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Jun 23, 2021

Dr. Jason Luke, director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center, discusses advances in immunotherapy across the spectrum of malignancies featured at the 2021 ASCO Annual Meeting.



ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Jason Luke, the director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center. Dr. Luke also serves as associate professor of medicine at the University of Pittsburgh School of Medicine.

His clinical focus is on immunotherapy for advanced solid tumors, as well as cutaneous malignancies and melanoma. He joins me to discuss advances in immunotherapy featured at the 2021 ASCO Annual Meeting. Dr. Luke has relationships with most of the pharmaceutical companies that have funded the research discussed in this episode. His full disclosures are available on the transcript of this episode.

Dr. Luke, always great to have you on the podcast.

Dr. Jason Luke: Well, thanks so much for the invitation today.

ASCO Daily News: Well, there was an abundance of novel therapies and practice-changing studies presented during this year's [ASCO] Annual Meeting. Did you detect any themes among all of the great studies presented during the meeting?

Dr. Jason Luke: Well, I agree. And as I was sort of taking the fire-hose of abstracts in this year, I thought there were four themes that really seemed to stand out to me. And when I was thinking through them, I think the first one was the validation of a new checkpoint, or a third validated checkpoint for use in clinical practice. A second one was really the emergence of immunotherapy, now being used in the curative setting, meaning either in adjuvant studies or in neoadjuvant studies.

And the third area was advancements in this management of metastatic disease with practice-changing trials. And then the fourth area, which is always near and dear to me, is novel therapeutics with the development of the next generation of immunotherapies, and those early data that might give us a hint towards what might be coming next.

ASCO Daily News: OK, so let's first look at the third validated checkpoint for use in clinical practice. That's Abstract 9503.

Dr. Jason Luke: Yeah, absolutely. So this year at ASCO, we saw the results of a clinical trial described as the RELATIVITY-047 study, which was a global randomized double blind phase II/III study comparing anti-PD-1 antibody with nivolumab (nivo) versus a combination of nivolumab with the anti-LAG-3 antibody relatlimab. And so LAG-3 is a molecule that many will be familiar with, but perhaps not everyone. And LAG-3 is another receptor on T cells that can become up-regulated as T cells become dysfunctional in the tumor microenvironment.

And so all are aware of the concept that infiltrating lymphocytes can get into tumors, and then they get blocked by these immune checkpoints. And so LAG-3 is another immune checkpoint expressed on these tumor infiltrating lymphocytes. And I don't have time to go into all of this, but in the preclinical space, blocking LAG-3 with an antibody is actually, in many mouse models, more effective than blocking a PD-1 or PD-L1.

And so there's been a lot of interest. LAG-3 was one of the first targets to really develop as a co-target to PD-1. And just to zoom forward then to the clinical trial, this was a study where patients with advanced, untreated, metastatic melanoma were randomized one to one to either get relatlimab plus nivolumab, in what they are describing as a fixed dose combination, meaning that there's an infusion of the dose once a month, relatlimab 160 milligrams plus nivolumab 480 milligrams. And that was the same dose. And so it's only one infusion, even though it's two drugs, one infusion.

That was compared with nivolumab. And there were a number of stratification factors, et cetera, in the study. And they're useful to get into the minutia, but right now, I think not so important. This, like I said, was a gated study, meaning they did a phase II trial first, to try to prove that there was a benefit in a smaller sample of patients. And if they hit the endpoint, they then went on to a phase III trial. And that's exactly what happened.

So in this trial, progression-free survival (PFS) was the primary endpoint. And, interestingly, it was evaluated by blinded independent central radiology. And that may sound like a mouthful, but we'll come back to why that's important a little bit later. And there was a hierarchical testing strategy, such that the PFS had to be established first, before the investigators can look at overall survival and overall response rate.

But given that background, there really was a quite substantial and clinically impressive difference between these two arms. And so we call relatlimab "rela" for short. So rela plus nivo demonstrated a substantial improvement, markedly statistically significant improvement, compared with nivolumab monotherapy, so that at 1 year, at 12 months, the progression-free survival for the combination arm was 47.7%, compared to 36% for nivolumab.

And the median PFS was 10.1 months for the combination versus 4.6 months from nivolumab. So you can see that's more than a doubling of progression-free survival, with a hazard ratio at 0.75 and a p value at 0.006 or 0.0055. So why does that matter? Well, we have thought for a long time in the field about combination immunotherapy, and people think of PD-1 and CTLA-4 combination.

And these data, when compared sort of across trial comparison, which is always a little dangerous, but they look very similar to what we saw with nivolumab plus ipilimumab (ipi), in terms of the absolute improvement in the benefit in terms of median progression-free survival, between relatlimab plus nivo, as compared with ipi plus nivo in the CheckMate-067 study. And I mentioned this blinded independent central radiology, that complicates things a little bit, because the landmark comparisons between having the radiologist evaluate the scans and having the investigators evaluate the scans, actually gives a little bit of variation in terms of the outcomes. But if you just compare them on a high level, they actually look very similar.

And along those lines, the really important thing is that relatlimab plus nivolumab is much better tolerated with much less side effects than nivolumab plus ipilimumab. So, in fact, in this clinical trial, we see that the rates of grade 3-4 adverse events are on the order of what we saw with nivolumab monotherapy in CheckMate-067. Now, interestingly, in this study, RELATIVITY-047, the rates of grade 3 adverse events for nivolumab monotherapy were actually about half of what they had been seen in the previous phase III trial.

And I think that that just suggests that all of us, as a field, are getting better at managing these immune therapy toxicities. One other piece of information that was very interesting to look at was when the outcomes were broken down by subgroups, particularly the biomarkers of PD-L1 positivity, and LAG-3 positivity. These biomarkers actually did not inform the outcomes, in which case, I mean, that nivolumab plus relatlimab was actually effective across all the subgroups.

And so one might have hypothesized, going into this, that patients with high LAG-3 would do better with a LAG-3 treatment. That was not what was seen. In fact, all patients benefited with the combination. And that's relevant to clinical practice, because, as we think about applying this treatment, I do not think we're going to be able to use biomarkers, at least initially, to be able to differentiate who should get what. And rather this just suggests that basically all patients who are going to get PD-1 monotherapy would be better served by giving the combination.

So I was the discussant actually for this abstract, and one of the questions I tried to get at was, well, does that mean that you would just essentially replace PD-1 monotherapy across the board in melanoma with this combination? And I think the answer is, not quite yet, but maybe someday. And what I mean by that, is that there are still some very high-risk patients that we treat. And particularly those are patients with high lactate dehydrogenase, brain metastases, rapid progression, et cetera.

And those are the patients where, at least I, predominantly use nivolumab plus ipilimumab, or nivo plus ipi. And that's because nivo plus ipi is the treatment for which we have the best long-term data, and we know the most about it in terms of treating high risk patients. So I would continue to use that until this trial, at least. Is more mature, so that we can get data about the response rate, the overall survival, and so on and so forth.

But I think there's really no question, looking at this relatlimab plus nivolumab data, that it does change the standard of care in melanoma, and that, for most patients, who would have gotten PD-1 monotherapy, they're now going to be directed towards this combination, given it's well tolerated and appears to be highly active. And I think, thinking beyond melanoma now, if this is now a second, a third checkpoint, but a second one we can combine with nivolumab with little toxicity, I think it opens up a huge new world of clinical investigation, possibly adding doublet checkpoint to chemotherapy.

Basically everyone everywhere we've seen PD-1 combined with chemotherapy, and obviously that's quite exciting just thinking about improving outcomes. And we're going to discuss all the different ways that PD-1's been impacting the standard of care across different settings.

ASCO Daily News: Excellent. Well, let's shift our focus now to the curative use of immunotherapy. Let's start in the adjuvant setting with the KEYNOTE-564 study. That's LBA 5.

Dr. Jason Luke: So plenary presentation for the KEYNOTE-564 study, which was adjuvant pembrolizumab versus placebo in high-risk renal clear cell renal cell carcinoma. And so this is an important trial, because there have been decades, actually, of immunotherapy clinical trials in the adjuvant setting, which have not demonstrated a benefit. That also includes actually VEGF-TKIs, which also did not show a benefit.

But in this large study, so almost 1,000 patients, 994 patients, they were randomized one to one to receive pembrolizumab or placebo. And the eligibility population were pathological T2 with intermediate and high risk features all the way through metastatic disease that's been fully resected. And the outcomes here, again, I think were very impressive. And so the disease-free survival was statistically significant, with a hazard ratio of 0.68.

And what does that mean in reality? Well, the 2 year disease-free survival was 77.3% for the patients getting pembrolizumab compared to 68.1% for those getting the placebo. So you can see basically a 10% 2 year improvement in disease-free survival. And though the data were quite immature, the early analysis of overall survival also suggested a statistically significant benefit.

So p value was 0.02 and hazard ratio was 0.54. Now we'll be very interested to see how that matures over time. But I think again these are practice-changing data, to suggest that, basically, all high-risk patients with clear cell renal cell cancer are now going to be receiving anti-PD-1 immunotherapy in the adjuvant setting. I think it does raise the question, and we'll discuss it now across other diseases as well, in terms of, are we over-treating patients.

But this has been a constant struggle in medical oncology for many, many years. But it's very hard to see a treatment like this, with such a benefit, and not think that you want to give this basically to almost all the patients. But, hopefully, biomarkers to inform which patients benefit most will be coming over the relatively near future for renal cell. But I think those are becoming a little bit more obvious in some other diseases.

ASCO Daily News: Looking at non--small cell lung cancer, Abstract 8500, that's the IMPOWER-10 trial, that caught a lot of attention. That was trending on Twitter for a while. What are your thoughts on that trial?

Dr. Jason Luke: Yeah, absolutely, so the IMPOWER-010 or 010 study, this study looked at PD-L1 inhibition in the adjuvant setting, versus a placebo. So this was another very large trial where patients with early to later high-risk disease, so stage 1b to 3a, they received standard chemotherapy as adjuvant treatment, but then were randomly assigned to get PD-L1 versus best supportive care. And this was an interesting clinical trial, [ and] had a complicated statistical design where the first analysis was to look at the impact in PD-L1 positive patients.

Secondarily, then, they looked at randomized patients. And then thirdly, they looked at intention-to-treat. And this was a positive study. So in the disease-free, in the PD-L1 high patient population, the disease-free survival did not reach the median, with a 2 year benefit at 74.6% versus 61%, so again a 13% improvement in 2 year disease-free survival.

And that was highly statistically significant, hazard at 0.66. And, again, that's the PD-L1 high population. So, thinking about biomarkers then, it looks clear that the PD-L1 positive group is the one that disproportionately benefits, because as we went through the rest of the hierarchical testing, the disease-free survival in randomly assigned patients, and then in intention-to-treat patients, those numbers got a little less strong. And it really probably suggests that the PD-L1 positive group is the one that's going to drive almost all of the benefit.

So it'll be interesting to see how this data matures, and how it's interpreted in the community. I mean, you mentioned the discussions on Twitter, which I sometimes participate in. And I'm going to come back to a little later how it's very interesting to see how thought leaders for various malignancies sort of take these data into consideration. I think clearly in GU cancers, when we talked about the KEYNOTE-564 pembrolizumab data, the sense was, this is an immediate change in the standard of care.

When we look at this data for non--small cell lung cancer, however, the sense I've gotten from some investigators is, this is early data. And they really do want to see that overall survival before that's really going to have high uptake. But we'll have to kind of see how that goes.

Maybe selecting for PD-L1 in that population would make that difference, to really let you feel confident. But it'll be interesting again, like I said, as more time passes and as we see more data, and as other PD-1, PD-L1 agents come into this same space, if there's reproducible data that will help them feel more confident.

ASCO Daily News: Right, well, another trial that attracted a lot of attention was CheckMate-577. That's Abstract 4003. Do you think this trial will move the needle in esophageal or esophagogastric junction (GEJ) cancers?

Dr. Jason Luke: So I think this is a real important trial, because we've historically thought of certain tumor types as immunotherapy sensitive versus not sensitive, melanoma, lung cancer, et cetera. And gastrointestinal (GI) tumors predominantly have fallen into that latter group, where we think where there isn't as much of a benefit. Obviously there are approvals for esophageal and gastric cancers, but I think this study really shows how we can move the needle in terms of maybe curing more patients.

So CheckMate-577 looked at adjuvant nivolumab. And these were stage II and stage III patients with esophageal or GEJ, and they got neoadjuvant chemoradiation treatment and then surgery, all of that being standard of care, but then went on to get a randomization 2 to 1 to either nivolumab or placebo. And again, as you mentioned, this is an important trial. The disease-free survival (DFS) was statistically and substantially improved for the patients getting nivolumab versus placebo, after that definitive therapy.

So in the group receiving nivolumab, the median disease-free survival was 22.4 months, compared to only 11 months in the patients getting the placebo. That was a hazard of 0.69 and a p value at 0.003. And, again, thinking about biomarkers here, there was a broad population of patients treated. But when you look at the breakdown of who benefited the most, the patients benefiting in this trial were almost entirely those patients who had a PD-L1 composite signature at greater than 5,  combined positive score (CPS) greater than 5.

And so it's really the case that the PD-L1 positive patients with esophageal cancer seemed to benefit the most. And so I don't know how you think this doesn't impact the standard of care. In the total population there was a doubling of DFS, and in the PD-L1 high it was actually almost a tripling. And so I think, immediately, at least for PD-L1 high patients, they should go on to get adjuvant PD-1 after definitive chemotherapy, radiotherapy (RT), then surgery. And I think this is really exciting, when we think about, this is disease, obviously, it's very, very difficult to treat. And outcomes in metastatic disease are not what we want. And this really suggests we may be able to really benefit a lot of patients moving forward.

ASCO Daily News: Excellent. So what are your takeaways from Abstract 9500, the KEYNOTE-054 trial of adjuvant pembrolizumab for melanoma?

Dr. Jason Luke: Yeah. Thanks, so in melanoma we've had immunotherapy with checkpoint blockade now for a decade. And adjuvant clinical trials have been ongoing for most of that decade. And it's been standard of care to give our patients checkpoint blockade again for several years. I think what was really interesting about the update for KEYNOTE-054, which was the study of pembrolizumab (pembro)  versus placebo in stage III melanoma, was the authors on this update looked at the impact of crossover after initial progression.

So in the clinical trial, patients were randomized one to one to either receive pembro or placebo. And at the time of progression, they could then cross over and get the other treatment, right? So this trial was the first trial to be designed to be able to ask that question, immunotherapy now versus immunotherapy later.

And what we observed in this study was that the response rate to getting pembrolizumab in the metastatic setting, if you had gotten the placebo on the adjuvant trial, was approximately similar. It was right around 40% And that's actually what we saw on the KEYNOTE-006 study that got pembrolizumab registered. So that was really, really interesting. And it suggested that if patients progress in the adjuvant setting and get treatment with PD-1 in the frontline metastatic, and they're still in good shape, they actually can have similar outcomes than what we would have expected if they had not had that adjuvant experience.

And so I think this is really important. It doesn't actually answer the question about overall survival, which is really what we want to know. Does adjuvant immunotherapy improve overall survival? But it does suggest that patients can have this benefit, even if they wait for treatment. One thing that was really interesting to see was that, for those patients who had pembrolizumab, in the adjuvant setting, and then had a progression event, who went on to get pembrolizumab again, actually had much lower outcomes.

And so I think that that's something to be cautious about. I think if patients progress on adjuvant PD-1, the data from this trial really suggest that going back to PD-1, even if there's been a period of time, is not a real great idea. And many of us in the field have kind of advocated of going to CTLA-4 combination in those patients anyway. But I would think these data really do suggest that that's important.

So broadly speaking, then, I think these data are important to suggest that if you wait to give immunotherapy, you can still get a good benefit, at least in melanoma. And what I thought was really interesting across all of these abstracts, so for kidney cancer, lung cancer, esophageal, melanoma, was we saw, I think, based on the investigator feedback, or the thought leaders in the field, was that disease-free survival or relapse-free survival was really interpreted somewhat differently in different settings. And so I think, in melanoma, I think we have for a long time thought that adjuvant therapy was important, despite the fact, we don't have overall survival for PD-1 antibodies.

In the renal cell data, again, where immunotherapy has been a backbone, albeit with IL-2 and various different immunotherapies, again, a lot of enthusiasm. When we looked at lung cancer and esophageal cancer, where I think investigators are more used to biomarker selection, they were a little more nitpicky about which populations we should treat. And so I'm very interested to see how this entire field sort of develops, and how the thought leaders for each disease take these data in.

But, if you take a step back, on a really high level, when we think about giving PD-1 checkpoint blockade, it's generally speaking a low-toxicity treatment. And there's a tremendous impact on recurrence and potentially cure in the adjuvant setting. And that is just so exciting when we think about truly making a difference on cancer. We're talking about people never having recurrence and never dying of metastatic disease.

And if we think about the outliers among the thousands of patients that have these diseases, and just go out to 5 years, 10 years from now, that's going to be a lot of people alive because they got immunotherapy after surgery.

ASCO Daily News: Well, that would be fantastic. Thanks, Dr. Luke, for your great analysis of the adjuvant setting. Let's focus now on the neoadjuvant setting. Abstract 8503, the CheckMate-816 trial, seems to be on everyone's radar. What can you tell us about it?

Dr. Jason Luke: Absolutely, so I think we just got done talking about adjuvant therapy. But an alternative would be to say, is there a way that we can deliver this immunotherapy, perhaps to enhance the immunotherapy and either improve the surgery or actually maybe even avoid the surgery, moving into the future. And so that is a really exciting paradigm as well.

And so the first of these was in non--small cell lung cancer, the CheckMate-816 study. And the initial results of this study were actually presented at AACR earlier this year, but now updated here at ASCO. And what we saw was that there was a major improvement, 10 times improvement, in pathologic complete response for giving nivolumab plus chemotherapy. I mean literally 2% pathologic complete response with chemotherapy, up to more than 20% with this combination with immunotherapy.

And what the investigators updated here was a number of details around the surgical plans, showing that the surgeries were easier, and the patients had better time recovering, due to lower disease burden for those that got the combination with immunotherapy. And I think that's really, really exciting, because, I mean, it suggests a paradigm in the future where we can reduce the amount of surgery. So one of the things was they looked at the number of open thoracotomies versus VATS procedures.

And a number of patients who got immunotherapy had a much lower surgical burden. So, I think those data are really exciting. They're not quite ready for prime time yet, because I think we need larger studies to prove this, but I think the trend is, we'll talk through these different disease settings, really does suggest that immunotherapy is going to really change all of oncology, in terms of surgical paradigms, how we follow patients, et cetera.

ASCO Daily News: Excellent. Dr. Luke, you spoke earlier about the phase III study of relatlimab and nivolumab. There's another study, Abstract 9502 in the neoadjuvant setting, right?

Dr. Jason Luke: Yep, and so, in addition to the phase III data for relatlimab, there was also a neoadjuvant study from The University of Texas MD Anderson Cancer Center group, which I think was really, really useful in helping us feel more confident actually about the metastatic disease data, and about understanding where the field in melanoma is going. So, in melanoma, that's where, sort of taking a step back quickly to note that there have been a whole bunch of neoadjuvant clinical trials done over the last 3 to 4 years, and actually so many that we've already started to have meta-analyses to look and see and observe, I should say, that those patients actually who have major pathologic responses, and those with complete responses, generally speaking, don't recur. And this is really exciting.

It's actually even led to clinical trial designs where we're actually deferring surgery in melanoma, where we give neoadjuvant therapy. We take out one node. And if it's a complete response (CR) we don't even do the surgery. So in the Abstract 9502, again relatlimab, the anti-LAG-3 antibody was combined with nivolumab.

And I think what the important thing to highlight here was that the rates of pathologic complete response and major partial response actually looked very similar to what we saw with nivo plus ipi in previous clinical trials. So if you remember, the relatlimab data in the metastatic setting was only the PFS data, due to the statistical plan. But what we see here is that in the neoadjuvant setting, very similar outcomes for relatlimab plus nivo as what would have been expected for ipi plus nivo.

And I think that gives us, again, more strength and more confidence that this is a very active combo, again, with lower toxicity relative to nivo plus ipi.

ASCO Daily News: OK, well, Abstracts 4503 and Abstract 4504 looked at alternative management strategies in bladder cancer. Can you tell us about these data?

Dr. Jason Luke: So these were two really interesting abstracts, I thought, from my perspective. And they really looked at management, alternative management strategies for muscle invasive bladder cancer. And so the first one, 4503, was the Hoosier Oncology GU study 16-257. And this was a study that looked at neoadjuvant nivolumab plus gemcitabine and cisplatin, with an evaluation for clinical outcome.

So what I mean by that was, after the patients got this treatment, they were evaluated for whether or not they had had a clinical complete response, and then they were offered the opportunity to either not pursue cystectomy, which obviously is highly morbid, or to continue to be followed. And, very interesting, the study, for those patients who were deemed to have had a complete clinical response, 70% of them did not recur. And that's really exciting, because if you think about the population of patients with bladder cancer, many of them elderly, those cystectomies are highly morbid surgeries.

And this suggests that we may be able to move into a future where we could give them upfront medical therapy and actually potentially avoid that surgery. The other abstract I thought was really interesting was sort of married to that, which was the 4504 abstract. And that was a clinical trial that looked at the neoadjuvant administration of pembrolizumab plus gemcitabine chemotherapy and radiation treatment. And, again, what they observed in that study was very high rates of pathologic complete response, and longer term outcomes that looked very exciting.

And I think what both of these studies show, as phase II studies, is the possibility that medical therapy might actually be curative in some patients. And there are a number of phase III efforts now ongoing to try to amplify these trials and actually confirm them on a larger scale.

ASCO Daily News: Shifting our focus now to practice-changing trials in metastatic disease, GI oncologists were very pleased to see the data from CheckMate-648. What was observed in this trial, LBA 4001?

Dr. Jason Luke: So CheckMate-648 in esophageal cancer was a study in the frontline metastatic setting, looking at the impact of immunotherapy plus chemotherapy, or immunotherapy alone versus chemotherapy. And so what I mean by that was one arm in the study looked at nivolumab with standard chemotherapy, compared to chemotherapy, and the other arm looked at nivolumab plus ipilimumab versus chemotherapy. And, very briefly, what was observed was that both of the active arms, so the immunotherapy containing arms, the nivo plus chemotherapy or the nivo plus ipi, both of them improved outcomes compared with chemotherapy.

And so, moving forward, there's really no question now that the standard of care in the frontline management of esophageal cancer should include immunotherapy, either as a combination with chemotherapy, or possibly with leaving out the chemotherapy and giving just nivolumab plus ipilimumab. Now the sub-stratification of patients and their outcomes by sub-stage was important in this study, and again emphasized that it's mostly the PD-L1 positive patients who benefited the most from immunotherapy. So but the idea of potentially having a regimen that's chemotherapy-free for frontline esophageal cancer, I think is really exciting.

And I'd be really interested to follow where this field goes in terms of which patients are getting selected for the nivo chemotherapy versus ipi plus nivo arms, in standard practice kind of moving into the future. And obviously further biomarkers will be really important. But I think this is really a practice-changing trial, again, to emphasize that all patients with esophageal cancer should be getting immunotherapy in the frontline, moving forward.

ASCO Daily News: Indeed, what can you tell us about Abstract 6000 using camrelizumab for nasopharyngeal carcinoma (NPC)?

Dr. Jason Luke: Yeah, absolutely. So I think that this is a really interesting study and I think important. This is a study actually looking at the impact of adding immunotherapy to chemotherapy in nasopharyngeal carcinoma. So all the oncologists in the United States will be like NPC, oh, yeah, I heard about that during fellowship. But this is actually a major source of morbidity and mortality throughout the rest of the world, especially in the developing world.

And so this clinical trial to me is very interesting. So the short story here is that adding camrelizumab improved outcomes relative to chemotherapy, which I think is probably not surprising, because across many other settings we've seen that adding PD-1 to chemotherapy would improve outcomes. I think the difference here was that this is an antibody that was developed in China. And is it part of a growing trend to see competitor PD-1 PD-L1 antibodies entering the space.

So to close the loop on NPC, I think these data really strongly suggest that we should be giving immunotherapy in combination with chemotherapy in the frontline to these patients. But I think, more broadly, start to open this conversation about how are we going to evaluate new drugs that are getting developed, say, only in China, or in other parts of the world where there are no patients from the United States that are actually participating in the clinical trial. Are those drugs going to get approved by the U.S Food and Drug Administration (FDA)?

And if they do get approved by the FDA, how are they going to get priced, because as we're moving into the era now of more than 10 anti-PD-1, PD-L1 antibodies that have shown a benefit in the metastatic setting in phase III trials, one could imagine the time has finally come for price control, and not control, but price competition. It'll be really interesting to see whether or not that actually comes true. I don't know the answer yet. But this trial, I think, is very important in that regard.

ASCO Daily News: And back to melanoma, can you tell us about advances in the metastatic setting?

Dr. Jason Luke: Absolutely. So I think there were two to hit on quickly. Obviously there were more, but two quickly to hit on. One was Abstract 9506, which was the long term update, 6 and a half years of CheckMate-067, which people remember was the nivolumab plus ipilimumab versus ipi trial. And just to summarize this quickly, it really was amazing to see that now at 6 and a half years, we finally hit the median for overall survival for patients with metastatic melanoma in the frontline setting.

And the median was 49%. So it just barely went under the median. But I just can't emphasize, when I was a fellow, and actually I'm a melanoma oncologist, and coming into this, the outcomes for patients at that time, the median survival was 9 months. And now we're talking about 10 years later, and the median is basically, it's 6 and a half years, almost 50%. So it's just outstanding. And I can't emphasize it enough.

Clearly not good enough. We still have 50% of patients who need better treatments. But it's pretty exciting. The other abstract I wanted to highlight, because I think it differentiates where things stand, was the Abstract 9505, which was the tumor infiltrating lymphocyte (TIL) lifileucil in melanoma. And, again, just to highlight this, 36.5% response rate to re-infusion of TIL with interleukin-2. And I think that that's going to be an important part of the armamentarium for melanoma management, moving into the future.

One final metastatic disease abstract to highlight was the development of T cell receptor (TCR) T cells for synovial sarcoma. So this was a really important abstract as well, going along with the lifileucil abstract, because I think this showed that this is a really active regimen with adoptive cell transfer for synovial sarcoma. And I would very much expect to see that both the TCR T cells and the TIL product get approved by the FDA within the coming year.

ASCO Daily News: Excellent, well, before we wrap up the podcast, can you share some highlights from your main research area, developmental therapeutics?

Dr. Jason Luke: Yeah, finally, so in the realm of developmental therapeutics, which is my major research area, there's always a lot going on. And I think this year's ASCO Annual Meeting I would just highlight a few things. So one is the continued development of VEGFR2 tyrosine kinase inhibitors (TKIs) with immunotherapy, we saw long term updates with lenvatinib and pembrolizumab in melanoma (Abstract 9504). And we saw other updates with new combinations in colorectal cancer.

Another area in terms of considerations were small molecule inhibitors. And so there was a really interesting abstract about an MDM2 inhibitor. And people will remember that's a regulator of P-53, being combined with pembrolizumab. And preclinically and translationally, in this abstract, it appears that modulating the P-53 pathway via MDM2 actually has immunomodulatory effects. So it'll be very interesting to see where alrizomadlin goes (Abstract 2506). 

There are a number of other novel targets. And there's so many abstracts on these that I'm not going to really go through them in a lot of detail. But TLR-7/8 agonism with checkpoint blockade looks interesting (Abstract 2512). There were a number of abstracts around transforming growth factor, TGF beta. And this is a really important target in cancer. And it'll be interesting to see how that gets developed out further.

There were a number of approaches looking at targeting of human papillomavirus or HPV, one of them, which was a triplet regimen of an HPV vaccine plus a cytokine plus a PD-L1 antibody, and another one which was some viral vectors expressing HPV proteins. So all of this, I think, very interesting and taking sort of orthogonal to checkpoint approaches in terms of immunotherapy, vaccines, cytokines, viral vectors, et cetera.

And then the final area, just to highlight, there was one very interesting Abstract 2507, which was a novel CAR T-cell product, which included a 41BB activation domain, attached actually to a bispecific CAR that binds to both CD19 and CD20. And this was Abstract 2507, and what I thought was very interesting was the rates of response for this molecule are really high, almost 100%. And that even included patients who had previously progressed on other CAR T products.

So not enough time to go and give justice to any of these, but there's so much going on in developmental therapy for immuno-oncology. And I think that just emphasizes how bright the future is, building on this tremendous benefit in the standard of care setting in the adjuvant and metastatic settings. So, very excited to see where all these molecules go, and hopefully to advance the outcomes for all of our patients.

ASCO Daily News: Indeed. Dr. Luke, thank you, as always, for your fantastic insight on some tremendous advances in immunotherapy, across the spectrum of malignancies. Our listeners will find links to all of the studies that you discussed in the transcript of this episode. Thank you, Dr. Luke.

Dr. Jason Luke: Well, thanks so much for the opportunity.

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Disclosures: Dr. Jason Luke

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

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, Immunocore, KSQ Therapeutics, Inzen, Pfizer, Silicon Therapeutics, TRex Bio

Research Funding (Institution): Merck, Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor,

Research Funding: 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., Trishula Therapeutics, BioNTech AG, Scholar Rock

Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), 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

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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.