The DNFs of the Moderna Personalized Cancer Vaccine

Drs. Diwakar Davar and Jason Luke discuss KEYNOTE-716, KEYNOTE-942, RELATIVITY-047, and other key advances in melanoma, including the promise of mRNA vaccines in melanoma and potentially other cancers, as well exciting advances in neoadjuvant therapies across malignancies featured at the 2023 ASCO Annual Meeting.

TRANSCRIPT

Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh Hillman Cancer Center. I'm delighted to have my colleague and good friend Dr. Jason Luke on the podcast today to discuss some practice-changing studies and other advances in immunotherapy that were featured at the 2023 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapy Center, as well as the associate director of clinical research at the University of Pittsburgh's Hillman Cancer Center.

You can find both of our disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.

Jason, there was a lot of exciting data in the immunotherapy space highlighted at the Annual Meeting, and it's great to have you back on the podcast to discuss some of this work.

Dr. Jason Luke: Thanks for having me.

Dr. Diwakar Davar: So, the abstracts that we had selected have several key themes. We'll be covering some of the early advances in melanoma in the stage 2 and stage 2B/C space with KEYNOTE-716. I think this is a study that you know a little bit about seeing you are the presenting author and the principal investigator for the study, as well as the pivotal KEYNOTE-942 trial. And then going on to themes with using third-generation checkpoints, neoadjuvant therapy in non-small-cell lung cancer, and cutaneous squamous cell carcinoma.

But we'll start with KEYNOTE-716. So, this is LBA9505, the study which evaluated pembrolizumab versus placebo as adjuvant therapy in stage 2B and stage 2C melanoma patient population for which historically there was no real effective therapy other than remotely interferon. And these are the final results of the DMFS analysis from this phase 3 trial. So, Jason, what are your thoughts about this, and can you contextualize the results relative to the recent publication?

Dr. Jason Luke: Thanks. I think the important point to level set on this was just a few years ago; this was a population of patients that we didn't treat in clinic. In fact, sometimes they weren't even referred to medical oncology for evaluation. And that was despite the fact that we knew from historical data that the risk of melanoma-specific survival, death from melanoma, was just as high for this population of patients as it was for the patients with stage 3 melanoma, where obviously adjuvant immunotherapy has been a standard for quite some time. And so we launched this clinical trial, KEYNOTE-716. It was a global, randomized phase 3 study of almost 1,000 patients, randomizing patients to either get pembrolizumab or placebo. Importantly, these patients being those with deep primary lesions, stage 2B and 2C with negative sentinel lymph node evaluation.

People will recall that this study hit its primary endpoint on the first protocol-specified analysis at a year. And what we updated at ASCO this year was the final analysis of distant metastasis-free survival. Obviously, an important secondary endpoint because if patients eventually going to develop metastatic disease and pass away, it's the distant metastasis that we worry about. And what we saw in this trial with a landmark 36-month follow-up median of 39 months was that the benefit was increasing. In other words, the magnitude of the hazard ratio change was increasing over time as would be expected, such that at this analysis there was a 41% reduction in the risk of distant metastasis for patients treated with pembrolizumab versus placebo. And we saw a consistent benefit in the recurrence-free survival also out through that same period of time and importantly no change in the safety summary with of course the adverse event profile of pembrolizumab being what it is and well understood across oncology.

So I think these are very important data because they really kind of set the stage for the field. It is now the case that at least discussing adjuvant therapy for patients with stage 2B and 2C is the standard of care; it should be offered to all the patients. Of course, it's always a risk-benefit about whether or not patients want to pursue adjuvant therapy versus consideration of treatment at the time of recurrence. But in my clinic at least, many patients do prefer to try to eliminate the possibility of recurrence and distant metastasis as much as possible.

So I think these are very important data because they really level set the field for what to expect in this population of patients and then they also start to set the table for what's going to come after this. And that's going to be sort of the next step in our conversation here because the next generation of adjuvant studies in melanoma are now going to think about all of melanoma in the adjuvant setting as really one entity, starting from stage 2B going all the way through stage 4 resected. And that'll be relevant actually as we talk about the next abstract that will come in this discussion.

Dr. Diwakar Davar: Just to underscore, positive RFS data, positive DMFS data, and now this therapy has currently got regulatory approval in this investigation and is approved in the United States and certainly in Europe and Australia. One interesting point that we will probably have to contend with, and some of the listeners may be thinking about, is overall survival. So the last adjuvant study that demonstrated overall survival benefit was actually ipilimumab, and increasingly, the Illuminati in melanoma do not believe that we will ever see OS benefit in this disease going forward, even though it has to be an endpoint in all registration phase 3 trials. So, Jason, what are your thoughts about whether or not we'll have a positive OS readout, and even if we don't, why this is still a very important advance in this disease at this time?

Dr. Jason Luke: Your points are well taken. I think it's unclear, probably trending towards unlikely, that we would see an overall survival advantage in this trial given that we have not seen that in the stage 3 adjuvant studies. Now people can debate if, whether or not overall survival is the only meaningful endpoint for patients. I personally do not believe that's true. And to me, preventing recurrence has a value in and of itself, whether or not that's connected to overall survival. And part of the reason that I say that is that for an average patient, the median patient on a trial, of course, we can tell them treatment now, treatment later. It's a wash when you look at the overall study. And yet at the same time, for an individual person who's facing melanoma or cancer, generally they're not going to be the average patient; they're going to be one patient. And it's very possible they could end up with the type of recurrence that in fact is not highly treatable at that time.

So I think that's really the nuance that goes into those adjuvant discussions. The regulatory endpoints have been recurrence in melanoma for a long time. And I think it's important that patients understand the pros and the cons of each. The complexity in adjuvant therapy and neoadjuvant therapy is you don't necessarily know that you had to have it. You're only really going to know whether or not it didn't work if you recur later on. But to me and in my clinic, most patients are willing and interested to want to pursue those therapies in the perioperative setting to try to reduce the possibility of ever developing metastatic disease.

Dr. Diwakar Davar: Excellent. So I think key advance [is] positive DMFS data to add to the earlier reported RFS data and truly practice-changing.

So, moving on to the next study, LBA9503. This is the phase 2 trial of the Moderna vaccine. This is the trial that almost every medical oncologist knows intimately or has been called about by either the press or patients. So what is this study? This essentially is a phase 2 trial evaluating the personalized cancer vaccine PCV Moderna, made by Moderna, the mRNA vaccine, that is being studied in combination with anti-PD-1 pembrolizumab in the stage 3 BCD and stage 4 resected setting. And so there are really two very interesting results here because this is an update of the RFS data that was presented at AACR earlier this year, which was positive. What are your takes on the DMFS results, and maybe a quick blurb on how is this vaccine generated for those who may not be aware of this particular platform?

Dr. Jason Luke: Yeah, certainly. So this individualized neo-antigen therapy, as we're now calling it, is a technology platform that allows us to develop an individualized treatment for each patient based on their own cancer. So taking the actual tumor specimen, whole exome sequencing is performed to try to identify changes in the DNA, and then through a reasonably complex bioinformatic pipeline, those mutations that are likely to generate proteins that can be bound within class 1 MHC molecules are then identified in the computer and then synthesized with an mRNA, very similar to the way that the COVID vaccines were made. And then that becomes the actual drug.

So in the clinical trial, which was KEYNOTE-942, about 160 patients were randomized 2 to 1 to receive either pembrolizumab for a year as per standard adjuvant therapy but then with the addition of the individualized neoantigen therapy starting with dose 3 and throughout the rest of the year versus the control arm of pembrolizumab as the standard of care. As you mentioned, the recurrence-free survival were highly positive in this trial when it was first presented earlier this year, and at the updated ASCO we see the 18-month RFS in which the hazard ratio continues to be maintained. But I think most impressively is that distant metastasis-free survival, where we saw an even greater advantage for distant metastasis-free survival – hazard ratio here being 0.35. And so that's a huge advantage for distant metastasis-free survival in this population of patients.

And very interestingly in the clinical trial, when you follow the Kaplan-Meier plots, what you see over time is that they overlap almost the entire first year. And it's really at about a year, basically after the vaccine has had time to kick in and these neoantigens have been identified, that we then start to see the separation of the curve, which looks very flat over time. And so I think this is a very, very exciting kind of technology platform and very exciting results because there was minimal increase in toxicity – just at the site of the local injection – for the addition of the individualized neoantigen therapy.

And beyond that, hypothetically, this is not necessarily just a melanoma thing. So, of course, based on these phase 2 results, a phase 3 clinical trial called KEYNOTE-V940 is going to be launching later this year to compare pembrolizumab versus pembrolizumab plus this V940 individualized neoantigen therapy. And we're very, very excited in the field to see what those results will look like because the concept here is you could really, really enhance adjuvant therapy with this kind of an approach. Meanwhile, we're just about to talk in a little bit about all the exciting things happening in the neoadjuvant space as well. And with no increase in toxicity, obviously, that looks really good.

Suffice it to say that this technology is not specific to melanoma but rather could be applied almost to any cancer where we think about an adjuvant therapy platform. So I think the results are very, very exciting. It is a phase 2 study and it does have some caveats about not being the largest study and some other things, but you can't help but be impressed by the data that have been presented here so far.

Dr. Diwakar Davar: One important plug, I guess, in addition to that is that you mentioned that there's data using the platform in other diseases. And one really exciting paper that came out recently was Dr. Vinod Balachandran's paper; for those who haven't read it, it's in Nature, and really in a very provocative proof of concept study, they studied the platform, the vaccine plus checkpoint inhibitor therapy plus chemotherapy in a highly adverse tumor patient population. So these are patients with resectable pancreatic cancer who had the vaccine generated from pancreatic cancer that was resected after Whipple surgery. And extraordinarily, out of the 16 patients who had immune responses, 8 of them did not have relapse at a median follow-up of almost a year and a half, which is really quite extraordinary given the lack of really any effective drug outside of chemotherapy in that setting.

So, the point that you're making regarding the benefit of this therapy, suggesting that it could potentially be extended to not just melanoma, potentially other tumors such as highly immunogenic tumors, and potentially even nonimmunogenic tumors such as pancreatic cancer, really suggests that this is going to be a very exciting landscape. And potentially this area, adjuvant therapy and neoadjuvant therapy, like we'll talk about, is potentially an area in which other drugs and potentially combinations will be developed.

So next, we will be discussing 3 abstracts evaluating the theme of combinations, and these abstracts are 9501, 9502, and 4010. Abstract 9501 is an evaluation of the combination of fianlimab and cemiplimab anti-LAG-3 and anti-PD-1, respectively, in advanced melanoma, specifically focusing on the post-PD-1 experience in this disease by Dr. Omid Hamid. 9502 is the updated 2-year survival results from RELATIVITY-047, which evaluated nivolumab and relatlimab against nivolumab alone in frontline metastatic melanoma. And Abstract 4010 are the results from the MORPHEUS platform study, specifically looking at tiragolumab and atezolizumab in patients with advanced unresectable HCC.

But focusing on 9501 and 9502, Jason, what do you make of the combination of fianlimab and cemiplimab post-PD-1 setting?

Dr. Jason Luke: I think the data look very intriguing for this second combination of PD-1 and LAG-3 combination. When nivolumab and relatlimab, the approved LAG-3 inhibitor, kind of burst on the scene a couple of years ago, it was somewhat to the surprise of a lot of people in the community who had really come to think that while PD-1 and CTLA-4 were core molecules for therapeutics and cancer, that we just weren't ever really going to see something else come along in checkpoint blockade. And so nivo and rela got approved. We'll talk about them again in a second. But the data now coming forward for another PD-1 LAG-3 combination, again with cemiplimab PD-1 and fianlimab LAG-3, looks very, very promising.

So in Abstract 9501, they updated a phase 1 expansion cohort, phase 2 cohort looking at patients across the various different settings. And whereas in the treatment naive frontline metastatic setting they had previously described about a 63% response rate, they saw a similar level of response rate in patients who had previously gotten adjuvant anti-PD-1, had a period of time off treatment, and then were treated again. And that was reassuring because it suggested that this is still an active combination even with prior exposure to IO in the past.

Now, the thing that I found to be the most interesting about this combination was whereas with nivo and rela, at least from the RELATIVITY-047 phase 3 trial, it looked like there was less benefit in some of the high-risk population cohorts, at least for this combination in early testing for cemi and fian; like we talk about it sometimes, we saw there was a high response rate even in patients with liver metastases and some other high-risk features. And so I think this combination looks quite potent, and I'm very excited to see what the data will look like. I think it's very unlikely we'll ever actually get a randomized trial of two PD-1 LAG-3 combinations against each other. But suffice it to say that the data we've seen so far for fianlimab LAG-3 with cemiplimab PD-1 looks very intriguing. It certainly justifies the frontline metastatic phase 3 and the adjuvant phase 3 trials that are already in planning or ongoing.

Dr. Diwakar Davar: So one thing to consider is on the RELATIVITY-020 trial – the early trial that was led by Dr. Ascierto that really took a long time to read out – the response rate in patients with prior checkpoint inhibitor therapy was quite low. In fact, the data was quite surprising, as you'd mentioned that we had even seen this movement in the frontline setting because the response rate by BICR was only about 12%. So do you feel like the 2 LAG-3 inhibitors are fundamentally different? And if so, can you speculate as to why that might be? Again, with the caveat to the fact that these are very early data and we don't have enough information. And maybe we can also talk a little bit about the 2 pending trials that are ongoing in the advanced and adjuvant therapy landscapes perspective.

Dr. Jason Luke: I think we don't have enough data yet to truly understand whether or not they're really different. The trials that have been run so far are so different that it's hard to compare things back and forth. You can notice that the dose, the milligram dosage of fianlimab in terms of anti-LAG-3 is quite a bit higher, like a log fold higher almost than with relatlimab. And so there's some question of whether or not just merely more drug-blocking LAG-3 might in fact be more efficacious relative to the dose that's approved for relatlimab in melanoma. But beyond that, I think the data hold up very well for this new combination, again noting all the caveats about cross-trial comparison to, say, it looks to be at least as potent, possibly more potent than the relatlimab combination. But again, I think probably we need to see the data from randomized trials and how that fits into the landscape when the trials actually read out because there's a lot of things going on in melanoma that are likely to change between now and then.

Dr. Diwakar Davar: So just to draw people's attention, there are actually 2 ongoing pivotal phase 3 trials: fian plus cemi versus pembro in patients with advanced metastatic and locally advanced, previously untreated melanoma, as well as an adjuvant trial of the combination against pembrolizumab. Again, highly high-risk resected melanoma. These trials are ongoing. We don't have the results yet and we are looking forward to them.

Now, 9502, a 2-year RELATIVITY-047 result presented by Dr. Hussein Tawbi.

Dr. Jason Luke: So this is the study we were just alluding to before, the randomized phase 3 study of nivolumab versus nivolumab plus for relatlimab. To me, the most useful data sort of updating with this two-year survival follow-up is to show the maintenance of benefit between the 2 arms. And so, consistent with what we saw with nivolumab and ipilimumab, there seems to be a persistent delta between the arms for both progression-free and for overall survival out over that extended period of time, where we can see with that updated data now, at 2 years, that it's 52% of patients still alive on the relatlimab combo versus 42 with nivolumab. And it does seem like this is probably a higher-risk population of patients than participated in CheckMate-067.

So it's a little bit difficult to compare the landmarks except to notice that that difference between the control and experimental groups is consistent over a long period of time and that there were no new safety signals either, and so that was also reassuring. To me, the most interesting nugget of data in the abstract, though, is to look at what happened to patients after they were on the first-line treatment. So one of the big questions in our field is really "If patients get nivolumab and relatlimab upfront, what should they get after that?" Should they then get nivo plus ipi, or vice versa? And I think we don't have an answer clearly to that question just yet.

There was an important letter to the editor of the New England Journal now going on about a year ago by Alex Menzies and colleagues that suggested that the use of ipilimumab was attenuated, the utility of it, after a prior exposure to nivolumab plus relatlimab. They quoted a response rate on the order of only about 10% for patients who got an ipilimumab-containing regimen after initial LAG-3. In the data from Hussein Tawbi at ASCO, however, in a small number of patients, caveat, the response rate was more in sort of the low 20% range, 22% to 25%. And so that would be a much more meaningful and important sort of consideration. If we do have independent activity, then lining up sequential therapies and the toxicities associated with each will become increasingly important as we think about how to maximize these kinds of treatments for our patients, but important longer-term data to show that the benefit is holding up and it's safe, and some new insights into what to do after progression on one of these regimens.

Dr. Diwakar Davar: So, pivoting slightly to combinations, we are going to be discussing a combination of TIGIT plus checkpoints. So tiragolumab is the FC-active TIGIT inhibitor from Regeneron-Roche and this is currently in multiple pivotal phase 3 trials, several of which have been negative, including SKYSCRAPER-01 in non-small cell lung cancer and SKYSCRAPER-03 in small cell lung cancer. The MORPHEUS platform trial essentially is a platform study evaluating multiple different combinations, in this case in liver cancer. And so we have a very interesting Abstract 4010, which is giving us an early readout of the evaluation of tiragolumab plus atezolizumab along with bevacizumab in unresectable, locally advanced or metastatic hepatocellular carcinoma giving us a result that is a little different from what we had seen from the prior negative results of TIGIT. So Jason, what do you make of these early results in the advanced HCC setting?

Dr. Jason Luke: I think these are cautiously intriguing results to really highlight the point is the third checkpoint possibly being LAG-3, now a fourth checkpoint maybe with TIGIT, but with all the caveats that you talked about. In this study, the flow is that there's a continuously accruing control arm which in hepatocellular carcinoma is a combination of atezolizumab plus bevacizumab, and then other arms are added where you add in a third agent. In this case, it's the anti-TIGIT tiragolumab. And in an intriguing fashion, the response rate to the triplet was 42.5% compared to the doublet which was only 11%. So that's a pretty big difference in this population.

Now, it wasn't the largest study, only 58 patients, but it was a randomized clinical trial. And so I think those data really make people kind of open their eyes again. It's worth a little bit of a caveat here that HCC is an unusual cancer in that what is deemed to be unresectable and therefore amendable to systemic therapy is a moving target and that requires multidisciplinary evaluation of patients. And so I think a larger number of patients would really be needed to fully understand this. But certainly, a fourfold increase in the benefit or in terms of response rate looks quite intriguing.

I think the other piece of this is to be just cautious a little bit was when the initial data in non-small cell lung cancer in the CITYSCAPE study came forward, and they looked roughly sort of like this: There was more than a doubling in the PFS and the response rate, which is what triggered all of those phase 3 studies. So to me, this is enough to continue to be very interested in TIGIT as a therapeutic target. And there are many phase 3 trials already ongoing. And so I think, I'm cautiously optimistic that some of those actually will be positive and we could see more movement around TIGIT becoming a standard of care agent.

Dr. Diwakar Davar: To your point about TIGIT being an interesting target, recent data looking at the neoadjuvant landscape in melanoma from Merck, with Merck, also FC-active TIGIT and also some data from authors looking at that TIGIT also presented in this case at ASCO specifically from the ARC-7 study. So very interesting target. Several pivotal trials have been announced. Do you know of any trials that are ongoing in the adjuvant setting in other diseases?

Dr. Jason Luke: Well, as you alluded to, the vibostolimab data in melanoma for TIGIT in the neoadjuvant setting was interesting. And in fact, that has been enough to trigger a global, randomized phase 3 adjuvant study of pembrolizumab and vibostolimab versus pembrolizumab in melanoma. And that sort of takes us back to the beginning of our discussion here, building on the KEYNOTE-716 data. So, yes, TIGIT will be moving forward in the adjuvant space in melanoma and obviously at a static setting for several different tumor types with a PD-1 or PD-L1 backbone.

Dr. Diwakar Davar: So now pivoting towards neoadjuvant therapy and non-small cell lung cancer. The standard of care in this setting was established by the CheckMate-816 trial that essentially established nivolumab plus chemotherapy in the setting of resectable non-small cell lung carcinoma path. Response rate in this setting is approximately 21%. And we have several studies that are essentially looking at novel combinations or in this case, different PD-1 inhibitors in this setting. So Abstract 8500 essentially looked at nivolumab plus relatlimab from a NEOpredict-Lung trial. Jason, do you want to tell us a little bit about this?

Dr. Jason Luke: Yes, I think this is a very interesting study and that this is sort of our first peek at targeting LAG-3 in the context of lung cancer. So obviously we talked about LAG-3 for melanoma. Although the audience is probably aware that there have been neoadjuvant data for LAG-3 with relatlimab in melanoma that substantiated the phase 3 data for the metastatic setting. So one of the questions as we start to apply the LAG-3 in other diseases would be, "Do we see it hold up in both metastatic disease and in the neoadjuvant space?" But in this study, while there were no changes in the safety profile; it didn't impact on whether or not patients could have surgery. There really didn't look to be a big difference in this study between nivolumab and nivolumab plus relatlimab, with the major pathologic response as you alluded to right around 30% for both arms.

Now, it wasn't really the biggest study, but that's certainly quite a bit in contrast with what we've seen in melanoma, where with a PD-1 inhibitor you get again 25%-30%, but with adding on LAG-3, that pushes you up closer to 60%. So I think these were very interesting data that probably put a little bit of an eyebrow raise to say, "Well, let's see what happens in the metastatic setting in lung cancer with the addition of relatlimab LAG-3 on top of a PD-1." I think it might not be quite so straightforward as what we saw in melanoma, but we'll look forward to those results because those phase 3 trials in metastatic lung cancer should be maturing sometime in the next year or two.

Dr. Diwakar Davar: The theme of neoadjuvant therapy non-small lung cancer, LBA100, which has again previously been discussed in an episode of this podcast by Dr. Jack West and Dr. Velcheti is KEYNOTE-671. And this is a study essentially that looked at pembrolizumab or placebo with platinum-based chemotherapy doublet and followed by resection. So again, a direct parallel to CheckMate-816. What do you make of the results that were reported by our colleagues in this setting, Jason?

Dr. Jason Luke: So not to rehash this, because our colleagues in the lung cancer group have already discussed this at length and obviously they're experts in that disease, but we'll just note that there was a threefold increase in major pathologic response, which turned into a major advantage for event-free survival. And so I think this is at least the third PD-1, PD-L1 combination regimen for neoadjuvant lung cancer that looks very, very promising. It certainly, to me, seems like neoadjuvant consideration really should be the standard of care already moving forward.

To me, what the big question that is left with is "Do we still need the adjuvant component after we give the neoadjuvant?" So, some of the trials are including neoadjuvant and adjuvant, some of them are only neoadjuvant. And I think that's going to be a really important question as we move into the future, both in terms of what is that contribution of the adjuvant component, and then again, going back to earlier in our discussion here, if there could be a major advantage to adding individualized neoantigen therapy, maybe it is important to have both. But I think that's one of the big questions we have to get teased out by the field over the next couple of years.

Dr. Diwakar Davar: And finally pivoting towards cutaneous squamous cell carcinoma. We have 2 abstracts discussing perioperative therapy. So cutaneous squamous cell carcinoma is a high-TMB tumor. The median tumor mutation burden in this disease is threefold that of melanoma. This is a disease in which checkpoint inhibitor therapy is approved as a single agent both with pembrolizumab and cemiplimab on the basis of nonrandomized phase 2 trials. And increasingly, there has been early development in the perioperative setting. The first data in this space came from our colleague Dr. Gross at MD Anderson, who reported in a small, nonrandomized phase 2 trial of 20 patients, a path CR rate with two cycles of cemiplimab at approximately 50%.

A larger multi-institutional phase 2 trial demonstrated that a longer duration of perioperative therapy of four cycles or 3 months of cemiplimab did not particularly improve the path response rates. The response rates were similar at approximately 50% as well. And what we have right now are 2 other trials. The first is the MATISSE trial, Abstract 9507 ,that evaluated nivolumab or nivolumab plus epilimumab in this disease. And the other one was the NEO-CESQ trial, or Abstract 9576, that evaluated neoadjuvant plus adjuvant therapy that's cemiplimab in the high-risk patient population. So we're starting with 9507. Jason, what do you make of the ipi and ipi-nivo data reported in this setting?

Dr. Jason Luke: So I think this is a really interesting study because I think part of the intent is the clinical aspect of how you manage patients with cutaneous squamous cell carcinoma. For those that don't do cutaneous oncology, many of these patients have the development of lesions, which can be actually quite difficult to resect in a way that's not otherwise mutilating or cosmetically quite problematic. And that was part of the impetus for this trial where, again, they looked at either monotherapy PD-1 or a PD-1 plus CTLA-4, and they saw great success. As was predicted based on the other data that you alluded to, response rates are more than 50% near 60%, with actually a substantial number of patients on the trial actually refusing to have surgery after they received their neoadjuvant therapy because they were so certain that they had had a good outcome.

So I think these data are quite reassuring in the context of all of this emerging data around cutaneous squamous cell carcinoma. We'll talk about this NEO-CESQ trial in just a second, but I think it really is emerging to be the standard of care very soon for the use of perioperative PD-1 for cutaneous squamous cell.

Dr. Diwakar Davar: What do you feel about the dose and schedule of checkpoint inhibitor therapy used here? So the dose of ipilimumab used was ipi-1 and not ipi-3, and they waited 4 weeks. So when patients only got two cycles of Q2 weekly nivo, and one cycle of ipilimumab, do you think the responses would have been deeper if they'd waited longer?

Dr. Jason Luke: I think it is possible that they might have been deeper, although I'm not totally sure about that. One of the other abstracts we're not directly mentioning here was a study in Merkel cell carcinoma which suggested that in fact, adding ipi and that also highly immuno-oncology-responsive tumor type did not add to the response rate. So I'm not totally sure about that. I think rather what would be most interesting here is sort of the sort of next generation of biomarker work.

As part of their presentation, the MATISSE trial team showed gene expression profiling that really strongly identified which patients were going to do well on the trial. And I think that's probably eventually going to be how we need to think about this. There are patients in the neoadjuvant setting who are going to do really well with anti-PD-1 alone. And then for those who aren't, that's where we probably really need to think about do we need combos, how long to give the treatment, etc. And I think we're really only on the cusp in the beginning of this, which is exciting as we think about moving into the future.

Dr. Diwakar Davar: Certainly, many combinations are being evaluated in this space and we are very excited for the data that it's about to hopefully come in the next couple of months to years.

So the NEO-CESQ – it's quite a puzzle as to how to pronounce this acronym – and this evaluated cemiplimab in the high-risk setting. So it's worthwhile noting that Dr. Gross's first trial looked at high-risk stage 2, 3, and 4 disease. So the context of cutaneous squamous cell carcinoma that's node-positive disease and distant metastatic disease that is in one location or patients with node-positive disease invention. And his multi-institutional cemiplimab trial of four cycles evaluated included patients with stage 2, 3, and 4 disease.

So here in a study just in stage 3 and 4 diseases, Dr. Ascierto reported the results of 2 cycles of cemiplimab and importantly, these patients had both the neoadjuvant and the adjuvant portion of cemiplimab. So, Jason, you mentioned earlier that one of the key aspects that we start thinking about neoadjuvant therapy is exactly how much do you need. Do you need both the pre-surgical therapy and the post-surgical therapy? Is the presurgical therapy enough? After all, neoadjuvant response equals cure. How much benefit are you getting from post-surgical portions? So what do you make of the results that they've seen here and what is the impact? How do you think we'll be disentangling the impact of the neoadjuvant and the adjuvant portion of the immunotherapy upon response and survival?

Dr. Jason Luke: So just to leverage those comments, I think these data are reassuring because in this higher-risk group of patients, they saw excellent outcomes very similar to what Gross et al had previously reported. So that's good. To your question about how we are going to disentangle this adjuvant versus non-adjuvant question, there's a trial in melanoma called the NADINA trial which is ongoing now in which the use of the adjuvant therapy is actually risk-adapted. So after patients have an initial neoadjuvant treatment they're evaluated, and if they have had a pathologic complete response, they're actually going to stop that treatment and they're not going to give the neoadjuvant therapy. And so I think obviously it's a slightly different disease, but those kinds of data, I think, will be very meaningful to help us sort this out.

And I'm not sure whether or not in cutaneous squamous we would need a different trial than in melanoma, although I think in a different tumor, maybe like, say, lung cancer, you probably would need a dedicated study to try to look at that because I think just the responsiveness to checkpoint blockade is going to vary quite a bit once you get outside of cutaneous oncology. But to summarize, reassuring that a similar pathologic response rate, and I think this question of adjuvant or nonadjuvant, I think that's the next question we've got to answer in the field.

Dr. Diwakar Davar: We have now come to the end of our back-and-forth discussion on these very, very exciting abstracts. So Jason, thank you for highlighting these advances and for engaging in a robust discussion.

Dr. Jason Luke: Thanks for having me.

Dr. Diwakar Davar: And thank you to our listeners today for taking the time to listen to this podcast. You will find the links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear in the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.

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Disclosures:

Dr. Diwakar Davar:

Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences

Consulting or Advisory Role: Instil Bio, Vedanta Biosciences

Consulting or Advisory Role (Immediate family member): Shionogi

Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences

Research Funding (Inst.): Zucero Therapeutics

Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy

Dr. Jason Luke:

Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX

Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine

Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure

Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)

Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio