ASCO Daily News

Dr. Monty Pal and Dr. Vamsi Velcheti discuss the evolving treatment landscape in EGFR-mutated non-small cell lung cancer, including landmark trials like FLAURA2, novel drug therapies, and the growing importance of ctDNA and MRD testing.
TRANSCRIPT
Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist and professor and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. Today, I'm truly delighted to introduce Dr. Vamsi Velcheti, who's a professor of medicine and the chief of hematology-oncology at the Mayo Clinic in Jacksonville, Florida. We'll be discussing the expanding treatment landscape in EGFR-positive lung cancer and how to navigate the challenges of balancing treatment efficacy, toxicity, and patient quality of life in the EGFR-positive space. 
Just FYI, our full disclosures are available in the transcript of this episode. 
Vamsi, it's so great to have you on the podcast. Thank you so much for being here.
Dr. Vamsi Velcheti: Thank you, Monty. It's a pleasure to be here with you. It's a really exciting topic and there are a lot of updates in the EGFR space.
Dr. Monty Pal: So, I'm going to need your help with this because I'll be honest with you, I see very little lung cancer, if any, in my practice. I'm pretty much exclusively kidney cancer these days. I'm coming on 20 years at City of Hope now, and I still remember when trials like ECOG 1599 were presented with, you know, platinum doublets. And, of course, the field has changed a lot since then.
But tell us a little bit about the first-line landscape, and I think just for the sake of time, we're going to stick with EGFR-positive disease here. What does it look like these days?
Dr. Vamsi Velcheti: Monty, the foundation of care remains the third-generation EGFR inhibitors. These are selective EGFR inhibitors, like osimertinib. We've had an evolution of the development of these TKIs. Like, you know, we had the first-generation, second-generation, not-so-selective EGFR inhibitors. Now we have mutant-selective EGFR inhibitors in the clinic, and they're doing a really good job. And these are quite effective in patients who have classical activating mutations. But the reality is that these have not been transformative. These agents have fundamentally changed the response patterns, excellent CNS penetration, and very good tolerability profile. However, we don't see a lot of durability in terms of the response.
So, what's different today is now there have been several trials in combination with these third-generation EGFR inhibitors that have really laid the foundation of how we kind of think about EGFR-positive disease. At the high level, there are a lot of challenges to selecting the patients for these combination-based modalities. I'm assuming we'll be talking more about these different trials and different approaches. Some of these combination-based strategies have really moved the needle in terms of improving overall survival and really improving long-term outcomes and durability in our patients.
Dr. Monty Pal: And we are going to get into the weeds on this in just a moment. But I did kick off this podcast talking about chemotherapy, ECOG 1599. It does seem as though chemotherapy is still a component of management in advanced non-small cell lung cancer. So, can you tell us about, perhaps first, you mentioned osimertinib, you know, some of these next-generation EGFR inhibitors. Tell us about the role of chemo plus osimertinib.
Dr. Vamsi Velcheti: That's exactly where I was going with the combination-based strategies. You know, we first started off with our earlier trials in the EGFR space evaluating the question of, are targeted therapies, are these highly effective, third-generation, EGFR-selective inhibitors, superior to platinum-doublet chemotherapy? And we've had multiple trials demonstrating that, like the FLAURA trial and in the past with second-generation EGFR inhibitors like erlotinib and gefitinib and afatinib. So, we know that these TKIs actually perform better than platinum-doublet chemotherapy.
Now, we have a large, global, phase 3 trial data from the FLAURA2 trial, which looks at the question, "Hey, you know, osimertinib is better than chemotherapy, platinum-doublet chemotherapy. Can we do even better by combining osimertinib with platinum-doublet chemotherapy?"
So, FLAURA2 answered that question. This is a large, phase 3 trial, and it's a positive trial with improved durability of disease control and improving overall survival with combination with chemotherapy. So, it's a very important and landmark trial, and essentially combining osimertinib with a platinum-based chemotherapy improved responses, deepened responses, and improved overall survival and really changing the disease trajectory. And this strategy is definitely compelling, especially in patients who have certain clinical high-risk features like, you know, patients who have high disease burden or patients who are sometimes having rapid disease progression early on osimertinib, especially with patients who have a lot of visceral disease burden. So, intensifying treatments up front could alter the natural trajectory of the disease.
Dr. Monty Pal: So, you sort of alluded to this in that last part there, but is that kind of how you in clinical practice select? Is it based on, you know, visceral involvement? Is it based on rapidity of disease where you think about adding chemotherapy to osimertinib? Maybe you can give us the corollary. Which patients do you just use osimertinib alone in, for instance?
Dr. Vamsi Velcheti: Definitely, there are some patients who have low disease burden and they have the classical mutations, like an exon 19 deletion. And these patients, especially if they don't have a lot of disease burden, they don't have CNS involvement, there may be a subset of patients who could just do fine on osimertinib of course, with close monitoring of the disease. I guess we'll get into that later, how do we do that with either ctDNA or like closer imaging or both. So, there may be some opportunity to kind of escalate patients' treatments based on certain clinical characteristics or radiographic characteristics or certain biological characteristics informed by ctDNA or other approaches.
Dr. Monty Pal: No, that's interesting. And you're right, we will chat about ctDNA in just a bit. But before we get there, I think one of the big agents that has really sort of come to the fore in advanced non-small cell lung cancer is amivantamab. I've heard a lot about this in the context of even kidney cancer because in certain subsets, I'm interested in MET-directed therapies and so forth, right? So maybe tell us a little bit about the mechanism of amivantamab first, and then maybe tell us about this pivotal MARIPOSA trial where it's combined with lazertinib.
Dr. Vamsi Velcheti: So, the MARIPOSA trial compared lazertinib alone with amivantamab plus lazertinib. And this trial demonstrated overall survival advantage, and there were key differences in terms of tolerability and the safety of amivantamab, which is an EGFR and MET bispecific, and there were certain kind of unique toxicity profiles that make it a little different than the intensification approach with chemotherapy through the FLAURA2 trial.
So, there's a trade-off in terms of the toxicity profile. It's a different agent and a different management protocol in terms of dermatological toxicity management that clinicians need to be comfortable with. And also, there are certain unique issues in terms of amivantamab; there's a higher rate of infusion-related reactions, there's an increased risk for edema and VTEs because of amivantamab. Certainly a different toxicity profile, different management paradigm there in terms of longitudinal care of these patients requiring dermatological care and like, you know, close monitoring and prophylaxis VTEs. But having said that, definitely it's a different strategy, and it kind of changes the biology and the natural history of the cancers, and we do see some durability of responses that we see with the MARIPOSA. So, it's certainly a great alternative, at least for some patients.
Dr. Monty Pal: That was a great overview of MARIPOSA. Now comes the really difficult question, which is, how do you choose between the two? You have these two great options, right, for EGFR-positive patients. You've already highlighted some of the distinctions in terms of toxicity. I think the audience is well aware of the side effects of chemo-doublet, perhaps even the EGFR-based therapies. Amivantamab is quite new. Give us a sense of how you in clinical practice decide between the two potential options here.
Dr. Vamsi Velcheti: Yeah, I think that's the big challenge. I think these are two independent strategies that have evolved through the phase 3, and both of them have demonstrated overall survival benefit. So, the way I think about this is in three dimensions, right? Like, the disease biology, the patient priorities, and feasibility of care delivery.
So, when I talk about the disease biology, you know, the mechanism is very different, and MET is a very dominant driver of disease in EGFR-altered patients and it's a significant mechanism of resistance, acquired resistance to TKIs. So, certainly I think there's a patient population that could benefit from a MET-directed therapy up front. However, we don't have great data to kind of really demonstrate how using amivantamab in the front line is going to change that. And are there like perhaps like some patients who we could identify who would benefit from such a strategy?
Very recently, there have been some approvals in the second-line setting in lung cancer, not in the EGFR space, but like in generally in lung cancer, with the MET ADCs, and those drugs are approved with a companion diagnostic, which requires MET IHC testing. So, what has happened, at least in large academic practices and also I think in the community now, they have been checking for MET IHC expression more routinely in lung cancer. What we have been doing in our institution is we have been doing MET IHC as a reflex for all patients with EGFR, not just EGFR, but all non-small cell lung cancer patients. What that has done is now, like, we have been increasingly testing patients with EGFR for MET. And there's clearly a subset of patients who have de novo MET expression and a high MET expression. And those patients, I've been kind of like preferentially treating them with the MARIPOSA regimen.
But again, I have to caution the audience that we still don't have data that MET IHC is going to help us make those decisions, whether it's better than like a FLAURA2 regimen. But however, in the second-line setting in the CHRYSALIS trial, we know that MET is a very powerful predictor of response to amivantamab. We really need more data there, but that's what I have been doing in my practice. But also, there's a lot of patient preference here. Like, there are some patients who don't want chemotherapy, and they want a non-chemotherapy approach. So, certainly there are some patients who prefer to have amivantamab. And now with the amivantamab, the subcutaneous version, the infusion reactions and the logistics of actual administration of amivantamab are more favorable with the subcutaneous approval. So, those are some of the elements that we need to take into account.
Dr. Monty Pal: Well, I want to hone in on that because this subcutaneous administration route has been a big debate that I've seen on social media. Tell us, how much easier does it actually make the amivantamab experience? Does it cut down on the rash? Is it just infusion reactions? What's been your clinical experience?
Vamsi Velcheti, MD: So, the subcutaneous administration of amivantamab has definitely improved the infusion reaction issue. Very rarely patients have infusion reaction now with the subcutaneous injections. And also, the infusion time is much, much shorter. Like we don't need a lot of infusion time, which is sometimes a challenge in busy infusion clinics. We need to take that into account.
As far as the impact of the subcutaneous formulation on dermatological toxicity, we haven't really seen significant difference in terms of the intensity or rates of dermatological toxicity with subcutaneous. The benefits are really with the infusion reaction, the ease of administration. And interestingly, in the PALOMA trial, it also seems to be, even though this was not the primary endpoint of the study, there seems to be some suggestion that the subcutaneous amivantamab seems to have improved OS compared to the IV amivantamab. We don't really understand why, but that's a finding from the trial that's very intriguing.
Dr. Monty Pal: That is really fascinating. I'm kind of curious to see how that's going to pan out. I'm going to shift gears a little bit here. And, you know, as we sort of close, I wanted to talk a little bit about biomarkers. I mean, this is obviously not a lung cancer-specific issue. It's something we think about across the board. But what I will say is that there are certain commonalities, and in bladder cancer, we think a lot now about ctDNA. But you've been way ahead of the game in lung cancer. Tell us how you guys use ctDNA, maybe both from the standpoint of monitoring for mutational status, but if you can, maybe offer some insights into some of these new MRD tests that are available too.
Dr. Vamsi Velcheti: Yeah, it's rapidly evolving. Certainly, I think in the lung cancer space, you know, this has really kicked off in the lung cancer space with incorporating ctDNA into the workflow. Of course, you know, like baseline evaluation, we still kind of heavily rely on tissue genomic sequencing. But as you know, with targeted therapy, a lot of these patients have disease that evolves over time, and changes in terms of mutational pattern driving acquired resistance is a major issue across different molecular subtypes. And especially so in EGFR, when there are certain actionable opportunities associated with that transformation. So, we need to kind of have like a longitudinal snapshot of how we monitor these patients. So, the ctDNA has come to be like a tool that has now come to the forefront of clinical workflow, and almost all my patients who are having disease progression have ctDNA for kind of evaluating for resistance and informing treatment decisions, especially in EGFR.
But having said that, there are a lot of challenges in terms of using ctDNA as a tool for monitoring. There are a lot of different types of assays and different platforms, and being able to use this as a quantitative tool that would be used along with the CT scans that we routinely use in clinical practice has been a challenge. And I think I would love to hear your perspectives as well, Monty, about how you're thinking about that in bladder and other disease contexts.
But having said that, I think there's a lot of opportunity to incorporate ctDNA and MRD assays into clinical decision-making. Right now, in terms of clinical trials and clinical development, there have been some very interesting trials that are currently ongoing, especially in the EGFR space. We know that patients who clear ctDNA, based on some retrospective data and also like some retrospective-prospective data from trials that have already read out, that patients who clear ctDNA early with target therapy tend to do much better. They have a longer durability of response. There may be a subset of patients who have, even though they're having radiographic response, they have persistent ctDNA after a certain time point of initiation of targeted therapy. Those patients may require escalation of therapy. We don't yet know. I can't recommend that as a standard right now because we don't have clinical evidence to support that. But however, some of the clinical trials, like the ELIOS trial that's being done right now, that's actually completed enrollment, we'll hopefully see the results very soon.
So, there is an emerging thought that instead of intensifying treatment for all patients with EGFR, there may be a population that may be just fine with frontline osimertinib monotherapy and introducing the intensification strategy at the time of emergence of MRD or progression on ctDNA before radiographic progression. So, there are a lot of adaptive molecular response criteria that we are kind of exploring in clinical trials that could inform how the future is going to look like for EGFR and other perhaps targeted therapies as well. So, it's fascinating, and I think there's a lot of opportunity there.
Dr. Monty Pal: You know, you asked for my perspective. I actually think that what you highlighted there is the most interesting opportunity for ctDNA: the ability to de-escalate therapy. In terms of drug development, we've done so much to bring new therapies to patients, and now it's a bit of an embarrassment of riches, but the downside is that I feel like we tend to overtreat a lot of patients in the clinic. So, I definitely view MRD, you know, some of these other ctDNA techniques with methylation and so forth that may not be sort of tumor-dependent or bespoke could be incredibly, incredibly helpful.
You touched on sort of the future, right, in this last section here with biomarkers. But give us a sense now in terms of novel drug therapies in the EGFR space. What are you most excited about moving forward in 2026 and beyond?
Dr. Vamsi Velcheti: Yeah, I think there's a lot going on in this space, and not just this space, but across lung cancer and others as well. Like looking at the next generation of targets for ADCs. And I think a lot of these have to do with…so far in the drug development space, as you know, the improvements in clinical outcomes has been very incremental. So, we really need to make that big leap. And I think the big leap is not going to come from, in my opinion, from the next ADC, but it's going to come from how we tailor treatments and how we monitor disease better and how do we kind of incorporate the next treatment earlier and not wait for the radiographic progression.
So, there's a lot of opportunity there to integrate biomarkers and dynamic biomarkers into clinical trial design and incorporating the recent advances in terms of drug design. You know, we have a lot of assets in the EGFR space, the next-generation EGFR inhibitors that are kind of designed with resistance in mind and rational combination, knowing when to introduce those combinations is also equally important. So, there's a lot going on, really exciting times to be in drug development. The one thing that I really hope will come to the forefront in drug development, not just for lung cancer, but all disease groups, is to kind of really be thoughtful about how we incorporate these really cool molecular monitoring tools and creating a composite score with imaging to be able to like really design the next generation of clinical trials.
Dr. Monty Pal: You're so spot-on with that. I definitely think that we're getting to this point where, you know, we could think about the next BiTE, the next CAR-T, the next ADC. But, you know, maybe it's time for us to start really honing in on appropriate applications of these drugs, honing in on the right dose and what have you, because I definitely see some issues there. 
Vamsi, this has just been terrific. I really want to thank you so much for sharing your fantastic insights with us today on the ASCO Daily News Podcast, and I really appreciate all your efforts to move the field of lung cancer forward.
Dr. Vamsi Velcheti: Thanks, Monty. I really enjoyed the conversation.
Dr. Monty Pal: Yeah, this was terrific. 
And thanks to our listeners as well. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.
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Dr. Monty Pal and Dr. Andrea Apolo discuss practice-changing studies and other novel approaches in bladder, kidney, and prostate cancers that were presented at the 2026 ASCO Genitourinary Cancers Symposium.
TRANSCRIPT
Dr. Monty Pal: Hello and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist, professor and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. 
And today is super exciting, we're highlighting key abstracts that were presented at the 2026 ASCO GU Cancers Symposium, and I'm just delighted to be joined by the chair of this year's meeting, who is also a dear friend, Dr. Andrea Apolo. Dr. Apolo serves within the Center for Cancer Research at the NCI as head of the Bladder Cancer Section, and she is also acting deputy chief of the Genitourinary Malignancies Branch. 
Welcome, Andrea, it is so great to have you on the podcast.
Dr. Andrea Apolo: Oh, thank you so much for having me. What a great ASCO that we had, it is really exciting, lots of really great data. So I look forward to chatting about it.
Dr. Monty Pal: Excellent. And you know, our full disclosures are available in the transcript of this episode in case our listeners want to have a peek. 
The theme of this year's GU meeting was "Patient-Centered Care: From Discovery to Delivery." I love that theme. And really, this is one of the most competitive meetings out there, more than 850 abstracts being presented on high-impact science. Andrea, I just wanted to get right into it and dive into what I think we both felt were some of the most exciting abstracts of the meeting. 
And the first of those is one that I know is near and dear to your heart, being a bladder cancer expert yourself, and that is the KEYNOTE-B15 study presented by Matt Galsky. Can you give us a flavor for what that study entailed and some of the key results?
Dr. Andrea Apolo: Yeah, I think this was kind of the missing study that we have been waiting for since we saw the EV-302 data in metastatic disease in the frontline setting. We wanted to know how well this combination would work in muscle-invasive bladder cancer patients. And we saw half of that puzzle, you can say half of the piece of the puzzle, when we saw the data at ESMO, the EV-303 data in patients that were cisplatin-ineligible. And then now we are getting the full story with patients that are platinum-eligible, cisplatin-eligible, with the EV-304 data. So that study randomized patients to receive chemotherapy, so different than the EV-303 where the patients were randomized just to receive the radical cystectomy. These patients were randomized to receive neoadjuvant EV plus pembro and then adjuvant EV plus pembro versus neoadjuvant gemcitabine and cisplatin with no adjuvant component to the control arm. So I think this is a really, really important study.
Dr. Monty Pal: And share with us some of the results because this in my mind is definitely practice-changing. This is one of those studies that I think you walked into the office on Monday and you are like, "Okay, this is what I am doing now," right?
Dr. Andrea Apolo: Yeah. So the study was positive. The primary endpoint was event-free survival, and it met the primary endpoint. The secondary endpoint of overall survival was also met. So really, really great results. Consistent with what we saw with EV-303, the median event-free survival was not reached for the EV plus pembro arm, and it was 48 months for the patients receiving gem-cis. And then looking at the 24-month estimated event-free survival, it was 79% for the EV plus pembro and 66% for the chemo, the gem-cis arm. And that was a hazard ratio of 0.5. So that is really exciting. That is the event-free survival. And then the overall survival, the medians were not reached for either arm, but when you look at the 24-month estimated overall survival, it was 87% for the EV plus pembro versus 81% for the gem-cis, and that was a hazard ratio of 0.65. So very positive study. 
And then another question that we had was the pathologic CR rate. Very consistent with what we saw with the EV-303, the pathologic response rate was about 56% for the patients that received EV plus pembro and about 32%, 33% for the patients that received gem-cis. So very consistent with the findings that we have been kind of seeing in phase 2 studies, and this is a pT0N0, so that is important.
Dr. Monty Pal: So Andrea, you know, I think that the big question in folks' minds is at this point, we see the data from NIAGARA, cis-gem-durva, we have now seen this data. Put it into context for us. Is there a patient in this day and age who maybe shouldn't get IO altogether, who should maybe get the NIAGARA regimen as opposed to EV-pembro in this context? What are your thoughts there?
Dr. Andrea Apolo: Now, that is a great question. I would say with this data, it is very enticing to give EV pembro to our patients in the perioperative setting, and for that to be the new standard of care for all patients, regardless of cisplatin eligibility. So similar to what we saw with EV-302 really changing the standard of care in the frontline setting, I think these two studies, the EV-303 and the EV-304, change the standard of care for patients with muscle-invasive bladder cancer in the perioperative setting, and this should be the new standard of care if the patients don't have a restriction to receiving an immunotherapy.
Dr. Monty Pal: I totally agree with that assessment. It is great to hear it from the expert's mouth as well. Thanks a lot for that, Andrea. 
The next abstract I wanted to tackle is one that is, I would say, near and dear to my heart because I know these folks really well. It is led by the SWOG group, and this is SWOG S1602. The number there for the audience gives you a sense of how long the study has been running for. The 16 prefix means it is something that we kicked off back in 2016. So this study is really 10 years in the making, right? So Rob Svatek presented this data. It is interesting, right, because it addresses this issue of the BCG (Bacille Calmette-Guérin) shortage, right, where we have needed to sort of rely potentially on other alternative sources or regimens and so forth. Tell us about this trial, Andrea.
Dr. Andrea Apolo: This is one of my favorite studies. We talked about putting it in the main oral abstracts, but we put it in one of the educational sessions that talked about non-muscle-invasive bladder cancer because we thought that would be the best audience for it. But it doesn't take away from how important this abstract is, and the tremendous effort that went into the study. Almost a thousand patients enrolled. I think 984 were eligible to enroll in this study. So it is a very high enrolling, randomized, cooperative group study in high-grade non-muscle-invasive bladder cancer. And really the study was designed to address two questions. One is the BCG shortage and can we use a different strain, Tokyo versus TICE? And whether there is a priming effect if you gave intradermal BCG to patients with non-muscle-invasive bladder cancer, can that enhance the effect if you gave it a little bit earlier?
I think the study is really important, and it met its primary endpoint, which was it is not inferior to TICE. The findings were really terrific in terms of the outcomes. Numerically. When you look at the endpoint, it looked like the Tokyo strain was as good, if not maybe a little bit better, but not statistically significant than the TICE. And then they broke it down by carcinoma in situ, they broke it down by papillary tumors, and the Tokyo strain was non-inferior in both of those instances. But interestingly, the intradermal BCG did not change outcomes. There was really no priming effect, which was really backed up by pre-clinical data that there would be, but there wasn't a priming effect when the intradermal BCG was given in the Tokyo strain. So that was a really, really interesting finding. But a great study, really important outcomes in the field for non-muscle-invasive bladder cancer.
Dr. Monty Pal: Totally. And it just seems like we can't get away from BCG, right? You know, as hard as we try, I mean, I appreciate the studies that sort of build on it that are emerging right now, but it seems like BCG at least for the foreseeable future is kind of here to stay, right?
Dr. Andrea Apolo: It works. It is one of the most effective treatments we have for non-muscle-invasive bladder cancer. So, you know, I think it is here to stay and, you know, we need to find alternatives in terms of strains so we don't deal with this shortage that we have been dealing with for so many years now.
Dr. Monty Pal: Yeah, indeed. Moving on to some of the other highlighted studies from the meeting, you had mentioned the EV-303 data, so we probably don't need to rehash that study design in much detail. But there was also a rapid oral abstract presented by Dr. Ullén that I think is of interest here, right, that really hones in on pathologic outcomes and DFS from that trial. Do you mind just outlining that for our listenership?
Dr. Andrea Apolo: This is the KEYNOTE-905, also known as the EV-303 study. This is a follow-up to the EV-303 data looking at the pathologic response rates, looking at the downstaging effect, looking at the surgical margins after treatment with the neoadjuvant EV plus pembro in the 303. Now, remember in the 303, patients got three cycles of neoadjuvant EV plus pembro and then six cycles in the adjuvant setting. A little bit different than the 304, where they got four cycles, which is really kind of the standard in the neoadjuvant setting, and then five cycles in the adjuvant setting. So still a total of nine cycles. But in the 303, the treatment arm had no systemic therapy, so it was just radical cystectomy. And they looked at the negative margins that you get with the EV plus pembro treatment, which was 92.6% versus 79% with patients receiving just the surgery alone. And then the pathologic CR rate, there was more follow-up on that, it was 57% for the patients receiving EV plus pembro, and as we would expect, about 9% for the patients that just went on to surgery alone because you can achieve a pathologic response rate with TURBT alone. Then they looked at the pathologic downstaging, so anything less than a pT2, and that was 66% in the patients that received the EV plus pembro.
So very interesting findings, and it is also really just nice to have now the EV-304 data, like I was saying, there were two pieces of it, the cisplatin-eligible and the cisplatin-ineligible, and just to have those contemporary controls are really important. How did the cisplatin-ineligible do versus the cisplatin-eligible patient in terms of the event-free survival and in terms of the overall survival? So I feel like now we have all of this data that we can kind of put together in the perioperative setting and we can really inform our patients a little bit more about their outcomes depending on whether they are cisplatin-eligible or not, which you know cisplatin-ineligible patients often just, they are sicker, they may have obstruction, their tumors may be larger, they just tend to be a more delicate population than the cisplatin-eligible patients. So not surprisingly, you know, we see that in the EV-303 the disease-free survival for the patients is pretty poor. So the disease-free survival that was reported for this follow-up of the specific abstract was 23.6 months for the patients that just got surgery, and it was not reached for the patients that had the EV plus pembro, and that was a hazard ratio of 0.37.
Dr. Monty Pal: Excellent, excellent distillation. So Andrea, in the interest of time, I mean, we could probably talk about bladder cancer forever, but I am going to move us on to the subject of kidney cancer. We have two late-breaking abstracts, LITESPARK-011, which looked at lenvatinib and belzutifan versus cabozantinib in the advanced setting, and then we have an adjuvant study, LITESPARK-022, that looked at pembrolizumab with or without belzutifan in the adjuvant setting. Both studies positive. One for progression-free survival, the other for disease-free survival. Both I think making a big dent in how we treat kidney cancer. Can you tell us a little bit about that?
Dr. Andrea Apolo: Yeah, we have been waiting for these trials for a long time. So one of the things that we have been talking about at GU ASCO is to have plenary sessions. And if we would have had a plenary session, these two abstracts would have been part of it because they are important data, really big studies where we are trying to improve the outcomes of our patients with kidney cancer. So the first one, the LITESPARK-011, like you said, this is for advanced renal cell carcinoma, clear cell renal cell carcinoma, where we really don't have a standard of care after IO therapy, right? So we give IO-IO, we give VEGF-IO, but we don't really have a good standard of care. We usually give monotherapy TKIs. So the combination of belzutifan and lenvatinib versus what a standard of care is, cabozantinib, is really an important question to ask. And you know, this is a pretty large study, about 750 patients were randomized. And belzutifan plus lenvatinib demonstrated an improvement in progression-free survival and overall survival versus cabozantinib, but not overall survival, at least not yet, is what the authors are saying.
So for the progression-free survival, the hazard ratio was 0.7 and it was 14.8 months for the combination, belzutifan plus lenvatinib arm versus cabozantinib, which was 10.7 months. So I think that is significant. And for the overall survival, it did favor the combination again with a hazard ratio of 0.85. The median was 35 months versus 28 months for the monotherapy cabozantinib, but it did not reach statistical significance. And the authors said that this will be further tested at a final analysis, these were the interim results. 
And for the overall survival, the overall survival was 53% for the combination versus 40%. This is significant. And the CR rates were lowish for both of them, it was like 5% for the combo and 1% for cabo monotherapy. So I think that the findings are important because we don't have a standard of care. And although there is no survival benefit, there was a trend. So I think this could be considered in patients that are fit, a treatment option for these patients in the later line settings.
Dr. Monty Pal: Great points. I mean lots of great discussion around toxicity as well as efficacy. I mean certainly this is a regimen that may not be suitable for every patient in my portfolio, but certainly one to consider. 
Now Andrea, let's shift focus to LITESPARK-022, the adjuvant trial that I mentioned previously. So this is again looking at pembrolizumab with or without belzutifan, met the primary endpoint of disease-free survival. What are your impressions there of the data?
Dr. Andrea Apolo: Yeah, the data looks great. And this was a really large study, 1,800 patients were randomized, and the study met the primary endpoint of disease-free survival, benefiting the combination of pembro plus belzutifan. And that is really terrific. The medians were not reached for either arm. And in terms of the overall survival results, also the medians were not reached, but the hazard ratio was 0.78 and did not reach a statistical significance. So there was again a statistically significant improvement in disease-free survival for the combination of pembrolizumab plus belzutifan, but not an overall survival benefit. 
So I guess, Monty, you know, we can kind of talk about what that means. There was a lot of discussion about belzutifan and some of the side effects, specifically anemia and managing anemia in this setting and requirements for transfusions. Generally, the authors said it was well tolerated, but we know that combination studies do have more toxicity. So it may be a select group of patients again, similar to the advanced setting, where we opt for a combination, possibly until we see more follow-up data in terms of the overall survival.
Dr. Monty Pal: I have to agree with you. You know, in my group, we have been talking about a lot of pembrolizumab-based studies that are running right now, some through the NCI, some, you know, our own sort of homegrown investigator-sponsored trials, and you know, I think for the foreseeable future we are comfortable just maintaining pembrolizumab. Things might change if, for instance, we ultimately see a survival advantage emerge, but I just have my own personal doubts around that, that will be interesting. 
Okay, so now we are going to move to the last disease category that we are going to cover, which is prostate cancer. So there, we have the long-awaited results from the PEACE-3 study. These are the final OS results from this trial looking at enzalutamide with or without radium-223 in metastatic castration-resistant prostate cancer. So Andrea, would love to get your perspectives on this.
Dr. Andrea Apolo: Yeah, so this study had been presented before and we had seen positive results for the combination of enzalutamide and radium with some interim overall survival results also showing a benefit. But like you said, these are the final results with a median follow-up of 58 months. So it was really nice to see the final results. And with the combination of enzalutamide and six cycles of radium, it did show an improvement in overall survival with a hazard ratio of 0.76. The median overall survival increased from 32.6 months to 38.2 months with the combination. So that is really great. There was some crossing over of the overall survival curves around 18 months was still seen. And again, there was also an improvement in the rPFS with a hazard ratio of 0.71, and the median rPFS improved from 16.4 to 19 months with the combination. So, you know, we have been awaiting the final results, but we kind of knew a lot about the benefits of the combination. And it is something that is kind of slowly trickling into the community in terms of adapting it and using it. There is more buzz now about it and I think these overall survival results will hopefully shift the community into incorporating the combination in these patients.
Dr. Monty Pal: Brilliant. So well said. I mean, Andrea, congratulations on a terrific meeting. You have really done it again. Incredible, incredible output from this year's ASCO GU. I just want to thank you for joining us on the program today.
Dr. Andrea Apolo: Oh, thank you so much for having me, Monty. It was really a joy to work with the ASCO team and with all the investigators and the Education Committee and the Scientific Committee. Everyone was really outstanding. So to me it was an honor to be part of this meeting, and I am so happy that it was so successful and really presented some amazing data that I think will be practice-changing to our patients.
Dr. Monty Pal: Oh, thanks a ton. And also a huge thanks to our listeners. If you enjoyed the content of today's podcast, please don't forget to like and subscribe to our channel wherever you listen to podcasts. Thanks so much.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview    
Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical    
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Dr. Monty Pal and Dr. Ari Rosenberg discuss the evolution of treatment strategies in head and neck cancers, including the challenges of treating both HPV-positive and HPV-negative disease and the emergence of blood-based biomarkers to advance personalized therapy across different subtypes.
TRANSCRIPT
Dr. Monty Pal: Hello and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist, professor, and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. Today, we're going to explore the evolving landscape of treatment strategies in head and neck cancer management, including locoregionally advanced head and neck squamous cell carcinoma, which happens to be on the rise in United States, in part due to spike in HPV-mediated oropharyngeal cancers.
We're also going to discuss the emerging strategies of using blood-based biomarkers to really advance personalized therapy. Joining me for this discussion is Dr. Ari Rosenberg. He's a medical oncologist focused on head and neck cancer, and he's an associate professor – congratulations on the recent promotion – at the University of Chicago. The University of Chicago has really produced luminaries in this field, Dr. Rosenberg included. I've had the pleasure of getting to know Dr. Ezra Cohen over the years, who really had his grounding there, and of course Everett Vokes, former ASCO President.
I'm really looking forward to this conversation, Ari. Thanks so much for joining us.
Dr. Ari Rosenberg: Thanks, Monty. Thanks for the invitation.
Dr. Monty Pal: You got it. And just a quick note for our listeners, our full disclosures are going to be in the transcript at the end of this episode. So let's start with the basics, if you don't mind. So, head and neck cancers are very diverse and they're challenging, right? In the sense that they're near vital organs, the treatments, you know, as we all saw during fellowship, if not now in clinical practice. They can really have such a major impact on vital organ function, speech, swallowing, et cetera. Can you just comment on head and neck cancers that are on the rise in the U.S.? I alluded to this briefly. Particularly, we've heard this in the context of colorectal cancer and so forth. Are you actually seeing younger adults being affected by this?
Dr. Ari Rosenberg: Yeah, thanks for that. The vast majority of head and neck cancers are head and neck squamous cell carcinomas, as I'm sure many of the listeners recall as well from fellowship or their current training. And as you alluded to, the organ function, long-term and functional quality of life outcomes are quite important, particularly in the context that these develop in high value real estate, parts of our head and neck area that we use for speaking, swallowing, all sorts of other essential functions as well. As you also alluded to, we think of this in two different particular subtypes of head and neck cancer. The historical head and neck cancer from 50, 60 years ago was almost exclusively related to carcinogen exposure, tobacco, alcohol use, and that subtype of carcinogen-induced head and neck cancer has been slowly declining. However, over the last now several decades, we've been seeing an increase in primary oropharyngeal squamous cell carcinoma, mostly tonsil, base of tongue. These are attributable to HPV, human papillomavirus exposure. And that's now the majority of the head and neck cancers that we tend to see in our clinic. As you also alluded to, these have very different prognoses as well. HPV-related head and neck cancer has a much more favorable prognosis where much of the interest has been in can we de-intensify to optimize long-term function?
But then the non-HPV-related head and neck cancer, or what we call HPV-negative head and neck cancer, continue to be very, very challenging. We only managed to cure about half of these folks, with many of these patients developing the current disease. These patients, in addition to being difficult to treat, also have major impacts both in terms of the treatments they undergo as well as their disease that can impact their function and quality of life. And you hinted at this a little bit, but we have been seeing an increase in younger patients with HPV-negative head and neck cancer as well, which is quite concerning. Younger patients, oftentimes never smokers, never drinkers, who are developing non-HPV-negative head and neck cancer. And that's been a little bit of a more recent trend that we've been seeing as well. So, definitely a lot of work to be done to optimize and improve outcomes across all of these different head and neck cancer subtypes.
Dr. Monty Pal: I mean, I'm just curious, you know, in the context of colorectal cancer, one of the things that we talk about is the potential role of the microbiome driving some of these young-onset cancers with, you know, perhaps there being an impact on, for instance, inflammation and the gut and what have you. Tell me about head and neck cancer. Is this anything known as to why younger patients might be getting diagnosed with non-HPV type cancers? It's odd to me.
Dr. Ari Rosenberg: Yeah, it's a great question. A lot of people are working on it. I think we folks have hypotheses, but it hasn't totally panned out exactly what's going on there. It does have a little bit more of a tendency towards women, whereas historically head and neck cancer is much more common in men than it is in women. But lots of people working on that, whether it's related to chronic inflammation, whether it's related to the microbiome. Whether it's related to dental exposure, dental work. So, a lot of folks trying to parse that out because I agree with you, it needs to be identified alongside improving treatment paradigms for these patients, the young ones and the older patients as well.
Dr. Monty Pal: Interesting, interesting. You know, one of the phenomena that was sort of coming around when I was in training 25 years ago was this role of sort of induction therapy for head and neck cancers. And of course, it's really come full circle now to include checkpoint inhibitors and so forth. Tell me a little bit about this and how you apply it, maybe in an HPV-mediated context, maybe in a non-HPV context.
Dr. Ari Rosenberg: Yeah, absolutely. Induction chemotherapy, as you alluded to, or neoadjuvant chemotherapy, depending on what the locoregional treatment approach is. Similar to other cancer types where systemic control early on has many potential advantages in this setting. Now, in head and neck cancer, even though induction chemotherapy is quite active in head and neck cancer, both HPV-positive and HPV-negative with pretty good response rates. A survival advantage for all comers with local regionally advanced disease remains unproven. There's been two randomized trials, both underpowered, but essentially did not show a survival advantage, showing that induction chemotherapy for all patients with locoregionally advanced and neck cancer can't be justified for a survival advantage.
That being said though, there remains a number of potential advantages of giving induction or neoadjuvant chemotherapy, of course, improving systemic control and debulking the disease early on has potential advantages, and predicting the responsiveness to subsequent radiation treatment. We know for some time in head and neck cancer that the percentage of shrinkage or the response to induction chemotherapy actually predicts outcome related to radiation as a dynamic biomarker where response can be used to select patients, for example, for de-escalated radiation has been an area of active investigation, active research. And it also remains a key opportunity to evaluate predictive biomarkers and understanding pre and post treatment to better understand the biology. I'll just add to your question that recently over this past year, we also saw phase 3 data for neoadjuvant immunotherapy for a subset of head and neck cancer that is surgically resectable. And so that's reintroducing the potential benefit in the immunotherapy era of incorporating immunotherapy in the neoadjuvant or the induction setting as part of the evolving treatment paradigm for these diseases.
Dr. Monty Pal: That's really interesting. And you kind of alluded to already several topics that I plan to hit on, you know, for instance, the role of immune checkpoint inhibitors, induction, chemotherapy, and so forth. And you started to touch on biomarkers. And of course, I think that's something near and dear to many of us in academic oncology. One thing that we've started talking a lot about in the context of colorectal cancer is circulating tumor DNA. How do you think this might fit in the context of head and neck cancer? Can you give us a flavor for that?
Dr. Ari Rosenberg: Yeah, absolutely. In head and neck cancer, the current landscape is most developed for circulating tumor DNA for HPV-related head and neck cancer. The advantage of HPV-related head neck cancer is that you have a distinctive HPV DNA that does tend to spill out into the peripheral blood and can be detected using various different blood-based assays. And because of that advantage as a tissue agnostic approach, it turns out that a number of HPV DNA plasma assays are actually quite sensitive and quite specific. And a number of them have indeed been commercialized. Of course, not only for detecting a baseline, but also grading responsiveness during treatment and probably most importantly in the post-treatment surveillance setting, the detection of HPV DNA in the plasma remains a very important and substantial predictor of developing recurrent disease. There's been a number of trials that have been emerging looking at ctDNA and HPV-related head and neck cancer, using it, for example, as a strategy to deescalate patients. That was something we saw this past ASCO from the Dana-Farber group, and also using it to early detect recurrence and potentially intervene earlier for patients with minimal residual disease positivity. So, that remains evolving and as many folks are, I think, already using it in the clinic. But ctDNA also has a lot of potential for HPV-negative head and neck cancer. This is actually a bit more challenging to develop because you don't have that HPV DNA that you can track predictably because the tumor is an HPV- negative disease are much more heterogeneous, but there are a number of data that are coming out both for personalized assays such as Signatera or some of the other assays that require tumor. Unlike colon cancer, which you referenced, where most patients get surgery upfront, in head and neck cancer, many of the patients receive non-surgical pre-chemoradiation. So sometimes the amount of tumor available to generate a personalized assay is more limited and can be one of the challenges that we see in head neck cancer. But certainly that also seems to be emerging. And there's also further assays that are being developed for HPV-negative head neck cancers, such as methylomic signatures and others that may be tissue informed or tissue agnostic. And these are also emerging, particularly in the post-treatment surveillance setting as strong predictors of recurrent disease. So while we're certainly behind some of these other more common tumor types, colon cancer, lung cancer, we're right there with them and more and more trials are going report out, including a number of trials in our upcoming [University of Chicago] Head and Neck Cancer Symposium where I'll be presenting some data and others in the field will be presenting some data looking at ctDNA both for HPV-positive and for HPV- negative to try to improve outcomes for these patients.
Dr. Monty Pal: That's so interesting. I've got to tell you that in kidney cancer, what I deal with day to day is a very low shedding disease, right? So techniques as opposed to ctDNA looking for tumor-informed information, that might be less preferred to something like methylomics where you might not necessarily be so contingent on what's happening in the primary tumor. I'm really interested in you mentioning that. Just a point of clarification, this is something I'm trying to wrap my head around. You'd mentioned circulating tumor HPV DNA, right? I assume this is markedly different from just looking for HPV titers in the patient, right? So is this actually incorporated elements of HPV within, you know, essentially host genome, if you will?
Dr. Ari Rosenberg: Yeah, correct. This is circulating tumor HPV DNA. And we think of it biologically as a plasma-based tumor DNA biomarker that's specific for HPV-related head and neck cancers.
Dr. Monty Pal: Got it, got it. It makes me wonder whether or not this might be applicable to diseases like cervical cancer and so forth where there's also extensively, you know, biology driven by HPV. Is that fair?
Dr. Ari Rosenberg: Yes, definitely. And in the head and neck cancer field, much of this ctDNA actually was derived from a different viral mediated head neck cancer, is less common in the U.S., but nasopharyngeal cancer, which is oftentimes associated with EBV. That has been a biomarker for quite some time in nasopharyngeal cancer. Of course, in places where EBV-associated nasopharyngeal cancer, is endemic, such as East Asia, this has been around for quite some time, but we've been using that in the U.S., and there's been trials that have used EBV DNA plasma to predict recurrence and stratify for adjuvant treatment, for example. And so now with HPV, it's much more applicable to our US population because the vast majority of our head and neck cancer patients that we see in the US that are viral mediated in the US tend to be HPV-related. So having assays that we can use to improve outcomes for that biological subset remains of particular interest for us.
Dr. Monty Pal: Yeah, that's fascinating. By the way, for the fellows listening, there's tons of boards pearls here that Dr. Rosenberg shared, EBV-associated cancers, the role of HPV and treatment association. So if you're recertifying anytime soon, I definitely think there's notes to take from this conversation indeed. I wanted to shift gears a little bit. And obviously, you're a prolific researcher. I don't think anyone goes through their fellowship in medical oncology without recounting these experiences of our head and neck patients really suffering from treatment-related toxicities. It's a real challenge. And I'm just wondering, I know a big body of work that you're focused on is really using multimodality treatment paradigms to perhaps reduce the cumulative treatment burden of patients with head and neck cancers. Can you talk about that a little bit?
Dr. Ari Rosenberg: Yeah, definitely. Thanks for the question. And before I start going into some of the strategies, I'll just say that head and neck cancer, this is particularly for the fellows that are listening as well, just in reference to your prior comment, that this is really a multidisciplinary disease. At our center, all head and neck cancer patients are seen upfront at that first visit by all three specialties, med onc, rad onc, and surgery, because the choice and sequencing of modalities to optimize not only survival, but also functional quality of life outcome is so critical. And I think that's probably the biggest takeaway for anyone who treats a lot of head and neck cancer or will be treating a lot of head and neck cancer in the clinic. But in terms of more specific attempts at trying to optimize some of those parameters that you described, we really think about these separately in terms of HPV-positive and HPV-negative head and neck cancer. For HPV-positive head and neck cancer, the cure rates are quite high with chemo radiation, although not for everyone. There's still about 15, 10 to 15 % of folks that will develop a recurrence. But for the vast majority of patients, standard chemoradiation is quite a cure to therapy, but the toxicity associated with that can be quite substantial. And so there's been a number of attempts to try to deescalate treatment. It turns out that deescalating everyone with locoregionally advanced HPV-positive head and neck cancer is not a good strategy because it's not able to select out the patients that really do need full dose treatment. And we have seen some negative trials that show inferior outcomes when everyone is deescalated. But what does remain promising is again, trying to select out who the best candidates are for deescalated treatment.
The folks at MSK have hypoxia imaging that they're using in trials that looks quite promising to select for the more favorable deescalatable biology. At our center, we've been interested in using induction chemotherapy to stratify response and select patients for deescalated treatment with excellent survival outcomes and reduce toxicity with deescalated treatment. And more recently, ctDNA that us and other groups, such as the Dana-Farber group, is using. And that also looks quite promising. Again, how do you select the patient who will do well with less radiation versus the ones that really need the full doses and volumes of radiation? And then for HPV-negative head and neck cancer, this is a much trickier disease because already the survival outcomes are not like we want it to be. Trying to figure out how to improve survival outcomes remains an important thing. Using immunotherapy seems to be one of the key cornerstones to that.
But these are patients that also suffer from a lot of toxicity related to their treatment. We completed a trial not too long ago that we published this past year where we, in HPV-negative head and neck cancer patients, de-intensified the radiation for responders to neoadjuvant chemoimmunotherapy. And those patients did similar, if not even a little bit better, than the non-responders who got full dose treatment. So something that does warrant further investigation as well. How do we not only improve survival for those patients, but also reduce some of the long-term toxicities?
Dr. Monty Pal: This is brilliant. I'm taking so many notes as you were mentioning these items. There are so many areas where I think the research crosses over. I already mentioned, know, ctDNA, for instance, and metabolomics and the places where that might apply to kidney cancer. The hypoxia imaging really caught my ear too. Obviously, kidney cancer is disease highly predicated on hypoxia. So thank you for all of this. We've got about a minute or so. So, I'm going to ask you for a really tall task here. Can you tell us what you foresee being some of the biggest challenges that sort of lie ahead and head and neck cancer. You've already kind of alluded to it with ongoing research, but if you had to pick maybe 2, 3 problems, the very most that we really need to get to and head and neck cancer, what would that be?
Dr. Ari Rosenberg: Yeah, that's a great question. Obviously, lots of things to be done, but if I'm going to limit it to just a couple, I would say number one is really trying to improve the survival for HPV negative local regionally advanced head and neck cancer. We talked early on about how we are seeing, you know, of course we see many of these people that were smokers and drinkers, but also seeing these in younger patients, in patients without a history of tobacco use. Some of these are very biologically aggressive and we need better treatments beyond surgery, beyond chemo radiation, beyond immunotherapy to improve outcomes for these patients and cure more of them. So, I would say that's one big area. And the other is, which we didn't speak about so much in this talk, but remains one of the biggest challenges that we see in the clinic is the recurrent metastatic head and neck cancer patients. This is an incredibly challenging disease to treat, not only with poor survival, but also with substantial impacts on quality of life and function. mean, these are bad recurrences that cause a lot of pain, functional deficits, really impacts quality of life as well. So developing novel therapies, many of which are currently in clinical trials and many of which are currently continuing to be developed, remains so critical. How do we develop better systemic therapies, better targeted therapies, better biomarkers for recurrent metastatic head neck cancer to improve their survival and quality of life and functional outcomes. Those are the two big areas that require the most work at this time within the head and neck cancer field.
Dr. Monty Pal: That's brilliant. I mean, I have to tell you I could probably talk to you all day about this, such a fascinating topic. It's a very exciting time in the field. Thank you, Dr. Rosenberg, for all your incredible contributions and thanks for sharing with us your insights on the ASCO Daily News Podcast.
Dr. Ari Rosenberg: Yeah, and thanks for the introduction. Hope to do it again soon.
Dr. Monty Pal: And many thanks to our listeners for your time today. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.
More on today's speakers:     
Dr. Monty Pal  
@montypal 
Dr. Ari Rosenberg
@AriRosenbergMD
Follow ASCO on social media:          
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Disclosures:       
Dr. Monty Pal:      
Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview     
Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical     
Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis 
Dr. Ari Rosenberg:    
Stock and Other Ownership Interests: Privo Technologies
Consulting or Advisory Role: Nanobiotix, EMD Serono, Vaccitech, Novartis, Eisai, Astellas Pharma, Regeneron, RAPT Therapeutics, Geovax Labs, Janssen, Summit Therapeutics
Speakers' Bureau: Coherus Biosciences
Research Funding (Inst.): Hookipa Biotech, EMD Serono, Purple Biotech, Bristol-Myers Squibb/Celgene, BeiGene, Abbvie, Astellas Pharma, Pfizer, Janux Therapeutics

Dr. Monty Pal and Dr. Atul Batra discuss the PLANeT study from India, which evaluated low-dose pembrolizumab in addition to neoadjuvant chemotherapy for triple-negative breast cancer, and its place among a growing body of international research on improving efficacy while reducing costs and toxicity with lower doses of immunotherapy.
TRANSCRIPT
Dr. Monty Pal: Hello and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist, professor, and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center, Los Angeles.
My guest today, I think, is going to be a really riveting one. It's Dr. Atul Batra, who is an additional professor of medical oncology at the All India Institute of Medical Sciences, or AIIMS, in New Delhi. And he's also the senior author of the PLANeT study. It's a very compelling study that evaluated low-dose pembrolizumab in addition to neoadjuvant chemotherapy for triple-negative breast cancer. And it's really a big part of a growing body of research that's showing balanced efficacy when we use lower doses of immunotherapy instead of standard doses to reduce cost, as well as potentially toxicity. I think this has huge implications for our global audience, and I'm so thrilled to have you on the podcast today, Dr. Atul Batra, welcome.
Dr. Atul Batra: Thank you, Dr. Pal.
Dr. Monty Pal: And we'll just take it with first names from here since we're both friends. I have to give the audience some context. Atul, I had the great honor of visiting AIIMS New Delhi. For those that don't know, this is really, you know, the Harvard Medical School of India. It's the most competitive institution for medical training. And on the back end of that, there's also incredible resources when it comes to clinical trials and infrastructure. I just wanted to have you give the audience sort of a scope of the types of trials that you've been able to do at AIIMS New Delhi.
Dr. Atul Batra: Thank you, Monty. So, I work at the All India Institute of Medical Sciences, and we had the honor and pleasure of having Monty here this month. And people are still in awe of his lectures that he delivered there.
Coming back to our institute, so it's kind of a medical college. It's one of the oldest ones, it was built in 1956. We are lucky enough that we get the best of the residents and fellows because they have to go through an exam, a competitive exam, and mostly it's them who come to us and we're able to do some good work out here.
Regarding the trials that we have conducted, we do conduct some investigator-initiated studies, and we try to answer the questions where we can help our own patients. Like, for example, this PLANeT study. Every other patient in the clinic was almost not able to afford Keytruda at the full dose, pembrolizumab, and we had a lot of evidence creeping in that a lower dose might be helpful. And that's how we planned this study.
Before that, there are certain cancers that are peculiar to India, like gallbladder cancer, head and neck cancers. These are much more common in India as compared to the U.S., and there are some good studies that have been conducted from our own institute by our senior colleagues which have been presented at ASCO and published in the JCO.
We also did the capecitabine hand-foot syndrome study that was known as the D-ToRCH study: 1% diclofenac gel that became the standard of care to prevent hand-foot syndrome. 
So, that's kind of a brief overview of investigator-initiated studies. India is slowly and steadily becoming a partner of the global registration trials. And it's more recently, the last five years or so, we have seen that the number of phase 2 and phase 3 trials are increasing and we are able to offer now these trials as well to our patients.
Dr. Monty Pal: That was a terrific overview. I just want to highlight for the audience, as we go through some of your discussions today around specific trials, the speed at which this can be done. Just for context, for me to accrue a clinical trial of 30 patients – I think many people have probably come across some of the work that I've done in the microbiome space – at a single institution, 30 patients, right, takes me about a year and a half, two years. We're going to go through some trials today where Dr. Batra and his team have actually, in fact, accrued close to 200 patients over a span of just a year, which is just remarkable by, I would say, any American standard.
So, I see a real need for partnership and Atul, I'll kind of get back to that at the end. But without further ado, the focus of this podcast today, I think, is really this terrific presentation you gave in an oral session at ESMO and subsequently published in Annals of Oncology related to the PLANeT study. Would you give the listeners some context around what the study entailed and population and so forth?
Dr. Atul Batra: So, we know the KEYNOTE-522 became the standard of care for triple-negative breast cancer, where Keytruda, when added at 200 mg, the standard dose every three weeks with neoadjuvant, increases the pCR from around 51% to 64% by a magnitude of around 13%. However, in India and other low-middle income countries, less than 5% of the patients actually have access to this dose of pembrolizumab.
So, our standard of care was actually just chemotherapy till now. And this kind of led us to design this trial. There are data that come from previous trials conducted in India, from the Tata Memorial, done in head and neck space, some other studies done in Hodgkin's lymphoma, that a much lower dose, probably around one-tenth of the dose, works well in these cancers.
So, that's where we designed the PLANeT study, where we gave the standard neoadjuvant chemotherapy in the control arm, and in the experimental arm we added 50 mg of pembrolizumab. This was given every six weeks for three doses. So, that's a total of 150 mg over the neoadjuvant period as compared to 1,600 mg that was given in the KEYNOTE-522 study. So, this was almost one-tenth of the study.
Dr. Monty Pal: So, a tenth of the dose, which is just remarkable. I mean, that's just such an interesting concept.
Dr. Atul Batra: And the results, when we – the primary outcome, this was a phase 2 study. We just wanted to see, is there a signal of activity? And to even our surprise, when we looked at the pathological complete response rates, in the control arm this was 40.5%, and in the experimental arm this was 53.8%. So, a difference came to around 13.3%; it was numerically, I mean, so much similar to what KEYNOTE-522 had with just these many doses.
So, this was around 160 patients randomized over one year. We could randomize them in one year because of the load that we see. And the primary endpoint was met, and we could see that the path complete response did show a remarkable increase. We are still following these patients to see whether there is a difference in event-free survival at a longer follow-up. Until now, it's a small follow-up, so the number of events absolute, are different: four events in the experimental arm and 11 events in the control arm. So, we are seeing some signal even in this much short follow-up period as well. But we need to see more of what happens in the longer term.
Dr. Monty Pal: That's so impressive. I wonder, with this lower dose, do you attenuate toxicity at all as far as you can gather?
Dr. Atul Batra: So, although we shouldn't be doing kind of cross-trial comparisons, but if you look at thyroid dysfunction, we saw that around 10% of our patients had this thyroid dysfunction. This was compared to 15% in the KEYNOTE-522, that was a larger sample size though. But we're seeing that all the toxicities are somewhat less as compared to those in the standard dose. So, the exposure is less, but I mean, I can't really commit definitely on this. For this we would need much more data to say this with more confidence.
Dr. Monty Pal: Yeah. I'm going to ask you a really tough question to follow up, and this is probably something that's on everyone's mind after reading a study like this. Is this something that is disease-specific that needs to be replicated across other histologies? The reason I ask this is, you know, you think about paradigms like, for instance, in the States we're toying between intravenous versus subcutaneous delivery of checkpoint inhibitors, and we have studies focused in specific histologies that might justify use across all histologies. With this particular phenomenon, do you think we need to do dedicated studies in renal cell or in colon cancer and other places where, you know, in selected settings we might use checkpoint inhibitors and then decide whether or not there's this dose equivalence, if you will?
Dr. Atul Batra: That's a real tough one, though. But I'm happy to share that there are several ongoing studies within India currently. At our institute, my colleagues are leading studies in lung cancer space, cervical cancer. There was already a publication from Tata Memorial Hospital in head and neck cancers and we see that the signal has been consistent throughout.
Regarding renal cancer, there was one study that was presented for sure at ASCO from CMC Vellore, that's again a center in South India. That was in RCC at a much lower dose. And for patients who cannot take the full dose, we actually are offering lower dose nivolumab in such patients and we are seeing responses. I mean, we haven't done those randomized trials again because the numbers are much lower in kidney cancers, we know. We could do this trial in triple-negative ones because we had support and we had numbers to conduct this trial.
But I'm sure this should be a class effect. I mean, when we can get tumor-agnostic approvals, then some real-world data has come up in almost all tumors, we have seen that consistent effect across tumors.
And as we speak of today, I'm also delighted to share that in India, yesterday, we had the first biosimilar of nivolumab and that's now available at a much, much lower price than the original patent product. There was a long ongoing lawsuit that was there, that's over now, and from yesterday onwards, I'm so happy to share here that we would have the first biosimilar of nivolumab that's available. That's going to bring the cost to almost like one-tenth already.
Dr. Monty Pal: Wow. That's huge. 
I'm going to be very selfish here for a second and focus on a study that is in the renal cell space that your group has done. You know, when it came out, I was really sort of intrigued by this study as well and it reflects sort of a different capability, I think, of AIIMS New Delhi, and that's in the, what I'm going to call, biomarker space.
This, for the audience, was a prospective effort to characterize germline variants in patients with advanced kidney cancer. And it's something that we talk about a lot in the kidney cancer literature, whether or not we're missing a lot of these so-called hereditary patterns of RCC. Can you tell us a little bit about that study too?
Dr. Atul Batra: Yeah, so that was led by one of our fellows, Chitrakshi Nagpal, and she's just completed her fellowship. And two years back we published that. So, that was done in almost 160 consecutive patients that we recruited over the span of just one year and we saw, apart from the common known mutations in RCC, that was around 5% or so, but a lot of other mutations were also seen that we don't generally see in kidney cancers and we see in other cancers like BRCA1, BRCA2 and others. We are still, I mean, doing those analyses to see whether we get more things out of there in the somatic: is there a loss of heterozygosity or was it just present and in there?
Dr. Monty Pal: I thought it was a terrific study and again, I was just so blown away at the pace. I mean, as I look at 140 patients accrued over a span of one year, this is something that would take us perhaps three times as long at City of Hope, and that's with a very sort of, what I consider to be large and dedicated kidney cancer program. So, it really underscores, I think, the need for collaboration.
And ever since I came back from my visit to you at AIIMS Delhi, I think I've just been sort of transformed in the sense of trying to think of better ways for us to collaborate. One tangible thing that I'm going to get cracking on is seeing whether or not perhaps we can form some partnerships through SWOG or what we call the NCTN, the National Clinical Trials Network here within the U.S.
Talk to me about collaboration. I mean, you've been really terrific at this. How do you sort of envision collaboration enhancing the global landscape of oncology?
Dr. Atul Batra: That's really amazing, Monty. That's what we need. We have the infrastructure, we have the manpower, we have patients. I mean, these are all high-volume centers. Unfortunately, we are a little less in numbers, so we are more clinically occupied as well. So, sometimes it's kind of tougher, but again, when it comes to helping out the patients, global collaboration, we need to kind of take you guys along with us and have our patients finish trials earlier.
This is a win-win situation for patients, one, because they also get exposure or an option to participate in the clinical trials, and second, we can answer all these scientific questions that we have at a much faster pace. All those things can be done within a much shorter span of time for sure. We are so happy to hear that, and with open hands we are ready to collaborate for all these efforts.
Dr. Monty Pal: That's awesome. You know, I came back thinking, gosh, this would be so ideal for some of these rare subtypes of kidney cancer. Prospective clinical trials that I'm running in that space where really we're threatened with closure all the time. And if we just sort of extended a hand to, you know, our partners in India and other countries, you know, I'm sure we could get this research done in a meaningful way and that's got to be a win for patients.
Atul, I had such a terrific time chatting with you today. I'm looking forward to seeing lots more productivity from your group there. By the way, for our viewership here, take a look and see what AIIMS New Delhi is doing under the leadership of Dr. Batra and others. It is just a real powerhouse and I think that after doing so, you'll be enticed to collaborate as well. 
I'm hoping this is the first of many times that we have you on the podcast. Thank you so much for joining.
Dr. Atul Batra: Thank you so much for having me here, Monty. It was a pleasure as always speaking to you. And thank you again.
Dr. Monty Pal: You got it. 
Well, and thanks to our listeners. I encourage you to check out Dr. Batra's paper. We'll actually have a link to the study in the transcript of this episode. 
Finally, if you value the insights that you heard today on the ASCO Daily News Podcast, please rate, review, and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
More on today's speakers:    
Dr. Monty Pal  
@montypal
Dr. Atul Batra
@batraatulonc
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Disclosures:      
Dr. Monty Pal:     
Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview    
Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical    
Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis    
Dr. Atul Batra:
Stock and Other Ownership Interests: Zydus Pharmaceuticals, Glenmark, Caplin Point Laboratories, Laurus
Research Funding: AstraZeneca, Astellas Pharma, Alkem Laboratories

Dr. Monty Pal and Dr. Mary Feng discuss the latest advances in metastatic colorectal, gastric, and gastroesophageal cancers that were presented at the 2026 ASCO Gastrointestinal Cancers Symposium.