs. And to me, I really think these models can help scale access without overwhelming current care teams. So precision palliative care, Joe, in summary, I think should be flexible, scalable, and really needs to align based on what patients need. Dr. Joseph McCollom: No, I really appreciate, Ramy, you talking about that it really takes a village to get oncology care in both a competent and a compassionate way. And we need buy-in champions at all levels: the system level, the administrative level, the policy level, the tech level. And we need to change culture. I kind of want to just get your final impressions and also make sure that we make our listeners aware of our article. We should be able to have this in the show notes here as well to find additional tools and resources, all the studies that were discussed in today's episode. But, Ramy, what are some of your kind of final takeaways and conclusions? Dr. Ramy Sedhom: Before we wrap up, I just want to make sure we highlight a very exciting opportunity for residents considering a future in oncology and palliative medicine. Thanks to the leadership of Dr. Jamie Von Roen, who truly championed this cause, ASCO and the ABIM (American Board of Internal Medicine) have partnered to create the first truly integrated palliative care oncology fellowship. Trainees can now double board in just two years or triple board in three with palliative care, oncology, and hematology. And I think, Joe, as you and I both know, it's incredibly rewarding and meaningful to work at this intersection. To close our message, if there's one message I think listeners should carry with them, it's that palliative care is about helping people live as well as possible for as long as possible. And precision palliative care simply helps us do that better. We need to really develop systems that tailor support to individual need, value, and individual goals. Just like our colleagues in precision oncology mentioned, getting the right care to the right patient at the right time, and I would add in the right way. For those who want to learn more, I encourage you to read our full article in JCO, which is “Precision Palliative Care As a Pragmatic Solution for a Care Delivery Problem.” Joe, thank you so, so much for this thoughtful conversation and for your leadership in our field. And thank you to everyone for listening. Thank you all for being champions of this essential part of cancer care. If you haven't yet joined the ASCO Palliative Care Communities of Practice, membership is free, and we'd love to have you. Dr. Joseph McCollom: Thank you, Ramy, not only for sharing your insights today, but the pioneering work that you have done in our field. You are truly an inspiration to me in clinical practice, and it is an honor to call you both a colleague and friend.  And thank you for our listeners for joining us today. If you value the insights that you've heard on the ASCO Daily News Podcast, please subscribe, rate, and review wherever you get your podcasts. Thanks again. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today’s speakers:   Dr. Joseph McCollom @realbowtiedoc Dr. Ramy Sedhom @ramsedhom Follow ASCO on social media:   @ASCO on X (formerly Twitter) ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn   Disclaimer: Dr. Joseph McCollom: No relationships to disclose Dr. Ramy Sedhom: No relationships to disclose
    --------  
    28:05
  • From Clinic to Clinical Trials: Responsible AI Integration in Oncology
    Dr. Paul Hanona and Dr. Arturo Loaiza-Bonilla discuss how to safely and smartly integrate AI into the clinical workflow and tap its potential to improve patient-centered care, drug development, and access to clinical trials. TRANSCRIPT Dr. Paul Hanona: Hello, I'm Dr. Paul Hanona, your guest host of the ASCO Daily News Podcast today. I am a medical oncologist as well as a content creator @DoctorDiscover, and I’m delighted to be joined today by Dr. Arturo Loaiza-Bonilla, the chief of hematology and oncology at St. Luke’s University Health Network. Dr. Bonilla is also the co-founder and chief medical officer at Massive Bio, an AI-driven platform that matches patients with clinical trials and novel therapies. Dr. Loaiza-Bonilla will share his unique perspective on the potential of artificial intelligence to advance precision oncology, especially through clinical trials and research, and other key advancements in AI that are transforming the oncology field. Our full disclosures are available in the transcript of the episode. Dr. Bonilla, it's great to be speaking with you today. Thanks for being here. Dr. Arturo Loaiza-Bonilla: Oh, thank you so much, Dr. Hanona. Paul, it’s always great to have a conversation. Looking forward to a great one today. Dr. Paul Hanona: Absolutely. Let’s just jump right into it. Let’s talk about the way that we see AI being embedded in our clinical workflow as oncologists. What are some practical ways to use AI? Dr. Arturo Loaiza-Bonilla: To me, responsible AI integration in oncology is one of those that's focused on one principle to me, which is clinical purpose is first, instead of the algorithm or whatever technology we’re going to be using. If we look at the best models in the world, they’re really irrelevant unless we really solve a real day-to-day challenge, either when we’re talking to patients in the clinic or in the infusion chair or making decision support. Currently, what I’m doing the most is focusing on solutions that are saving us time to be more productive and spend more time with our patients. So, for example, we’re using ambient AI for appropriate documentation in real time with our patients. We’re leveraging certain tools to assess for potential admission or readmission of patients who have certain conditions as well. And it’s all about combining the listening of physicians like ourselves who are end users, those who create those algorithms, data scientists, and patient advocates, and even regulators, before they even write any single line of code. I felt that on my own, you know, entrepreneurial aspects, but I think it's an ethos that we should all follow. And I think that AI shouldn't be just bolted on later. We always have to look at workflows and try to look, for example, at clinical trial matching, which is something I'm very passionate about. We need to make sure that first, it's easier to access for patients, that oncologists like myself can go into the interface and be able to pull the data in real time when you really need it, and you don't get all this fatigue alerts. To me, that's the responsible way of doing so. Those are like the opportunities, right? So, the challenge is how we can make this happen in a meaningful way – we're just not reacting to like a black box suggestion or something that we have no idea why it came up to be. So, in terms of success – and I can tell you probably two stories of things that we know we're seeing successful – we all work closely with radiation oncologists, right? So, there are now these tools, for example, of automated contouring in radiation oncology, and some of these solutions were brought up in different meetings, including the last ASCO meeting. But overall, we know that transformer-based segmentation tools; transformer is just the specific architecture of the machine learning algorithm that has been able to dramatically reduce the time for colleagues to spend allotting targets for radiation oncology. So, comparing the target versus the normal tissue, which sometimes it takes many hours, now we can optimize things over 60%, sometimes even in minutes. So, this is not just responsible, but it's also an efficiency win, it's a precision win, and we're using it to adapt even mid-course in response to tumor shrinkage. Another success that I think is relevant is, for example, on the clinical trial matching side. We've been working on that and, you know, I don't want to preach to the choir here, but having the ability for us to structure data in real time using these tools, being able to extract information on biomarkers, and then show that multi-agentic AI is superior to what we call zero-shot or just throwing it into ChatGPT or any other algorithm, but using the same tools but just fine-tuned to the point that we can be very efficient and actually reliable to the level of almost like a research coordinator, is not just theory. Now, it can change lives because we can get patients enrolled in clinical trials and be activated in different places wherever the patient may be. I know it's like a long answer on that, but, you know, as we talk about responsible AI, that's important. And in terms of what keeps me up at night on this: data drift and biases, right? So, imaging protocols, all these things change, the lab switch between different vendors, or a patient has issues with new emerging data points. And health systems serve vastly different populations. So, if our models are trained in one context and deployed in another, then the output can be really inaccurate. So, the idea is to become a collaborative approach where we can use federated learning and patient-centricity so we can be much more efficient in developing those models that account for all the populations, and any retraining that is used based on data can be diverse enough that it represents all of us and we can be treated in a very good, appropriate way. So, if a clinician doesn't understand why a recommendation is made, as you probably know, you probably don't trust it, and we shouldn't expect them to. So, I think this is the next wave of the future. We need to make sure that we account for all those things. Dr. Paul Hanona: Absolutely. And even the part about the clinical trials, I want to dive a little bit more into in a few questions. I just kind of wanted to make a quick comment. Like you said, some of the prevalent things that I see are the ambient scribes. It seems like that's really taken off in the last year, and it seems like it's improving at a pretty dramatic speed as well. I wonder how quickly that'll get adopted by the majority of physicians or practitioners in general throughout the country. And you also mentioned things with AI tools regarding helping regulators move things quicker, even the radiation oncologist, helping them in their workflow with contouring and what else they might have to do. And again, the clinical trials thing will be quite interesting to get into. The first question I had subsequent to that is just more so when you have large datasets. And this pertains to two things: the paper that you published recently regarding different ways to use AI in the space of oncology referred to drug development, the way that we look at how we design drugs, specifically anticancer drugs, is pretty cumbersome. The steps that you have to take to design something, to make sure that one chemical will fit into the right chemical or the structure of the molecule, that takes a lot of time to tinker with. What are your thoughts on AI tools to help accelerate drug development? Dr. Arturo Loaiza-Bonilla: Yes, that's the Holy Grail and something that I feel we should dedicate as much time and effort as possible because it relies on multimodality. It cannot be solved by just looking at patient histories. It cannot be solved by just looking at the tissue alone. It's combining all these different datasets and being able to understand the microenvironment, the patient condition and prior treatments, and how dynamic changes that we do through interventions and also exposome – the things that happen outside of the patient's own control – can be leveraged to determine like what's the best next step in terms of drugs. So, the ones that we heard the news the most is, for example, the Nobel Prize-winning [for Chemistry awarded to Demis Hassabis and John Jumper for] AlphaFold, an AI system that predicts protein structures right? So, we solved this very interesting concept of protein folding where, in the past, it would take the history of the known universe, basically – what's called the Levinthal's paradox – to be able to just predict on amino acid structure alone or the sequence alone, the way that three-dimensionally the proteins will fold. So, with that problem being solved and the Nobel Prize being won, the next step is, “Okay, now we know how this protein is there and just by sequence, how can we really understand any new drug that can be used as a candidate and leverage all the data that has been done for many years of testing against a specific protein or a specific gene or knockouts and what not?” So, this is the future of oncology and where we're probably seeing a lot of investments on that. The key challenge here is mostly working on the side of not just looking at pathology, but leveraging this digital pathology with whole slide imaging and identifying the microenvironment of that specific tissue. There's a number of efforts currently being done. One isn't just H&E, like hematoxylin and eosin, slides alone, but with whole imaging, now we can use expression profiles, spatial transcriptomics, and gene whole exome sequencing in the same space and use this transformer technology in a multimodality approach that we know already the slide or the pathology, but can we use that to understand, like, if I knock out this gene, how is the microenvironment going to change to see if an immunotherapy may work better, right? If we can make a microenvironment more reactive towards a cytotoxic T cell profile, for example. So, that is the way where we're really seeing the field moving forward, using multimodality for drug discovery. So, the FDA now seems to be very eager to support those initiatives, so that's of course welcome. And now the key thing is the investment to do this in a meaningful way so we can see those candidates that we're seeing from different companies now being leveraged for rare disease, for things that are going to be almost impossible to collect enough data, and make it efficient by using these algorithms that sometimes, just with multiple masking – basically, what they do is they mask all the features and force the algorithm to find solutions based on the specific inputs or prompts we're doing. So, I'm very excited about that, and I think we're going to be seeing that in the future. Dr. Paul Hanona: So, essentially, in a nutshell, we're saying we have the cancer, which is maybe a dandelion in a field of grass, and we want to see the grass that's surrounding the dandelion, which is the pathology slides. The problem is, to the human eye, it's almost impossible to look at every single piece of grass that's surrounding the dandelion. And so, with tools like AI, we can greatly accelerate our study of the microenvironment or the grass that's surrounding the dandelion and better tailor therapy, come up with therapy. Otherwise, like you said, to truly generate a drug, this would take years and years. We just don't have the throughput to get to answers like that unless we have something like AI to help us. Dr. Arturo Loaiza-Bonilla: Correct. Dr. Paul Hanona: And then, clinical trials. Now, this is an interesting conversation because if you ever look up our national guidelines as oncologists, there's always a mention of, if treatment fails, consider clinical trials. Or in the really aggressive cancers, sometimes you might just start out with clinical trials. You don't even give the standard first-line therapy because of how ineffective it is. There are a few issues with clinical trials that people might not be aware of, but the fact that the majority of patients who should be on clinical trials are never given the chance to be on clinical trials, whether that's because of proximity, right, they might live somewhere that's far from the institution, or for whatever reason, they don't qualify for the clinical trial, they don't meet the strict inclusion criteria.  But a reason you mentioned early on is that it's simply impossible for someone to be aware of every single clinical trial that's out there. And then even if you are aware of those clinical trials, to actually find the sites and put in the time could take hours. And so, how is AI going to revolutionize that? Because in my mind, it's not that we're inventing a new tool. Clinical trials have always been available. We just can't access them. So, if we have a tool that helps with access, wouldn't that be huge? Dr. Arturo Loaiza-Bonilla: Correct. And that has been one of my passions. And for those who know me and follow me and we've spoke about it in different settings, that's something that I think we can solve. This other paradox, which is the clinical trial enrollment paradox, right? We have tens of thousands of clinical trials available with millions of patients eager to learn about trials, but we don't enroll enough and many trials close to accrual because of lack of enrollment. It is completely paradoxical and it's because of that misalignment because patients don't know where to go for trials and sites don't know what patients they can help because they haven't reached their doors yet. So, the solution has to be patient-centric, right? We have to put the patient at the center of the equation. And that was precisely what we had been discussing during the ASCO meeting. There was an ASCO Education Session where we talked about digital prescreening hubs, where we, in a patient-centric manner, the same way we look for Uber, Instacart, any solution that you may think of that you want something that can be leveraged in real time, we can use these real-world data streams from the patient directly, from hospitals, from pathology labs, from genomics companies, to continuously screen patients who can match to the inclusion/exclusion criteria of unique trials. So, when the patient walks into the clinic, the system already knows if there's a trial and alerts the site proactively. The patient can actually also do decentralization. So, there's a number of decentralized clinical trial solutions that are using what I call the “click and mortar” approach, which is basically the patient is checking digitally and then goes to the site to activate. We can also have the click and mortar in the bidirectional way where the patient is engaged in person and then you give the solution like the ones that are being offered on things that we're doing at Massive Bio and beyond, which is having the patient to access all that information and then they make decisions and enroll when the time is right.  As I mentioned earlier, there is this concept drift where clinical trials open and close, the patient line of therapy changes, new approvals come in and out, and sites may not be available at a given time but may be later. So, having that real-time alerts using tools that are able already to extract data from summarization that we already have in different settings and doing this natural language ingestion, we can not only solve this issue with manual chart review, which is extremely cumbersome and takes forever and takes to a lot of one-time assessments with very high screen failures, to a real-time dynamic approach where the patient, as they get closer to that eligibility criteria, they get engaged. And those tools can be built to activate trials, audit trials, and make them better and accessible to patients. And something that we know is, for example, 91%-plus of Americans live close to either a pharmacy or an imaging center. So, imagine that we can potentially activate certain of those trials in those locations. So, there's a number of pharmacies, special pharmacies, Walgreens, and sometimes CVS trying to do some of those efforts. So, I think the sky's the limit in terms of us working together. And we've been talking with corporate groups, they're all interested in those efforts as well, to getting patients digitally enabled and then activate the same way we activate the NCTN network of the corporate groups, that are almost just-in-time. You can activate a trial the patient is eligible for and we get all these breakthroughs from the NIH and NCI, just activate it in my site within a week or so, as long as we have the understanding of the protocol. So, using clinical trial matching in a digitally enabled way and then activate in that same fashion, but not only for NCTN studies, but all the studies that we have available will be the key of the future through those prescreening hubs. So, I think now we're at this very important time where collaboration is the important part and having this silo-breaking approach with interoperability where we can leverage data from any data source and from any electronic medical records and whatnot is going to be essential for us to move forward because now we have the tools to do so with our phones, with our interests, and with the multiple clinical trials that are coming into the pipelines. Dr. Paul Hanona: I just want to point out that the way you described the process involves several variables that practitioners often don't think about. We don't realize the 15 steps that are happening in the background. But just as a clarifier, how much time is it taking now to get one patient enrolled on a clinical trial? Is it on the order of maybe 5 to 10 hours for one patient by the time the manual chart review happens, by the time the matching happens, the calls go out, the sign-up, all this? And how much time do you think a tool that could match those trials quicker and get you enrolled quicker could save? Would it be maybe an hour instead of 15 hours? What's your thought process on that? Dr. Arturo Loaiza-Bonilla: Yeah, exactly. So one is the matching, the other one is the enrollment, which, as you mentioned, is very important. So, it can take, from, as you said, probably between 4 days to sometimes 30 days. Sometimes that's how long it takes for all the things to be parsed out in terms of logistics and things that could be done now agentically. So, we can use agents to solve those different steps that may take multiple individuals. We can just do it as a supply chain approach where all those different steps can be done by a single agent in a simultaneous fashion and then we can get things much faster. With an AI-based solution using these frontier models and multi-agentic AI – and we presented some of this data in ASCO as well – you can do 5,000 patients in an hour, right? So, just enrolling is going to be between an hour and maximum enrollment, it could be 7 days for those 5,000 patients if it was done at scale in a multi-level approach where we have all the trials available. Dr. Paul Hanona: No, definitely a very exciting aspect of our future as oncologists. It's one thing to have really neat, novel mechanisms of treatment, but what good is it if we can't actually get it to people who need it? I'm very much looking for the future of that.  One of the last questions I want to ask you is another prevalent way that people use AI is just simply looking up questions, right? So, traditionally, the workflow for oncologists is maybe going on national guidelines and looking up the stage of the cancer and seeing what treatments are available and then referencing the papers and looking at who was included, who wasn't included, the side effects to be aware of, and sort of coming up with a decision as to how to treat a cancer patient. But now, just in the last few years, we've had several tools become available that make getting questions easier, make getting answers easier, whether that's something like OpenAI's tools or Perplexity or Doximity or OpenEvidence or even ASCO has a Guidelines Assistant as well that is drawing from their own guidelines as to how to treat different cancers. Do you see these replacing traditional sources? Do you see them saving us a lot more time so that we can be more productive in clinic? What do you think is the role that they're going to play with patient care? Dr. Arturo Loaiza-Bonilla: Such a relevant question, particularly at this time, because these AI-enabled query tools, they're coming left and right and becoming increasingly common in our daily workflows and things that we're doing. So, traditionally, when we go and we look for national guidelines, we try to understand the context ourselves and then we make treatment decisions accordingly. But that is a lot of a process that now AI is helping us to solve. So, at face value, it seems like an efficiency win, but in many cases, I personally evaluate platforms as the chief of hem/onc at St. Luke's and also having led the digital engagement things through Massive Bio and trying to put things together, I can tell you this: not all tools are created equal. In cancer care, each data point can mean the difference between cure and progression, so we cannot really take a lot of shortcuts in this case or have unverified output. So, the tools are helpful, but it has to be grounded in truth, in trusted data sources, and they need to be continuously updated with, like, ASCO and NCCN and others. So, the reason why the ASCO Guidelines Assistant, for instance, works is because it builds on all these recommendations, is assessed by end users like ourselves. So, that kind of verification is critical, right? We're entering a phase where even the source material may be AI-generated. So, the role of human expert validation is really actually more important, not less important. You know, generalist LLMs, even when fine-tuned, they may not be enough. You can pull a few API calls from PubMed, etc., but what we need now is specialized, context-aware, agentic tools that can interpret multimodal and real-time clinical inputs. So, something that we are continuing to check on and very relevant to have entities and bodies like ASCO looking into this so they can help us to be really efficient and really help our patients. Dr. Paul Hanona: Dr. Bonilla, what do you want to leave the listener with in terms of the future direction of AI, things that we should be cautious about, and things that we should be optimistic about? Dr. Arturo Loaiza-Bonilla: Looking 5 years ahead, I think there's enormous promise. As you know, I'm an AI enthusiast, but always, there's a few priorities that I think – 3 of them, I think – we need to tackle head-on. First is algorithmic equity. So, most AI tools today are trained on data from academic medical centers but not necessarily from community practices or underrepresented populations, particularly when you're looking at radiology, pathology, and what not. So, those blind spots, they need to be filled, and we can eliminate a lot of disparities in cancer care. So, those frameworks to incentivize while keeping the data sharing using federated models and things that we can optimize is key. The second one is the governance on the lifecycle. So, you know, AI is not really static. So, unlike a drug that is approved and it just, you know, works always, AI changes. So, we need to make sure that we have tools that are able to retrain and recall when things degrade or models drift. So, we need to use up-to-date AI for clinical practice, so we are going to be in constant revalidation and make it really easy to do. And lastly, the human-AI interface. You know, clinicians don't need more noise or we don't need more black boxes. We need decision support that is clear, that we can interpret, and that is actionable. “Why are you using this? Why did we choose this drug? Why this dose? Why now?” So, all these things are going to help us and that allows us to trace evidence with a single click. So, I always call it back to the Moravec's paradox where we say, you know, evolution gave us so much energy to discern in the sensory-neural and dexterity. That's what we're going to be taking care of patients. We can use AI to really be a force to help us to be better clinicians and not to really replace us. So, if we get this right and we decide for transparency with trust, inclusion, etc., it will never replace any of our work, which is so important, as much as we want, we can actually take care of patients and be personalized, timely, and equitable. So, all those things are what get me excited every single day about these conversations on AI. Dr. Paul Hanona: All great thoughts, Dr. Bonilla. I'm very excited to see how this field evolves. I'm excited to see how oncologists really come to this field. I think with technology, there's always a bit of a lag in adopting it, but I think if we jump on board and grow with it, we can do amazing things for the field of oncology in general. Thank you for the advancements that you've made in your own career in the field of AI and oncology and just ultimately with the hopeful outcomes of improving patient care, especially cancer patients. Dr. Arturo Loaiza-Bonilla: Thank you so much, Dr. Hanona. Dr. Paul Hanona: Thanks to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your 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. More on today’s speakers:    Dr. Arturo Loaiza-Bonilla @DrBonillaOnc Dr. Paul Hanona @DoctorDiscover on YouTube Follow ASCO on social media:      @ASCO on Twitter      ASCO on Facebook      ASCO on LinkedIn    ASCO on BlueSky Disclosures: Paul Hanona: No relationships to disclose. Dr. Arturo-Loaiza-Bonilla: Leadership: Massive Bio Stock & Other Ownership Interests: Massive Bio Consulting or Advisory Role: Massive Bio, Bayer, PSI, BrightInsight, CardinalHealth, Pfizer, AstraZeneca, Medscape Speakers’ Bureau: Guardant Health, Ipsen, AstraZeneca/Daiichi Sankyo, Natera
    --------  
    24:01
  • Immunotherapy at ASCO25: Drug Development, Melanoma Treatment, and More
    Dr. Diwakar Davar and Dr. Jason Luke discuss novel agents in melanoma and other promising new data in the field of immunotherapy that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Diwakar Davar: Hello. My name is Diwakar Davar, and I am welcoming you to the ASCO Daily News Podcast. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh’s Hillman Cancer Center. Today, I'm joined by my colleague and good friend, Dr. Jason Luke. Dr. Luke is a professor of medicine. He is also the associate director of clinical research and the director of the Phase 1 IDDC Program at the University of Pittsburgh's Hillman Cancer Center. He and I are going to be discussing some key advancements in melanoma and skin cancers that were presented at the 2025 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode.  Jason, it is great to have you back on the podcast. Dr. Jason Luke: Thanks again so much for the opportunity, and I'm really looking forward to it. Dr. Diwakar Davar: Perfect. So we will go ahead and start talking a little bit about a couple of key abstracts in both the drug development immunotherapy space and the melanoma space. The first couple of abstracts, the first two, will cover melanoma. So, the first is LBA9500, which was essentially the primary results of RELATIVITY-098. RELATIVITY-098 was a phase 3 trial that compared nivolumab plus relatlimab in a fixed-dose combination against nivolumab alone for the adjuvant treatment of resected high-risk disease. Jason, do you want to maybe give us a brief context of what this is? Dr. Jason Luke: Yeah, it's great, thanks. So as almost all listeners, of course, will be aware, the use of anti–PD-1 immunotherapies really revolutionized melanoma oncology over the last 10 to 15 years. And it has become a standard of care in the adjuvant setting as well. But to review, in patients with stage III melanoma, treatment can be targeted towards BRAF with BRAF and MEK combination therapy, where that's relevant, or anti–PD-1 with nivolumab or pembrolizumab are a standard of care. And more recently, we've had the development of neoadjuvant approaches for palpable stage III disease. And in that space, if patients present, based on two different studies, either pembrolizumab or nivolumab plus ipilimumab can be given prior to surgery for somewhere in the 6- to 9-week range. And so all of these therapies have improved time-to-event endpoints, such as relapse-free or event-free survival. It's worth noting, however, that despite those advances, we've had a couple different trials now that have actually failed in this adjuvant setting, most high profile being the CheckMate-915 study, which looked at nivolumab plus ipilimumab and unfortunately was a negative study. So, with RELATIVITY-047, which was the trial of nivolumab plus relatlimab that showed an improvement in progression-free survival for metastatic disease, there's a lot of interest, and we've been awaiting these data for a long time for RELATIVITY-098, which, of course, is this adjuvant trial of LAG-3 blockade with relatlimab plus nivolumab. Dr. Diwakar Davar: Great. So with that, let's briefly discuss the trial design and the results. So this was a randomized, phase 3, blinded study, so double-blinded, so neither the investigators knew what the patients were getting, nor did the patients know what they were getting. The treatment investigational arm was nivolumab plus relatlimab in the fixed-dose combination. So that's the nivolumab standard fixed dose with relatlimab that was FDA approved in RELATIVITY-047. And the control arm was nivolumab by itself. The duration of treatment was 1 year. The patient population consisted of resected high-risk stage III or IV patients. The primary endpoint was investigator-assessed RFS. Stage and geography were the standard stratifying factors, and they were included, and most of the criteria were balanced across both arms. What we know at this point is that the 2-year RFS rate was 64% and 62% in the nivolumab and nivolumab-combination arms, respectively. The 2-year DMFS rate was similarly equivalent: 76% with nivolumab monotherapy, 73% with the combination. And similar to what you had talked about with CheckMate 915, unfortunately, the addition of LAG-3 did not appear to improve the RFS or DMFS compared to control in this patient population. So, tell us a little bit about your take on this and what do you think might be the reasons why this trial was negative? Dr. Jason Luke: It's really unfortunate that we have this negative phase 3 trial. There had been a lot of hope that the combination of nivolumab with relatlimab would be a better tolerated combination that increased the efficacy. So in the metastatic setting, we do have 047, the study that demonstrated nivolumab plus relatlimab, but now we have this negative trial in the adjuvant setting. And so as to why exactly, I think is a complicated scenario. You know, when we look at the hazard ratios for relapse-free survival, the primary endpoint, as well as the secondary endpoints for distant metastasis-free survival, we see that the hazard ratio is approximately 1. So there's basically no difference. And that really suggests that relatlimab in this setting had no impact whatsoever on therapeutic outcomes in terms of efficacy. Now, it's worth noting that there was a biomarker subanalysis that was presented in conjunction with these data that looked at some immunophenotyping, both from circulating T cells, CD8 T cells, as well as from the tumor microenvironment from patients who were treated, both in the previous metastatic trial, the RELATIVITY-047 study, and now in this adjuvant study in the RELATIVITY-098 study. And to briefly summarize those, what was identified was that T cells in advanced melanoma seemed to have higher expression levels of LAG-3 relative to T cells that are circulating in patients that are in the adjuvant setting. In addition to that, there was a suggestion that the magnitude of increase is greater in the advanced setting versus adjuvant. And the overall summary of this is that the suggested rationale for why this was a negative trial may have been that the target of LAG-3 is not expressed as highly in the adjuvant setting as it is in the metastatic setting. And so while the data that were presented, I think, support this kind of an idea, I am a little bit cautious that this is actually the reason for why the trial was negative, however. I would say we're not really sure yet as to why the trial was negative, but the fact that the hazard ratios for the major endpoints were essentially 1 suggests that there was no impact whatsoever from relatlimab. And this really makes one wonder whether or not building on anti–PD-1 in the adjuvant setting is feasible because anti–PD-1 works so well. You would think that even if the levels of LAG-3 expression were slightly different, you would have seen a trend in one direction or another by adding a second drug, relatlimab, in this scenario. So overall, I think it's an unfortunate circumstance that the trial is negative. Clearly there's going to be no role for relatlimab in the adjuvant setting. I think this really makes one wonder about the utility of LAG-3 blockade and how powerful it really can be. I think it's probably worth pointing out there's another adjuvant trial ongoing now of a different PD-1 and LAG-3 combination, and that's cemiplimab plus fianlimab, a LAG-3 antibody that's being dosed from another trial sponsor at a much higher dose, and perhaps that may make some level of difference. But certainly, these are unfortunate results that will not advance the field beyond where we were at already. Dr. Diwakar Davar: And to your point about third-generation checkpoint factors that were negative, I guess it's probably worth noting that a trial that you were involved with, KeyVibe-010, that evaluated the PD-1 TIGIT co-formulation of vibostolimab, MK-4280A, was also, unfortunately, similarly negative. So, to your point, it's not clear that all these third-generation receptors are necessarily going to have the same impact in the adjuvant setting, even if they, you know, for example, like TIGIT, and they sometimes may not even have an effect at all in the advanced cancer setting. So, we'll see what the HARMONY phase 3 trial, that's the Regeneron cemiplimab/fianlimab versus pembrolizumab control with cemiplimab with fianlimab at two different doses, we'll see how that reads out. But certainly, as you've said, LAG-3 does not, unfortunately, appear to have an impact in the adjuvant setting. So let's move on to LBA9501. This is the primary analysis of EORTC-2139-MG or the Columbus-AD trial. This was a randomized trial of encorafenib and binimetinib, which we will abbreviate as enco-bini going forward, compared to placebo in high-risk stage II setting in melanoma in patients with BRAF V600E or K mutant disease. So Jason, you know, you happen to know one or two things about the resected stage II setting, so maybe contextualize the stage II setting for us based on the trials that you've led, KEYNOTE-716, as well as CheckMate-76K, set us up to talk about Columbus-AD. Dr. Jason Luke: Thanks for that introduction, and certainly stage II disease has been something I've worked a lot on. The rationale for that has been that building off of the activity of anti–PD-1 in metastatic melanoma and then seeing the activity in stage III, like we just talked about, it was a curious circumstance that dating back about 7 to 8 years ago, there was no availability to use anti–PD-1 for high-risk stage II patients, even though the risk of recurrence and death from melanoma in the context of stage IIB and IIC melanoma is in fact similar or actually higher than in stage IIIA or IIIB, where anti–PD-1 was approved. And in that context, a couple of different trials that you alluded to, the Keynote-716 study that I led, as well as the CheckMate 76K trial, evaluated pembrolizumab and nivolumab, respectively, showing an improvement in relapse-free and distant metastasis-free survival, and both of those agents have subsequently been approved for use in the adjuvant setting by the US FDA as well as the European Medicines Agency.  So bringing then to this abstract, throughout melanoma oncology, we've seen that the impact of anti–PD-1 immunotherapy versus BRAF and MEK-targeted therapy have had very similar outcomes on a sort of comparison basis, both in frontline metastatic and then in adjuvant setting. So it was a totally reasonable question to ask: Could we use adjuvant BRAF and MEK inhibitor therapy? And I think all of us expected the answer would be yes. As we get into the discussion of the trial, I think the unfortunate circumstance was that the timing of this clinical trial being delayed somewhat, unfortunately, made it very difficult to accrue the trial, and so we're going to have to try to read through the tea leaves sort of, based on only a partially complete data set. Dr. Diwakar Davar: So, in terms of the results, they wanted to enroll 815 patients, they only enrolled 110. The RFS and DMFS were marginally improved in the treatment arm but certainly not significantly, which is not surprising because the trial had only accrued 16% to 18% of its complete accrual. As such, we really can't abstract from the stage III COMBI-AD data to stage II patients. And certainly in this setting, one would argue that the primary treatment options certainly remain either anti–PD-1 monotherapy, either with pembrolizumab or nivolumab, based on 716 or 76K, or potentially active surveillance for the patients who are not inclined to get treated.  Can you tell us a little bit about how you foresee drug development going forward in this space because, you know, for example, with HARMONY, certainly IIC disease is a part of HARMONY. We will know at least a little bit about that in this space. So what do you think about the stage IIB/C patient population? Is this a patient population in which future combinations are going to be helpful, and how would you think about where we can go forward from here? Dr. Jason Luke: It is an unfortunate circumstance that this trial could not be accrued at the pace that was necessary. I think all of us believe that the results would have been positive if they'd been able to accrue the trial. In the preliminary data set that they did disclose of that 110 patients, you know, it's clear there is a difference at a, you know, a landmark at a year. They showed a 16% difference, and that would be in line with what has been seen in stage III. And so, you know, I think it's really kind of too bad. There's really going to be no regulatory approach for this consideration. So using BRAF and MEK inhibition in stage II is not going to be part of standard practice moving into the future. To your point, though, about where will the field go? I think what we're already realizing is that in the adjuvant setting, we're really overtreating the total population. And so beyond merely staging by AJCC criteria, we need to move to biomarker selection to help inform which patients truly need the treatment. And in that regard, I don't think we've crystallized together as a field as yet, but the kinds of things that people are thinking about are the integration of molecular biomarkers like ctDNA. When it's positive, it can be very helpful, but in melanoma, we found that, unfortunately, the rates are quite low, you know, in the 10% to 15% range in the adjuvant setting. So then another consideration would be factors in the primary tumor, such as gene expression profiling or other considerations.  And so I think the future of adjuvant clinical trials will be an integration of both the standard AJCC staging system as well as some kind of overlaid molecular biomarker that helps to enrich for a higher-risk population of patients because on a high level, when you abstract out, it's just clearly the case that we're rather substantially overtreating the totality of the population, especially given that in all of our adjuvant studies to date for anti–PD-1, we have not yet shown that there's an overall survival advantage. And so some are even arguing perhaps we should even reserve treatment until patients progress. I think that's a complicated subject, and standard of care at this point is to offer adjuvant therapy, but certainly a lot more to do because many patients, you know, unfortunately, still do progress and move on to metastatic disease. Dr. Diwakar Davar: Let's transition to Abstract 2508. So we're moving on from the melanoma to the novel immunotherapy abstracts. And this is a very, very, very fascinating drug. It's IMA203. So Abstract 2508 is a phase 1 clinical update of IMA203. IMA203 is an autologous TCR-T construct targeting PRAME in patients with heavily pretreated PD-1-refractory metastatic melanoma. So Jason, in the PD-1 and CTLA-4-refractory settings, treatment options are either autologous TIL, response rate, you know, ballpark 29% to 31%, oncolytic viral therapy, RP1 with nivolumab, ORR about 30-ish percent. So new options are needed. Can you tell us a little bit about IMA203? Perhaps tell us for the audience, what is the difference between a TCR-T and traditional autologous TIL? And a little bit about this drug, IMA203, and how it distinguishes itself from the competing TIL products in the landscape. Dr. Jason Luke: I'm extremely enthusiastic about IMA203. I think that it really has transformative potential based on these results and hopefully from the phase 3 trial that's open to accrual now. So, what is IMA203? We said it's a TCR-T cell product. So what that means is that T cells are removed from a patient, and then they can be transduced through various technologies, but inserted into those T cells, we can then add a T-cell receptor that's very specific to a single antigen, and in this case, it's PRAME. So that then is contrasted quite a bit from the TIL process, which includes a surgical resection of a tumor where T cells are removed, but they're not specific necessarily to the cancer, and they're grown up in the lab and then given to the patient. They're both adoptive cell transfer products, but they're very different. One is genetically modified, and the other one is not. And so the process for generating a TCR-T cell is that patients are required to have a new biomarker that some may not be familiar with, which is HLA profiling. So the T-cell receptor requires matching to the concomitant HLA for which the peptide is bound in. And so the classic one that is used in most oncology practices is A*02:01 because approximately 48% of Caucasians have A*02:01, and the frequency of HLA in other ethnicities starts to become highly variable. But in patients who are identified to have A*02:01 genotype, we can then remove blood via leukapheresis or an apheresis product, and then insert via lentiviral transduction this T-cell receptor targeting PRAME. Patients are then brought back to the hospital where they can receive lymphodepleting chemotherapy and then receive the reinfusion of the TCR-T cells. Again, in contrast with the TIL process, however, these T cells are extremely potent, and we do not need to give high-dose interleukin-2, which is administered in the context of TIL. Given that process, we have this clinical trial in front of us now, and at ASCO, the update was from the phase 1 study, which was looking at IMA203 in an efficacy population of melanoma patients who were refractory at checkpoint blockade and actually multiple lines of therapy. So here, there were 33 patients and a response rate of approximately 50% was observed in this population of patients, notably with a duration of response approximately a year in that treatment group. And I realize that these were heavily pretreated patients who had a range of very high-risk features. And approximately half the population had uveal melanoma, which people may be aware is a generally speaking more difficult-to-treat subtype of melanoma that metastasizes to the liver, which again has been a site of resistance to cancer immunotherapy. So these results are extremely promising. To summarize them from what I said, it's easier to make TCR-T cells because we can remove blood from the patient to transduce the T cells, and we don't have to put them through surgery. We can then infuse them, and based on these results, it looks like the response rate to IMA203 is a little bit more than double what we expect from lifileucel. And then, whereas with lifileucel or TILs, we have to give high-dose IL-2, here we do not have to give high-dose IL-2. And so that's pretty promising. And a clinical trial is ongoing now called the SUPREME phase 3 clinical trial, which is hoping to validate these results in a randomized global study. Dr. Diwakar Davar: Now, one thing that I wanted to go over with you, because you know this trial particularly well, is what you think of the likelihood of success, and then we'll talk a little bit about the trial design. But in your mind, do you think that this is a trial that has got a reasonable likelihood of success, maybe even a high likelihood of success? And maybe let's contextualize that to say an alternative trial, such as, for example, the TebeAM trial, which is essentially a T-cell bispecific targeting GP100. It's being compared against SOC, investigator's choice control, also in a similarly heavily pretreated patient population. Dr. Jason Luke: So both trials, I think, have a strong chance of success. They are very different kinds of agents. And so the CD3 bispecific that you referred to, tebentafusp, likely has an effect of delaying progression, which in patients with advanced disease could have a value that might manifest as overall survival. With TCR-T cells, by contrast, we see a very high response rate with some of the patients going into very durable long-term benefit. And so I do think that the SUPREME clinical trial has a very high chance of success. It will be the first clinical trial in solid tumor oncology randomizing patients to receive a cell therapy as compared with a standard of care. And within that standard of care control arm, TILs are allowed as a treatment. And so it will also be the first study that will compare TCR-T cells against TILs in a randomized phase 3. But going back to the data that we've seen in the phase 1 trial, what we observe is that the duration of response is really connected to the quality of the response, meaning if you have more than a 50% tumor shrinkage, those patients do very, very well. But even in patients who have less than 50% tumor shrinkage, the median progression-free survival right now is about 4.5 months. And again, as we think about trial design, standard of care options for patients who are in this situation are unfortunately very bad. And the progression-free survival in that population is probably more like 2 months. So this is a trial that has a very high likelihood of being positive because the possibility of long-term response is there, but even for patients who don't get a durable response, they're likely going to benefit more than they would have based on standard chemotherapy or retreatment with an anti–PD-1 agent. Dr. Diwakar Davar: Really, a very important trial to enroll, a trial that is first in many ways. First of a new generation of TCR-T agents, first trial to look at cell therapy in the control arm, a new standard of efficacy, but potentially also if this trial is successful, it will also be a new standard of trial conduct, a new kind of trial, of a set of trials that will be done in the second-line immunotherapy-refractory space. So let's pivot to the last trial that we were going to discuss, which was Abstract 2501. Abstract 2501 is a first-in-human phase 1/2 trial evaluating BNT142, which is the first-in-class mRNA-encoded bispecific targeting Claudin-6 and CD3 in patients with Claudin-positive tumors. We'll talk a little bit about this, but maybe let's start by talking a little bit about Claudin-6. So Claudin-6 is a very interesting new target. It's a target that's highly expressed in GI and ovarian tumors. There are a whole plethora of Claudin-6-targeting agents, including T-cell bispecifics and Claudin-6-directed CAR-Ts that are being developed. But BNT142 is novel. It's a novel lipid nanoparticle LNP-encapsulated mRNA. The mRNA encodes an anti–Claudin-6 CD3 bispecific termed RiboMAB-021. And it then is administered to the patient. The BNT142-encoding mRNA LNPs are taken up by the liver and translated into the active drug. So Jason, tell us a little bit about this agent. Why you think it's novel, if you think it's novel, and let's talk a little bit then about the results. Dr. Jason Luke: So I certainly think this is a novel agent, and I think this is just the first of what will probably become a new paradigm in oncology drug development. And so you alluded to this, but just to rehash it quickly, the drug is encoded as genetic information that's placed in the lipid nanoparticle and then is infused into the patient. And after the lipid nanoparticles are taken up by the liver, which is the most common place that LNPs are usually taken up, that genetic material in the mRNA starts to be translated into the actual protein, and that protein is the drug. So this is in vivo generation, so the patient is making their own drug inside their body. I think it's a really, really interesting approach. So for any drug that could be encoded as a genetic sequence, and in this case, it's a bispecific, as you mentioned, CD3-Claudin-6 engager, this could have a tremendous impact on how we think about pharmacology and novel drug development moving into the future in oncology. So I think it's an extremely interesting drug, the like of which we'll probably see only more moving forward. Dr. Diwakar Davar: Let's maybe briefly talk about the results. You know, the patient population was heavily pretreated, 65 or so patients, mostly ovarian cancer. Two-thirds of the patients were ovarian cancer, the rest were germ cell and lung cancer patients. But let's talk a little bit about the efficacy. The disease control rate was about 58% in the phase 1 population as a whole, but 75% in the ovarian patient population. Now tell us a little bit about the interesting things about the drug in terms of the pharmacokinetics, and also then maybe we can pivot to the clinical activity by dose level. Dr. Jason Luke: Well, so they did present in their presentation at ASCO a proportionality showing that as higher doses were administered, that greater amounts of the drug were being made inside the patient. And so that's an interesting observation, and it's an important one, right? Suggesting that the pharmacology that we classically think of by administering drugs by IV, for example, would still be in play. And that did translate into some level of efficacy, particularly at the higher dose levels. Now, the caveat that I'll make a note of is that disease control rate is an endpoint that I think we have to be careful about because what that really means is sometimes a little bit unclear. Sometimes patients have slowly growing tumors and so on and so forth. And the clinical relevance of disease control, if it doesn't last at least 6 months, I think is probably pretty questionable. So I think these are extremely interesting data, and there's some preliminary sense that getting the dose up is going to matter because the treatment responses were mostly observed at the highest dose levels. There's also a caveat, however, that across the field of CD3 bispecific molecules like this, there's been quite a bit of heterogeneity in terms of the response rate, with some of them only really generating stable disease responses and other ones having more robust responses. And so I think this is a really interesting initial foray into this space. My best understanding is this molecule is not moving forward further after this, but I think that this really does set it up to be able to chase after multiple different drug targets on a CD3 bispecific backbone, both in ovarian cancer, but then basically across all of oncology. Dr. Diwakar Davar: Perfect. This is a very new sort of exciting arena where we're going to be looking at, in many ways, these programmable constructs, whether we're looking at in vivo-generated, in this case, a T-cell bispecific, but we've also got newer drugs where we are essentially giving drugs where people are generating in vivo CAR T, and also potentially even in vivo TCR-T. But certainly lots of new excitement around this entire class of drugs. And so, what we'd like to do at this point in time is switch to essentially the fact that we've got a very, very exciting set of data at ASCO 2025. You've heard from Dr. Luke regarding the advances in both early drug development but also in advanced cutaneous melanoma. And Jason, as always, thank you so much for sharing your very valuable and great, fantastic insights with us on the ASCO Daily News Podcast. Dr. Jason Luke: Well, thanks again for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for taking your time to listen today. You will find the links to the abstracts that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today’s speakers:    Dr. Diwakar Davar    @diwakardavar    Dr. Jason Luke @jasonlukemd Follow ASCO on social media:     @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn   Disclosures:     Dr. Diwakar Davar:      Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences     Consulting or Advisory Role: Instil Bio, Vedanta Biosciences     Consulting or Advisory Role (Immediate family member): Shionogi     Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences     Research Funding (Inst.): Zucero Therapeutics     Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy     Dr. Jason Luke:     Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX     Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine     Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure     Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)     Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio
    --------  
    27:01
  • Innovations in GU Cancer Treatment at ASCO25
    Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss important advances in the treatment of prostate, bladder, and kidney cancers that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am 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 am delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of the GU Center at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that were presented at the 2025 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode.  Jeanny, it is great to have you on the podcast. Dr. Jeanny Aragon-Ching: Oh, thank you so much, Neeraj. Dr. Neeraj Agarwal: Jeanny, let's begin with some prostate cancer abstracts. Let's begin with Abstract 5017 titled, “Phase 1 study results of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer.” Can you walk us through the design and the key findings of this first-in-human trial? Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So this study, presented by Dr. Capucine Baldini, introduces pasritamig, a first-in-class T-cell redirecting bispecific antibody that simultaneously binds KLK2 on prostate cancer cells and CD3 receptor complexes on T cells. KLK2 is also known as human kallikrein 2, which is selectively expressed in prostate tissue. And for reference, KLK3 is what we now know as the PSA, prostate-specific antigen, therefore making it an attractive and specific target for therapeutic engagement. Now, while this was an early, first-in-human, phase 1 study, it enrolled 174 heavily pretreated metastatic CRPC patients. So many were previously treated with ARPIs, taxanes, and radioligand therapy. So given the phase 1 nature of this study, the primary objective was to determine the safety and the RP2D, which is the recommended phase 2 dose. Secondary objectives included preliminary assessment of antitumor activity. So, pasritamig was generally well tolerated. There were no treatment-related deaths. Serious adverse events were rare. And in the RP2D safety cohort, where patients received the step-up dosing up to 300 mg of IV every 6 weeks, the most common treatment-related adverse events were low-grade infusion reactions. There was fatigue and grade 1 cytokine release syndrome, what we call CRS. And no cases of neurotoxicity, or what we call ICANS, the immune effector cell-associated neurotoxicity syndrome, reported. Importantly, the CRS occurred in just about 8.9% of patients. All were grade 1. No patients required tocilizumab or discontinued treatment due to adverse events. So, this suggests a favorable safety profile, allowing hopefully for outpatient administration without hospitalization, which will be very important when we're thinking about bispecifics moving forward. In terms of efficacy, pasritamig showed promising activity. About 42.4% of evaluable patients achieved a PSA50 response. Radiographic PFS was about 6.8 months. And among patients with measurable disease, the objective response rate was about 16.1% in those with lymph node or bone metastases, and about 3.7% in those with visceral disease, with a median duration of response of about 11.3 months. So, altogether, this data suggests that pasritamig may offer a well-tolerated and active new potential option for patients with metastatic CRPC.   Again, as a reminder, with the caveat that this is still an early phase 1 study. Dr. Neeraj Agarwal: Thank you, Jeanny. These are promising results for a bispecific T-cell engager, pasritamig, in prostate cancer. I agree, the safety and durability observed here stand out, and this opens the door for further development, possibly even in earlier disease settings.  So, shifting now from immunotherapy to the evolving role of genomics in prostate cancer. So let's discuss Abstract 5094, a real-world, retrospective analysis exploring the prognostic impact of homologous recombination repair gene mutations, especially BRCA1 and BRCA2 mutations, in metastatic hormone-sensitive prostate cancer. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So this study was presented by Dr. David Olmos, represents one of the largest real-world analyses we have evaluating the impact of homologous recombination repair, or what we would call HRR, alterations in metastatic hormone-sensitive prostate cancer. So, this cohort included 556 men who underwent paired germline and somatic testing. Now, about 30% of patients had HRR alterations, with about 12% harboring BRCA1 or BRCA2 mutations and 16% having alterations in other HRR genes. Importantly, patients were stratified via CHAARTED disease volume, and outcomes were examined across treatment approaches, including ADT alone, doublet therapy, and triplet therapy. The prevalence of BRCA and HRR alterations were about similar between the metastatic hormone-sensitive prostate cancer and the metastatic castrate-resistant prostate cancer, with no differences observed, actually, between the patients with high volume versus low volume disease.  So, the key finding was that BRCA and HRR alterations were associated with poor clinical outcomes in metastatic hormone-sensitive prostate cancer. And notably, the impact of these alterations may actually be even greater in metastatic hormone-sensitive prostate cancer than previously reported in metastatic CRPC. So, the data showed that when BRCA mutations are present, the impact of the volume of disease is actually limited. So, poor outcomes were observed across the board for both high-volume and low-volume groups. So, the analysis showed that patients with HRR alterations had significantly worse outcomes compared to patients without HRR alterations. Median radiographic progression-free survival was about 20.5 months for the HRR-altered patients versus 30.6 months for the non-HRR patients, with a hazard ratio of 1.6. Median overall survival was 39 months for HRR-altered patients compared to 55.7 months for the non-HRR patients, with a hazard ratio of 1.5. Similar significant differences were observed when BRCA-mutant patients were compared with patients harboring non-BRCA HRR mutations. Overall, poor outcomes were independent of treatment of ARPI or taxanes. Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data reinforce homologous recombination repair mutations as both a predictive and prognostic biomarker, not only in the mCRPC, but also in the metastatic hormone-sensitive setting as well. It also makes a strong case for incorporating genomic testing early in the disease course and not waiting until our patients have castration-resistant disease. Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. And I think this really brings home the point and the lead up to the AMPLITUDE trial, which is LBA5006, a phase 3 trial that builds on this very concept of testing with a PARP inhibitor, niraparib, in the hormone-sensitive space. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the AMPLITUDE trial, a phase 3 trial presented by Dr. Gerhardt Attard, enrolled 696 patients with metastatic hormone-sensitive prostate cancer and HRR gene alterations. 56% of these patients had BRCA1 and BRCA2 mutations. Patients were randomized to receive abiraterone with or without niraparib, a PARP inhibitor. The majority of patients, 78% of these patients, had high-volume metastatic hormone-sensitive prostate cancer, and 87% of these patients had de novo metastatic HSPC. And 16% of these patients received prior docetaxel, which was allowed in the clinical trial. So, with a median follow-up of nearly 31 months, radiographic progression-free survival was significantly prolonged with the niraparib plus abiraterone combination, and median was not reached in this arm, compared to abiraterone alone, which was 29.5 months, with a hazard ratio of 0.63, translating to a 37% reduction in risk of progression or death. This benefit was even more pronounced in the BRCA1 and BRCA2 subgroup, with a 48% reduction in risk of progression, with a hazard ratio of 0.52. Time to symptomatic progression also improved significantly across all patients, including patients with BRCA1, BRCA2, and HRR mutations. Although overall survival data remain immature, early trends favored the niraparib plus abiraterone combination. The safety profile was consistent with prior PARP inhibitor studies, with grade 3 or higher anemia and hypertension were more common but manageable. Treatment discontinuation due to adverse events remained low at 11%, suggesting that timely dose modifications when our patients experience grade 3 side effects may allow our patients to continue treatment without discontinuation. These findings support niraparib plus abiraterone as a potential new standard of care in our patients with metastatic hormone-sensitive prostate cancer with HRR alterations, and especially in those who had BRCA1 and BRCA2 mutations. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. This trial is especially exciting because it brings PARP inhibitors earlier into the treatment paradigm. Dr. Neeraj Agarwal: Exactly. And it is exciting to see the effect of PARP inhibitors in the earlier setting.  So Jeanny, now let's switch gears a bit to bladder cancer, which also saw several impactful studies. Could you tell us about Abstract 4502, an exploratory analysis from the EV-302 trial, which led to approval of enfortumab vedotin plus pembrolizumab for our patients with newly diagnosed metastatic bladder cancer? So here, the authors looked at the outcomes in patients who achieved a confirmed complete response with EV plus pembrolizumab. Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, EV-302 demonstrated significant improvements in progression-free and overall survival for patients previously treated locally advanced or metastatic urothelial cancer, I'll just call it metastatic UC, as a frontline strategy, establishing EV, which is enfortumab vedotin, plus pembro, with pembrolizumab as standard of care in this setting.  So, this year at ASCO, Dr Shilpa Gupta presented this exploratory responder analysis from the phase 3 EV-302 trial. Among 886 randomized patients, about 30.4% of patients, this is about 133, in the EV+P arm, and 14.5% of the patients in the chemotherapy arm, achieved a confirmed complete response. They call it the CCR rates. So for patients who achieved this, median PFS was not reached with EV+P compared to 26.9 months with chemotherapy, with a hazard ratio of 0.36, translating to a 64% reduction in the risk of progression. Overall survival was also improved. So the median OS was not reached in either arm, but the hazard ratio favored the EV+P at 0.37, translating to a 63% reduction in the risk of death. The median duration of complete response was not reached with EV+P compared to 15.2 months with chemotherapy. And among those patients who had confirmed CRs at 24 months, 78% of patients with the EV+P arm remained progression-free, and around 95% of the patients were alive, compared to 54% of patients who were progression-free and 86% alive of the patients in the chemotherapy arm. Safety among responders were also consistent with prior reports. Grade 3 or higher treatment-related adverse events occurred in 62% of EV+P responders and 72% of chemotherapy responders. Most adverse events were managed with dose modifications, and importantly, no treatment-related deaths were reported among those who were able to achieve complete response.  So these findings further reinforce EV and pembro as the preferred first-line therapy for metastatic urothelial carcinoma, offering a higher likelihood of deep, durable responses with a fairly manageable safety profile. Dr. Neeraj Agarwal: Thank you for the great summary, Jeanny. These findings underscore the depth and durability of responses achievable with this combination and also suggest that achieving a response may be a surrogate for long-term benefit in patients with metastatic urothelial carcinoma.  So now, let's move to Abstract 4503, an exploratory ctDNA analysis from the NIAGARA trial, which evaluated perioperative durvalumab, an immune checkpoint inhibitor, in muscle-invasive bladder cancer. So what can you tell us about this abstract? Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, in NIAGARA, presented by Dr. Tom Powles, the addition of perioperative durvalumab to neoadjuvant chemotherapy, gem/cis, significantly improved event-free survival, overall survival, and pathologic complete response in patients with cisplatin-eligible muscle-invasive bladder cancer. Recall that this led to the U.S. FDA approval of this treatment regimen on March 28, 2025.  So, a planned exploratory analysis evaluated the ctDNA dynamics and their association with clinical outcomes, which was the one presented recently at ASCO. So, the study found that the incidence of finding ctDNA positivity in these patients was about 57%. Following neoadjuvant treatment, this dropped to about 22%, with ctDNA clearance being more common in the durvalumab arm, about 41%, compared to the chemotherapy control arm of 31%. Notably, 97% of patients who remained ctDNA positive prior to surgery failed to achieve a pathologic CR. So, this indicates a strong association between ctDNA persistence and lack of tumor eradication. So, postoperatively, only about 9% of patients were ctDNA positive. So, importantly, durvalumab conferred an event-free survival benefit regardless of ctDNA status at both baseline and post-surgery. Among patients who were ctDNA positive at baseline, durvalumab led to a hazard ratio of 0.73 for EFS. So, this translates to a 27% reduction in the risk of disease recurrence, progression, or death compared to the control arm. In the post-surgical ctDNA-positive group, the disease-free survival was also improved with a hazard ratio of 0.49, translating to a 51% reduction in the risk of recurrence.  So, these findings underscore the prognostic value of ctDNA and suggest that durvalumab provides clinical benefit irrespective of molecular residual disease status. So, the data also supports that ctDNA is a promising biomarker for future personalized strategies in the perioperative treatment of muscle-invasive bladder cancer. Dr. Neeraj Agarwal: Thank you, Jeanny. It is great to see that durvalumab is improving outcomes in these patients regardless of ctDNA status. However, based on these data, presence of ctDNA in our patients warrants a closer follow-up with imaging studies, because these patients with positive ctDNA seem to have a higher risk of recurrence. Dr. Jeanny Aragon-Ching: I agree, Neeraj.  Let's round out the bladder cancer discussion with Abstract 4518, which reported the interim results of SURE-02, which is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab in cisplatin-ineligible muscle-invasive bladder cancer. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure, Jeanny. So, Dr Andrea Necchi presented interim results from the SURE-02 trial. This is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab, followed by a response-adapted bladder-sparing treatment and adjuvant pembrolizumab in patients with muscle-invasive bladder cancer.  So, in this interim analysis, 40 patients were treated and 31 patients were evaluable for efficacy. So, the clinical complete response rate was 38.7%. All patients achieving clinical complete response underwent bladder-sparing approach with a repeat TURBT instead of radical cystectomy. Additionally, 51.6% of patients achieved excellent pathologic response with a T stage of 1 or less after neoadjuvant therapy. The treatment was well tolerated, with only 12.9% of patients experiencing grade 3 or higher adverse events without needing dose reduction of sacituzumab. Molecular profiling, interestingly, showed that clinical complete response correlated with luminal and genomically unstable subtypes, while high stromal gene expression was associated with lack of response.  These results suggest that sacituzumab plus pembrolizumab combination has promising activity in this setting, and tolerability, and along with other factors may potentially allow a bladder preservation approach in a substantial number of patients down the line. Dr. Jeanny Aragon-Ching: Yeah, agree with you, Neeraj. And the findings are very provocative and support completing the full trial enrollment and further exploration of this strategy in muscle-invasive bladder cancer in order to improve and provide further bladder-sparing strategies. Dr. Neeraj Agarwal: Agree. So, let's now turn to the kidney cancer, starting with Abstract 4505, the final overall analysis from CheckMate-214 trial, which evaluated nivolumab plus ipilimumab, so dual checkpoint inhibition strategy, versus sunitinib in our patients with metastatic clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So, the final 9-year analysis of the phase 3 CheckMate-214 trial confirms the long-term superiority of nivolumab and ipilimumab over sunitinib for first-line treatment of advanced metastatic renal cell carcinoma. So, this has a median follow-up of 9 years. Overall survival remains significantly improved with the combination. So, in the ITT patient population, the intention-to-treat, the hazard ratio for overall survival was 0.71. So, this translates to a 29% reduction in the risk of death. 31% of patients were alive at this 108-month follow-up compared to 20% only in those who got sunitinib. So, similar benefits were observed in the intermediate- and poor-risk groups with a hazard ratio of 0.69, and 30% versus 19% survival at 108 months.  Importantly, a delayed benefit was also seen in those favorable-risk patients. So, the hazard ratio for overall survival improved from 1.45 in the initial report and now at 0.8 at 9 years follow-up, with 35% of patients alive at 108 months compared to 22% in those who got sunitinib. Progression-free survival also favored the nivo-ipi arm across all risk groups. At 96 months, the probability of remaining progression-free was about 23% compared to 9% in the sunitinib arm in the ITT patient population, 25% versus 9% in the intermediate- and poor-risk patients, and 13% compared to 11% in the favorable-risk patients. Importantly, at 96 months, 48% of patients in the nivo-ipi responders remained in response compared to just 19% in those who got sunitinib. And in the favorable-risk group, 36% of patients who responded remained in response, although data were not available for sunitinib in this subgroup.  So, this data reinforces the use of nivolumab and ipilimumab as a durable and effective first-line effective strategy for standard of care across all risk groups for advanced renal cell carcinoma. Dr. Neeraj Agarwal: Thank you, Jeanny. And of course, since ipi-nivo data were presented, several other novel ICI-TKI combinations have emerged. And I'm really hoping to see very similar data with TKI-ICI combinations down the line. It is really important to note that we are not seeing any new safety signals with the ICI combinations or ICI-based therapies, which is very reassuring given the extended exposure. Dr. Jeanny Aragon-Ching: Absolutely agree with you there, Neeraj.  Now, going on and moving on to Abstract 4514, which is the KEYNOTE-564 trial, and they reported on the 5-year outcomes of adjuvant pembrolizumab in clear cell RCC in patients who are at high risk for recurrence. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the KEYNOTE-564 trial established pembrolizumab monotherapy as the first adjuvant regimen to significantly improve both disease-free survival and overall survival compared to placebo after surgery for patients with clear cell renal cell carcinoma. So, Dr Naomi Haas presented the 5-year update from this landmark trial.  A total of 994 patients were randomized to receive either pembrolizumab or placebo. The median follow-up at the time of this analysis was approximately 70 months. Disease-free survival remained significantly improved with pembrolizumab. The median DFS was not reached with pembrolizumab compared to 68.3 months with placebo, with a hazard ratio of 0.71, translating to a 29% reduction in risk of recurrence. At 5 years, 60.9% of patients receiving pembrolizumab remained disease-free compared to 52.2% with placebo. Overall survival also favored pembrolizumab. The hazard ratio for OS was 0.66, translating to a 34% reduction in risk of death, with an estimated 5-year overall survival rate of 87.7% with pembrolizumab compared to 82.3% for placebo. Importantly, these benefits were consistent across all key subgroups, including patients with sarcomatoid features. In addition, no new serious treatment-related adverse events have been reported in the 3 years since treatment completion.  So, these long-term data confirm pembrolizumab as a durable and effective standard adjuvant therapy for patients with resected, high-risk clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Thank you for that wonderful summary, Neeraj. Dr. Neeraj Agarwal: That wraps up our kidney cancer highlights. Any closing thoughts, Jeanny, before we conclude? Dr. Jeanny Aragon-Ching: It's been so wonderful reviewing these abstracts with you, Neeraj. So, the 2025 ASCO Annual Meeting showcased a lot of transformative data across GU cancers, from first-in-class bispecifics to long-term survival in RCC. And these findings are already shaping our clinical practices. Dr. Neeraj Agarwal: I agree. And we have covered a broad spectrum of innovations in GU cancers with strong clinical relevance.  So, thank you, Jeanny, for joining me today and sharing your insights.  And thank you to our listeners for joining us. You will find links to the abstracts discussed today in the transcript of this episode. If you find these conversations valuable, please take a moment to rate, review, and subscribe to the ASCO Daily News Podcast wherever you listen. Thank you so much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:    Dr. Neeraj Agarwal     @neerajaiims     Dr. Jeanny Aragon-Ching   Follow ASCO on social media:       @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn       Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono   Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,    Speakers’ Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics
    --------  
    29:46
  • What Lung Cancer Abstracts Stood Out at ASCO25?
    Dr. Vamsi Velcheti and Dr. Nate Pennell discuss novel treatment approaches in small cell and non-small cell lung cancer that were featured at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host of the ASCO Daily News Podcast. I'm a professor of medicine and chief of hematology and oncology at the Mayo Clinic in Jacksonville, Florida. The 2025 ASCO Annual Meeting featured some exciting advancements in small cell lung cancer, targeted therapies for non-small cell lung cancer, and other novel [treatment] approaches. Today, I'm delighted to be joined by Dr. Nate Pennell to discuss some of the key abstracts that are advancing the lung cancer field. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and also the vice chair of clinical research at the Taussig Cancer Institute. Our full disclosures are available in the transcript of this episode. Nate, it's great to have you back on the podcast. Thanks so much for being here. Dr. Nate Pennell: Thanks, Vamsi. Always a pleasure. Dr. Vamsi Velcheti: Let's get started, and I think the first abstract that really caught my attention was Abstract 8516, “The Randomized Trial of Relevance of Time of Day of Immunotherapy for Progression-Free and Overall Survival in Patients With Non-Small Cell Lung Cancer.” What are your thoughts about this, Nate? Dr. Nate Pennell: I agree. I thought this was one of the most discussed abstracts, certainly in the lung cancer session, but I think even outside of lung cancer, it got some discussion. So, just to put this in perspective, there have been a number of publications that have all been remarkably consistent, and not just in lung cancer but across multiple cancer types, that immunotherapy, immune checkpoint inhibitors, are commonly used. And all of them have suggested, when looking at retrospective cohorts, that patients who receive immune checkpoint inhibitors earlier in the day – so in the morning or before the early afternoon – for whatever reason, appear to have better outcomes than those who get it later in the day, and this has been repeated. And I think many people just sort of assumed that this was some sort of strange association and that there was something fundamentally different from a prognostic standpoint in people who came in in the morning to get their treatment versus those who came later in the afternoon, and that was probably the explanation. The authors of this randomized trial actually decided to test this concept. And so, about 210 patients with previously untreated advanced non-small cell lung cancer were randomly assigned to get chemo and immune checkpoint inhibitor – either pembrolizumab or sintilimab – and half of them were randomly assigned to get the treatment before 3 PM in the afternoon, and half of them were assigned to get it after 3 PM in the afternoon. And it almost completely recapitulated what was seen in the retrospective cohorts. So, the median progression-free survival in those who got earlier treatment was 13.2 months versus only 6.5 months in those who got it later in the day. So, really enormous difference with a hazard ratio of 0.43, which was statistically significant. And perhaps even more striking, the median overall survival was not reached in the early group versus 17.8 months in the late group with a hazard ratio of 0.43, also highly statistically significant. Even the response rate was 20% higher in the early patients; 75% response rate compared to 56% in the late-time-of-day patients. So very consistent across all measures of efficacy with pretty good matched characteristics across the different groups. And so, I have to tell you, I don't know what to make of this. I certainly was a skeptic about the retrospective series, but now we have a prospective randomized trial that shows essentially the same thing. So, maybe there is a difference between getting treated in the morning, although I have yet to hear someone give a very good mechanistic explanation as to why this would be. What were your thoughts on this? Dr. Vamsi Velcheti: It's indeed fascinating, Nate, and I actually think this was a very interesting abstract. Really, I was caught off guard looking at the data. I mean, if it were a drug, we would be so excited, right? I mean, with those kind of survival benefits. I don't know. I think circadian rhythm probably has something to do with it, like different cytokine profiles at the time of administration. I mean, who knows? But I think it's a randomized trial, and I think I would expect to see a mad rush for treatment appointments early in the morning given this, and at least I want my patients to come in first thing in the morning. It'll be interesting to see. Dr. Nate Pennell: It’s important to point out that in this study, everyone got chemo and immunotherapy. And, at least in our cancer center, most patients who are getting platinum-doublet chemotherapy and immunotherapy actually do get treated earlier in the day already, just because of the length of the infusion appointment that's needed. So it really is oftentimes people getting single-agent immunotherapy who are often getting the later, shorter visits. But if you have a choice, I think it would be very reasonable to have people treated earlier in the day. And I do think most of the impressions that I got from people about this is that they would like to see it reproduced but certainly well worth further investigation. And I personally would like to see more investigation into what the rationale would be for this because I still can't quite figure out, yes, if you got it at, say, you know, 5 PM, that's later in the day and I can understand that maybe your immune system is somewhat less receptive at that point than it would be in the morning. But because these checkpoint inhibitors have such long half-lives, it's still in your system the next morning when your immune system is supposedly more receptive. So I don't quite understand why that would be the case. Well, let's move on to the next study. I would like to hear your thoughts on Abstract 8515, “Plasma-Guided, Adaptive First-Line Chemoimmunotherapy for Non-Small Cell Lung Cancer.” Dr. Vamsi Velcheti: Yeah, this was another abstract that seems to be really interesting in my opinion. I think there's kind of a lot of emphasis lately on ctDNA and MRD-based assays to monitor disease. In the lung cancer space, we haven't had a lot of clinical trials looking at this prospectively, and this was one of those pilot studies where they looked at circulating free DNA (cfDNA)-based response-adaptive strategy for frontline patients who are PD-L1 positive. So, patients started with pembrolizumab monotherapy, and based on plasma molecular response after 2 cycles, those patients without response received early treatment intensification with a platinum doublet. So the approach essentially was to reduce the chemotherapy exposure in patients who respond to immunotherapy. And only about 17.5% of the patients on the trial received chemotherapy based on lack of molecular response. So, in this trial, what they found was patients with the cfDNA response had a markedly improved PFS of 16.4 months versus 4.8 months. So essentially, like, this is a really nice study to set a foundation on which we have to do larger studies to incorporate molecular markers trying to look at cfDNA response to inform treatment strategy, either escalation or de-escalation strategies. So, I thought it was a very interesting study. Dr. Nate Pennell: Yeah. I mean, we always have this question for patients, “Should they get immunotherapy alone or combined with chemo?” and I think this certainly is intriguing, suggesting that there may be ways you can monitor people and perhaps rescue those that aren't going to respond to single agent. I'd like to see a randomized trial against, you know, this strategy, perhaps against everyone getting, say, chemoimmunotherapy or make sure that you're not potentially harming people by doing this strategy. But I agree, it's time to move beyond just observing that cell-free DNA is prognostic and important and start using it to actually guide treatment. Dr. Vamsi Velcheti: Yeah, and I would just caution though, like, you know, I think we need more data, but, however, it's certainly a very interesting piece of data to kind of help inform future trials. So, there was another abstract that caught my attention, and I think this would be a very interesting abstract in the EGFR space. Abstract 8506, "Patritumab Deruxtecan (HER3-DXd) in Resistant EGFR-Mutant Advanced Non-Small Cell Lung Cancer Patients After Third-Generation EGFR TKI," it’s the HERTHENA-Lung02 study. What do you think about the results of this study? Dr. Nate Pennell: Yeah, this was, I would say, very widely anticipated and ultimately a little disappointing, despite being a positive trial. So, these are patients with EGFR-mutant non-small cell lung cancer who have progressed after a third-generation EGFR TKI like osimertinib. This is really an area of major unmet need. We do have drugs like amivantamab in this space, but still definitely an area where essentially patients move from having a highly effective oral therapy to being in the realm of chemotherapy as their best option. So, this HER3 antibody-drug conjugate, patritumab deruxtecan, had some good single-arm data for this. And we're sort of hoping this would become an available option for patients. This trial was designed against platinum-doublet chemotherapy in this setting and with a primary endpoint of progression-free survival. And it actually was positive for improved progression-free survival compared to chemo with a hazard ratio of 0.77. But when you look at the medians, you can see that the median PFS was only 5.8 versus 5.4 months. It was really a modest difference between the two arms. And on the interim analysis, it appeared that there will not be a difference in overall survival between the two arms. In fact, the hazard ratio at the interim analysis was 0.98 for the two arms. So based on this, unfortunately, the company that developed the HER3-DXd has withdrawn their application to the FDA for approval of the drug, anticipating that they probably wouldn't get past approval without that overall survival endpoint. So, unfortunately, probably not, at least for the near future, going to be a new option for these patients. Dr. Vamsi Velcheti: Yeah, I think this is a space that's clearly an unmet need, and this was a big disappointment, I should say. I think all of us were going into the meeting anticipating some change in the standard of care here. Dr. Nate Pennell: Yeah, I agree. It was something that I was telling patients, honestly, that I was expecting this to be coming, and so now, definitely a bit of a disappointment. But it happens and, hopefully, it will still find perhaps a role or other drugs with a similar target. Certainly an active area. Well, let's leave the EGFR-mutant space and move into small cell. There were a couple of very impactful studies. And one of them was Abstract 8006, “Lurbinectedin Plus Atezolizumab as First-Line Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer, Primary Results from the Phase III IMforte Trial.” So, what was your impression of this? Dr. Vamsi Velcheti: Yeah, I think this is definitely an interesting study, and small cell, I remember those days when we had barely any studies of small cell at ASCO, and now we have a lot of exciting developments in the small cell space. It's really good to see. The IMforte trial is essentially like a maintenance lurbinectedin trial with atezolizumab maintenance. And the study was a positive trial. The primary endpoint was a PFS, and the study showed improvement in both PFS and OS with the addition of lurbinectedin to atezolizumab maintenance. And definitely, it's a positive trial, met its primary endpoint, but I always am a little skeptical of adding maintenance cytotoxic therapies here in this setting. In my practice, and I'd like to hear your opinion, Nate, most patients with small cell after 4 cycles of a platinum doublet, they're kind of really beaten up. Adding more cytotoxic therapy in the maintenance space is going to be tough, I think, for a lot of patients. But also, most importantly, I think this rapidly evolving landscape for patients with small cell lung cancer with multiple new, exciting agents, actually like some FDA-approved like tarlatamab, also like a lot of these emerging therapeutics like I-DXd and other ADCs in this space. You kind of wonder, is it really optimal strategy to bring on like another cytotoxic agent right after induction chemotherapy, or do you kind of delay that? Or maybe have like a different strategy in terms of maintenance. I know that the tarlatamab maintenance trial is probably going to read out at some point too. I think it's a little challenging. The hazard ratio is also 0.73. As I said, it's a positive trial, but it's just incremental benefit of adding lurbi. And also on the trial, we need to also pay attention to the post-progression second-line treatments, number of patients who received tarlatamab or any other investigational agents.  So I think it's a lot of questions still. I'm not quite sure I'd be able to embrace this completely. I think a vast majority of my patients might not be eligible anyway for cytotoxic chemotherapy maintenance right away, but yeah, it's tough. Dr. Nate Pennell: Yeah. I would call this a single and not a home run. It definitely is real. It was a real overall survival benefit. Certainly not surprising that a maintenance therapy would improve progression-free survival. We've known that for a long time in small cell, but first to really show an overall survival benefit. But I completely agree with you. I mean, many people are not going to want to continue further cytotoxics after 4 cycles of platinum-doublet chemo. So I would say, for those that are young and healthy and fly through chemo without a lot of toxicity, I think certainly something worth mentioning. The problem with small cell, of course, is that so many people get sick so quickly while on that observation period after first-line chemo that they don't make it to second-line treatment. And so, giving everyone maintenance therapy essentially ensures everyone gets that second-line treatment. But they also lose that potentially precious few months where they feel good and normal and are able to be off of treatment. So, I would say this is something where we're really going to have to kind of sit and have that shared decision-making visit with patients and decide what's meaningful to them. Dr. Vamsi Velcheti: Yeah, I agree. The next abstract that was a Late-Breaking Abstract, 8000, “Overall Survival of Neoadjuvant Nivolumab Plus Chemotherapy in Patients With Resectable Non-Small Cell Lung Cancer in CheckMate-816.” This was a highly anticipated read-out of the OS data from 816. What did you make of this abstract? Dr. Nate Pennell: Yeah, I thought this was great. Of course, CheckMate-816 changed practice a number of years ago when it first reported out. So, this was the first of the neoadjuvant or perioperative chemoimmunotherapy studies in resectable non-small cell lung cancer. So, just to review, this was a phase 3 study for patients with what we would now consider stage II or stage IIIA resectable non-small cell lung cancer. And they received three cycles of either chemotherapy or chemotherapy plus nivolumab, and that was it. That was the whole treatment. No adjuvant treatment was given afterwards. They went to resection. And patients who received the chemoimmunotherapy had a much higher pathologic complete response rate and a much better event-free survival. And based on this, this regimen was approved and, I think, at least in the United States, widely adopted.  Now, since the first presentation of CheckMate 816, there have been a number of perioperative studies that have included an adjuvant component of immunotherapy – KEYNOTE-671, the AEGEAN study – and these also have shown improved outcomes. The KEYNOTE study with pembrolizumab also with an overall survival benefit. And I think people forgot a little bit about CheckMate-816. So, this was the 5-year overall survival final analysis. And it did show a statistically and, I think, clinically meaningful difference in overall survival with the 3 cycles of neoadjuvant chemo-nivo compared to chemo with a hazard ratio of 0.72. The 5-year overall survival of 65% in the chemo-IO group versus 55% with the chemo alone. So a meaningful improvement. And interestingly, that hazard ratio of 0.72 is very similar to what was seen in the peri-operative pembro study that included the adjuvant component. So, very much still relevant for people who think that perhaps the value of those neoadjuvant treatments might be really where most of the impact comes from this type of approach. They also gave us an update on those with pathologic complete response, showing really astronomically good outcomes. If you have a pathologic complete response, which was more than a quarter of patients, the long-term survival was just phenomenal. I mean, 95% alive at 5 years if they were in that group and suggesting that in those patients at least, the adjuvant treatment may not be all that important.  So, I think this was an exciting update and still leaves very much the open question about the importance of continuing immunotherapy after surgery after the neoadjuvant component. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think the million-dollar question is: “Is there like a population of patients who don't have complete response but like maybe close to complete response?” So, would you like still consider stopping adjuvant IO? I probably would not be comfortable, but I think sometimes, you know, we all have patients who are like very apprehensive of continuing treatments. So, I think that we really need more studies, especially for those patients who don't achieve a complete CR. I think trying to find strategies for like de-escalation based on MRD or other risk factors. But we need more trials in that space to inform not just de-escalation, but there are some patients who don't respond at all to a neoadjuvant IO. So, there may be an opportunity for escalating adjuvant therapies. So, it is an interesting space to watch out for. Dr. Nate Pennell: No, absolutely. Moving to KRAS-mutant space, so our very common situation in patients with non-small cell lung cancer, we had the results of Abstract 8500, “First-Line Adagrasib With Pembrolizumab in Patients With Advanced or Metastatic KRASG12C-Mutated Non-Small Cell Lung Cancer” from the phase 2 portion of the KRYSTAL-7 study. Why was this an interesting and important study? Dr. Vamsi Velcheti: First of all, there were attempts to kind of combine KRASG12C inhibitors in the past with immune checkpoint inhibitors, notably sotorasib with pembrolizumab. Unfortunately, those trials have led to like a lot of toxicity, with increased especially liver toxicity, which was a major issue. This is a phase 2 study of adagrasib in combination with pembrolizumab, and this is a study in the frontline setting in patients with the G12C-mutant metastatic non-small cell lung cancer. And across all the PD-L1 groups, the ORR was 44%, and the median PFS was 11 months, comparable to the previous data that we have seen with adagrasib in this setting. So it's not like a major improvement in clinical efficacy. However, I think the toxicity profile that we were seeing was slightly better than the previous trials in combination with sotorasib, but you still have a fair amount of transaminitis even in the study. At this point, this is not ready for clinical primetime. I don't think we should be using sotorasib or adagrasib in the frontline or even in the second line in combination with checkpoint inhibitors. Combining these drugs with checkpoint inhibitors in the clinical practice might lead to adverse outcomes. So, we need to wait for more data like newer-generation G12C inhibitors which are also being studied in combination, so we'll have to kind of wait for more data to emerge in this space. Dr. Nate Pennell: I agree, this is not immediately practice changing. This is really an attempt to try to combine targeted treatment with immune checkpoint inhibitor. And I agree with you that, you know, it does appear to be perhaps a little bit better tolerated than some of the prior combinations that have tried in this space. The outcomes overall were not that impressive, although in the PD-L1 greater than 50%, it did have a better response rate perhaps than you would expect with either drug alone. And I do think that the company is focusing on that population for a future randomized trial, which certainly would inform this question better. But in the meantime, I agree with you, there's a lot of newer drugs that are coming along that potentially may be more active and better tolerated. And so, I'd say for now, interesting but we'll wait and see. Dr. Vamsi Velcheti: Yeah, so now moving back again to small cell. So, there was a Late-Breaking Abstract, 8008. This is a study of tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer. They presented the primary analysis of the phase III DeLLphi-304 study. What do you think about this? Dr. Nate Pennell: Yeah, I thought this was really exciting. This was, I would say, perhaps the most important lung study that was presented. Tarlatamab is, of course, the anti-DLL3 bispecific T-cell engager compound, which is already FDA approved based on a prior single-arm phase II study, which showed a very nice response rate as a single agent in previously treated small cell lung cancer and relatively manageable side effects, although somewhat unique to solid tumor docs in the use of these bispecific drugs in things like cytokine release syndrome and ICANS, the neurologic toxicities. So, this trial was important because tarlatamab was approved, but there were also other chemotherapy drugs approved in the previously treated space. And so, this was a head-to-head second-line competition comparison between tarlatamab and either topotecan, lurbinectedin, or amrubicin in previously treated small cell patients with a primary endpoint of overall survival. So, a very well-designed trial. And it did show, I think, a very impressive improvement in overall survival with a median overall survival in the tarlatamab group of 13.6 months compared to 8.3 months with chemotherapy, hazard ratio of 0.6. And progression-free survival was also longer at 4.2 months versus 3.2 months, hazard ratio of 0.72. In addition to showing improvements in cancer-related symptoms that were improved in tarlatamab compared to chemotherapy, there was actually also significantly lower rates of serious treatment-related adverse events with tarlatamab compared to chemotherapy. So, you do still see the cytokine release syndrome, which is seen in most people but is manageable because these patients are admitted to the hospital for the first two cycles, as well as a significant number of patients with neurologic side effects, the so-called ICANS, which also can be treated with steroids. And so, I think based upon the very significant improvement in outcomes, I would expect that this should become our kind of standard second-line treatment since it seems to be much better than chemo. However, tarlatamab is definitely a new drug that a lot of places are not used to using, and I think a lot of cancer centers, especially ones that aren't tied to a hospital, may have questions about how to deal with the CRS. So, I'm curious your thoughts on that. Dr. Vamsi Velcheti: Yeah, thank you, Nate. And I completely agree. I think the data looked really promising, and I've already been using tarlatamab in the second-line space. The durability of response and overall, having used tarlatamab quite a bit - like, I participated in some of the early trials and also used it as standard of care - tarlatamab has unique challenges in terms of like need for hospitalization for monitoring for the first few treatments and make sure, you know, we monitor those patients for CRS and ICANS. But once you get past that initial administration and monitoring of CRS, these patients have a much better quality of life, they're off chemotherapy, and I think it's really about the logistics of actually administering tarlatamab and coordination with the hospital and administration in the outpatient setting. It's definitely challenging, but I think it definitely can be done and should be done given what we are seeing in terms of clinical efficacy here. Dr. Nate Pennell: I agree. I think hospital systems now are just going to have to find a way to be able to get this on formulary and use it because it clearly seems to be more effective and generally better tolerated by patients. So, should move forward, I think. Finally, there's an abstract I wanted to ask you about, Abstract 8001, which is the “Neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone in resectable epidermal growth factor receptor-mutated non-small cell lung cancer: The NeoADAURA Study”. And this is one that I think was also fairly highly anticipated. So, what are your thoughts? Dr. Vamsi Velcheti: You know, I wasn't probably surprised with the results, and I believe we were all expecting a positive trial, and we certainly were handed a positive trial here. It's a phase III trial of osimertinib and chemotherapy or osimertinib in the neoadjuvant space followed by surgery, followed by osimertinib. It's a global phase 3 trial and very well conducted, and patients with stage II to stage IIIB were enrolled in the study. And in the trial, patients who had a neoadjuvant osimertinib with or without chemotherapy showed a significant improvement in major pathologic response rates over chemotherapy alone. And the EFS was also positive for osimertinib and chemotherapy, osimertinib monotherapy as well compared to chemotherapy alone. So overall, the study met its primary endpoint, and I think it sheds light on how we manage our patients with early-stage lung cancer. I think osimertinib, we know that osimertinib is already FDA approved in the adjuvant space, but what we didn't really know is how was osimertinib going to work in the neoadjuvant space. And there are always situations, especially for stage III patients, where we are on the fence about, are these patients already close to being metastatic? They have, like, almost all these patients have micrometastatic disease, even if they have stage III. As we saw in the LAURA data, when you look at the control arm, it was like a very short PFS. Chemoradiation does nothing for those patients, and I think these patients have systemic mets, either gross or micrometastatic disease at onset. So, it's really important to incorporate osimertinib early in the treatment course. And I think, especially for the locally advanced patients, I think it's even more important to kind of incorporate osimertinib in the neoadjuvant space and get effective local control with surgery and treat them with adjuvant. I'm curious to hear your thoughts, Nate. Dr. Nate Pennell: I am a believer and have long been a believer in targeted adjuvant treatments, and, you know, it has always bothered me somewhat that we're using our far and away most effective systemic therapy; we wait until after they go through all their pre-op treatments, they go through surgery, then they go through chemotherapy, and then finally months later, they get their osimertinib, and it still clearly improves survival in the adjuvant setting. Why not just start the osimertinib as soon as you know that the patient has EGFR-mutant non-small cell lung cancer, and then you can move on to surgery and adjuvant treatment afterwards? And I think what was remarkable about this study is that all of these patients almost - 90% in each arm - went to surgery. So, you weren't harming them with the neoadjuvant treatment. And clearly better major pathologic response, nodal downstaging, event-free survival was better. But I don't know that this trial is ever going to show an overall survival difference between neoadjuvant versus just surgery and adjuvant treatment, given how effective the drug is in the adjuvant setting. Nonetheless, I think the data is compelling enough to consider this, certainly for our N2-positive, stage IIIA patients or a IIIB who might be otherwise surgical candidates. I think based on this, I would certainly consider that. Dr. Vamsi Velcheti: Yeah, and especially for EGFR, like even for stage IIIB patients, in the light of the LAURA study, those patients who do not do too well with chemoradiation. So you're kind of delaying effective systemic therapy, as you said, waiting for the chemoradiation to finish. So I think probably time to revisit how we kind of manage these locally advanced EGFR patients. Dr. Nate Pennell: Yep, I agree. Dr. Vamsi Velcheti: Nate, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been an exciting ASCO again. You know, we've seen a lot of positive trials impacting our care of non-small cell lung cancer and small cell lung cancer patients. Dr. Nate Pennell: Thanks for inviting me, Vamsi. Always a pleasure to discuss these with you. Dr. Vamsi Velcheti: And thanks to our listeners for your time today. You will find links to all of the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today’s speakers:    Dr. Vamsi Velcheti   @VamsiVelcheti    Dr. Nathan Pennell   @n8pennell   Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn   ASCO on BlueSky   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 
    --------  
    29:49

Mais podcasts de Saúde e fitness

Sobre ASCO Daily News

The ASCO Daily News Podcast features oncologists discussing the latest research and therapies in their areas of expertise.
Site de podcast

Ouça ASCO Daily News, Huberman Lab e muitos outros podcasts de todo o mundo com o aplicativo o radio.net

Obtenha o aplicativo gratuito radio.net

  • Guardar rádios e podcasts favoritos
  • Transmissão via Wi-Fi ou Bluetooth
  • Carplay & Android Audo compatìvel
  • E ainda mais funções

ASCO Daily News: Podcast do grupo

Aplicações
Social
v7.22.0 | © 2007-2025 radio.de GmbH
Generated: 8/2/2025 - 6:58:48 AM