Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to “Investigator Perspectives on Available Research and Challenging Questions in the Management of Melanoma and Nonmelanoma Skin Cancer.” Today we’re going to talk about what happened at ASCO as it relates to these 2 critical tumors. We have a great faculty: Dr Nikhil Khushalani from the Moffitt Cancer Center in Tampa and Dr Jason Luke from the UPMC Hillman Cancer Center and University of Pittsburgh in Pittsburgh, Pennsylvania.

As always, if you have any questions or cases you’d like to run by us just type them into the chat room. We’ll talk about as many of these as we have time.

As we do in all of our webinars, there’s a 1-minute premeeting and postmeeting survey in the chat room for you to take. If you do that, you’ll get a lot more out of this experience.

We know a lot of people end up listening to our programs. If you’re into podcasts check out our Oncology Today series, including a recent program on nonmelanoma skin cancer with Dr Khushalani and Dr Pavlick.

We do webinars all the time now. We’ll be doing one next week with Dr Gubens talking about what’s happened in nontargeted approach with lung cancer, immunotherapy, ASCO and more. Another program following ASCO on renal cell cancer, and then we’ll be doing a program on triple-negative breast cancer with Drs Kalinsky and McArthur on the 20^th. A gynecologic oncology program talking about what’s going on there, particularly endometrial cancer is pretty hot nowadays. We’ll talk about that with Dr Chase. And then we’ll be doing a program on antibody-drug conjugates. We’re seeing that throughout oncology. We’ll see if we can see that in melanoma at some point. And then on the 26^th we’ll be doing a program there on breast cancer. We’ll talk about ALK-positive management with Dr Peters on the 27^th.

But today we’re here to talk about melanoma and nonmelanoma skin cancer, particularly what happened at ASCO, and particularly of course the huge plenary presentation on the neoadjuvant NADINA trial.

As always, we’ll be talking about some new agents that are not approved and new treatments not approved. Check out the package inserts for more information.

So basically, we asked the faculty here to put together a talk talking about what happened at ASCO. We’re going to explore what it means to clinical practice, but also a little bit about where we are today.

And I thought we could just start out, because we’re going to talk about melanoma to begin with, and Jason, I don’t have to tell you what the big story of the year in a long, long time now in melanoma, the NADINA trial. We’ve talked with Dr Georgina Long so many times over the last couple years about this study, the whole neoadjuvant approach. But here are some of the other data sets that we’re going to talk about here.

Evidence-Based Treatment of Nonmetastatic and Metastatic Melanoma — Dr Luke

DR LOVE: But let’s just talk a little bit, before we get into the NADINA study and all the other things that happened at ASCO, about where we are today in general, particularly from the point of view of the general medical oncologist in community-based practice in terms of neoadjuvant and adjuvant therapy, localized melanoma, and also metastatic disease, which of course we’ve seen a big shift towards immunotherapy first line.

So Jason, do you want to start out and just provide a little bit of a macro view about melanoma in the general medical oncology practice, some of the issues that you see docs confronting, before, we get into the new things?

DR LUKE: Yeah. So thanks very much for having us today and for facilitating this discussion. I really think in melanoma it’s become immunotherapy, immunotherapy, immunotherapy, right, and that’s moved from metastatic disease then to adjuvant and now into the presurgical neoadjuvant setting, where we had data dating back to a couple years ago suggesting that just moving a couple doses of pembro from adjuvant to neoadjuvant improved outcomes by upwards of 30%.

And now at this meeting, at ASCO, we have an update for combination immunotherapy with nivolumab and ipilimumab really showing an outstanding benefit to giving 2 doses prior to surgery, and we’ll go through the exact details of the trial here in a little bit. But I emphasize this point that for macroscopically palpable Stage III melanoma the standard of care now is for consideration of presurgical systemic therapy, and then likely a response-adapted therapy thereafter.

And that is a big-time shift from when I started my career 15 years ago, where dermatologists sent to surgeons, and they did the best they could, and then they sent to med onc, and there wasn’t much that could be done thereafter. And that’s completely flipped on its head now. So you really need multidisciplinary care of these patients and evaluation in order to appropriately adjudicate them.

DR LOVE: So Nikhil, multidisciplinary care has always been a huge theme in oncology, but in terms of melanoma and nonmelanoma it really seems at this point critical. And I wonder how this really plays out in the community. Who are the surgeons who actually do the surgery in the community? We were talking before about what kind of interdisciplinary setting melanoma/nonmelanoma skin cancer fits in. Any thoughts about that, Nikhil?

DR KHUSHALANI: Certainly. And again, thanks for inviting me to this program. It’s a pleasure and privilege to be here.

From a community perspective I think a lot of these operations for skin cancers are done by general surgeons, by certain surgical oncologists and certainly a lot by plastic surgeons, particularly when we are talking about skin cancers on the head and neck area. We also have a group of ENT specialists, as well as head and neck surgeons. So I think it becomes critically important for the point of view that Dr Luke mentioned, to have multidisciplinary involvement, because eventually all of these roads will end up coming to the radiation oncologist in selected cases, and certainly to the medical oncologist as well. So if we are able to harmonize their management from a multidisciplinary perspective early in the course of management, particularly given some of the changing paradigms that we’ll discuss for what traditionally was a surgical disease or diseases and now is actually rapidly changing to immunotherapy-responsive disease with surgery possibly even being de-escalated in some cases.

DR LOVE: So Jason, I have to ask. Susanna in the chat room asked about something I don’t know anything about. I just looked it up. The DECISionDX-Melanoma from Castle Biosciences. Any tools out there? Now we’re really digging deep into adjuvant therapy here, neoadjuvant therapy. Any thoughts about genomic evaluation, predictions of risk of recurrence, where you see that heading, Jason?

DR LUKE: Yup. That’s a great question and one that we’re still actually struggling with, I think, as a field. So whereas in breast cancer there are validated assays to help guide the use of chemotherapy in early-stage disease, in melanoma we’ve got hints of such a thing, but we haven’t really put that into practice yet.

So there is a clinical assay on the market, although not evaluated by the FDA, that can give a risk assessment that can sometimes be valuable in the context of standard AJCC staging. I’d caution that there are no data yet to suggest that a patient should be treated in the adjuvant setting based on those gene expression data, and yet there’s no doubt that we overtreat patients in the adjuvant setting because more than half of them are already cured, and we certainly — it would be valuable to figure out who we should really treat. And frankly, even in earlier stages of melanoma, Stage I/II, there’s a sizeable number of absolutely — on an absolute level of people who progress.

So I think that’s something to watch. We don’t get it on all of our patients, although it is pretty pervasively ordered from the dermatology community. So it’s something certainly patients will ask about and thinking about how to integrate that is important in your practice.

DR LOVE: So Nikhil, at Research To Practice we have a little joke. We have a poll on how long it’s going to take every time we do a webinar for somebody to ask about cell-free DNA. And I decided I’m going to like actually do it myself right now because when you talk about adjuvant therapy, and you look across oncology, colon cancer and more, that’s another issue that complements the strategy of risk of recurrence. What do we know about cell-free DNA, particularly in MRD, the BESPOKE type approach to melanoma, Nikhil?

DR KHUSHALANI: I think the data is still maturing. I think we will certainly see much more over the next probably year to 3, as existing trials that have incorporated using circulating tumor DNA into practice really try and help us discern which are patients, particularly from an adjuvant/neoadjuvant perspective, that are even higher risk for recurrence.

To me the ideal circumstance would have been, number 1, in patients who have already been resected and come to us for postoperative management, can we stratify, risk stratify that based on the presence or absence of cell-free DNA? But more importantly, the key issue, while they may serve as prognostic, does that matter? I mean, would that change our practice? And I think that’s where these prospective trials, that all of the adjuvant trials now virtually incorporate the use of circulating tumor DNA.

So I think we’re in for a large influx of data in this regard. Right now we don’t routinely use it in clinical practice. I certainly don’t use it to make changes to my practice paradigms, even in the metastatic setting. I do have patients referred to me from the outside where they’ve had serial, like for example the Signatera assay, that has been performed, and you get very good objective data, but what does that mean? Does it affect their prognosis? Does it predict whether or not we should treat them or not treat them or even make changes? So I think prospective validation is certainly pending.

DR LOVE: Yeah. It’s really interesting to see how different disciplines react in cell-free DNA. They start seeing people doing the assay. People are like where’s the data. How’s it going affect your decision?

It reminds me a little bit, though, in the early Oncotype days, and that people would say well, we don’t do an Oncotype in this situation. And I would go, well, suppose the surgeon did it, and the recurrence score was high and usual people react. So I don’t know if that’s coming to melanoma or not, but it certainly has come through a lot of parts of oncology.

So Jason, with that as just a little bit of a warmup, let’s talk about what happened at ASCO. And of course we’ll get into NADINA as well.

DR LUKE: Sure. So I mean I think we’ve seen some big-time changes throughout the course of the meeting, and a number of new therapeutic modalities that I think I want to make sure that people are cognizant of.

And so we will first talk about the NADINA trial. So this was neoadjuvant nivo plus ipi versus adjuvant nivolumab in macroscopic Stage III. And so the study design is important to be aware of in this trial. So these were patients who had high-risk disease that generally speaking was palpable, as you see on the left-hand side, stage III, and did not have prior therapy.

And patients then were randomized into 2 arms, A or B. And in Arm A they received 2 courses of neoadjuvant nivolumab and ipilimumab. And it’s important to point out that in this trial they used the putative flipped dose regimen with a higher dose of nivolumab and a lower dose of ipilimumab, and the idea here is to reduce toxicity while still maintaining the advantage.

Patients then went on to have a lymph node dissection. And you’ll notice on the top, for those who had a major pathologic response, which we’ll get to in a second, those patients did not go on to have any further therapy; they were just monitored. Whereas the patients who did not have a major pathologic response went on to get adjuvant anti-PD-1 or BRAF inhibitor if BRAF mutant. And in contrast the patients randomized to Arm B got standard therapy as it is, which was lymph node dissection and then adjuvant therapy.

And so these data resulted in really a land shift in terms of where the field is at now. You can see that the Kaplan-Meier survival plot shows a hazard ratio of 0.32 in terms of event-free survival, which of course is the neoadjuvant endpoint that takes into account anything that could have happened to the patient even before the surgery, then all the way through in terms of recurrences or aberrant outcomes. And so that’s an enormous advantage, so that’s a 68% improvement in the outcomes for patients.

On the right-hand side of the slide, I kind of put 2 slides together here, you see the major pathologic response was 59%. And so that’s really important to take awareness of. That means almost 60% of the patients did not — in the experimental arm did not need to go on to have the adjuvant portion of the treatment. And I think this will be refined over time but is likely leading to a paradigm where we’re going to give neoadjuvant combination immunotherapy and then many patients will actually not need to go on to have major surgery or adjuvant therapy, albeit these data haven’t quite moved us there yet. But there’s really no question that this is a major change in the way we manage patients, and just emphasizes that issue about multidisciplinary care moving into the future.

You have to put these data into the context of the adjuvant approvals that of course have underpinned standard medical therapy for melanoma for almost the past decade now. They’re outlined in this table, and I won’t belabor all of them because you can read the numbers, but basically monotherapy, anti-PD-1, nivo or pembro reducing the risk of recurrence by roughly about 40% to 50% in the Stage IIB through resected Stage IV setting and offering adjuvant therapy has been the standard of care over the past several years.

And so one other adjuvant update that’s worth being aware of was that from the COMBI-AD study, which looked at dabrafenib and trametinib. And in that study, which was updated with almost 10-year follow-up now, we saw that the final analysis for overall survival suggested a clinically meaningful difference between the populations, but they did not quite meet statistical significance. And so this is somewhat argued, but at this point there still no overall survival advantage to any intervention in the adjuvant setting except for ipilimumab as monotherapy, which we don’t really use anymore for either BRAF or anti-PD-1.

Within the study they did do a subgroup analysis where they looked at BRAF V600E versus V600K-mutant patients, and it did look like there was a bigger advantage in the V600E, albeit this was a non-preplanned subanalysis, and I think that likely this probably doesn’t change people’s perspective on a really high level about whether or not they’re using adjuvant therapy. And given the data for NADINA so far, likely adjuvant will be salvage if patients don’t have major pathological response.

DR LOVE: So we could spend the rest of the hour talking about what you just talked about, but let’s just do a little tasting menu because I know we’re going to be talking about this quite a bit.

First to Nikhil. And again, in terms of NADINA, one of the ways in adjuvant therapy of breast cancer, for example, is you find something that you’ve established works in higher-risk patients and then you take the hazard rate and consider whether you want to use lower-risk patients. You’ve got a hazard rate here of 0.3. What about using the NADINA strategy in people who were lower-risk in the adjuvant setting?

DR KHUSHALANI: I think that’s a great question, Neil, and that will certainly need to be studied prospectively. We do have selected lower stage, and when I define lower stage here in the context of what Jason just presented, I would probably only include Stage IIC because resectable Stage IIC patients still have about a 40% risk of recurrence. So there are patients who are — have deep melanomas that are ulcerated, so anything that’s greater than 4 mm in depth, and they have relapse rates that are closer to Stage IIIB patients.

So I think we have to be careful about simply moving what is actually a reasonably toxic regimen. Over 40% of patients had moderate to severe toxicity, and some patients may not necessarily be able to complete their treatment. This treatment can cause chronic toxicities, particularly endocrine toxicities, as well. So I don’t think combination immunotherapy is for everyone, but I think the fact that only 2 doses were required to elicit some of the responses that Dr Luke mentioned was actually very, very impressive. So I do think that there’s a role even for monotherapy, particularly for the earlier-stage patients, based on Dr Luke’s data in the KEYNOTE-716 trial for adjuvant pembrolizumab and then subsequently for the CheckMate study for adjuvant nivolumab for Stage IIB and IIC as well.

DR LOVE: So Jason, 1 question. I’ve like to pick the brain of Dr Georgina Long over the years about neoadjuvant therapy, and one thing I love to ask her was like why. Why do you see such a great benefit in the neoadjuvant setting? And also, when I was looking at that 59% major path CR I was thinking what’s more sensitive to IO, melanoma or MSI-high solid tumors. Anyhow, any comment about NADINA and why you saw this, Jason?

DR LUKE: Yeah. So this mechanistic rationale for neoadjuvant therapy has been bandied about by investigators, scientists, et cetera, and I think the working hypothesis is that the intact tumor microenvironment has different elements of the immune system that can be leveraged, which just isn’t present when you’re treating micrometastatic disease. In other words, something about having the totality of the tumor allows the immune system to more fully recognize it and mount a better response. And so I think beyond that we don’t have really better reasons to say it, but that’s just been the consistent observation, not just in melanoma, but in lung cancer, et cetera.

Your question about MSI versus melanoma is an interesting one. Obviously, both cancers have high tumor mutational burden, albeit that in melanoma we also see this interferon signature, which suggests T-cell infiltration to a greater degree. And I think that you just highlighted an area in the field that we just truly don’t yet fully understand, what really drives these immune responses. Is it just the neoantigens, or is there more to it about how the immune system engages with the cancer?

DR LOVE: So Nikhil, I like to brag that we have the best chat room in the business, but they keep putting things in that I have to look up that I’ve never heard of. So Ed wants to know “Any news yet from the ABC-X trial out of Australia; radiation/ipi/nivo in brain mets?”

DR KHUSHALANI: No. We don’t have updated data on that, at least not to my knowledge. Jason, are you aware of any data on that yet?

DR LUKE: Not yet.

DR LOVE: Rosanna also wants to know, Jason, “Do you think this neoadjuvant strategy is ready for prime time, or do we need to wait for event-free survival?”

DR LUKE: No. We want to emphasize this point. It’s ready for prime time. All of us have been expecting this, and we think these are the data that just like completely blows the doors off. This should be the new standard of care that should be evaluated for all reasonably — any patient who could reasonably tolerate nivo and ipi, this should be the standard of care.

DR LOVE: Right. So let’s move on because we have other things that Jason’s going to review. We may come back to some of these adjuvant questions, but I’ve been fascinated by this mRNA neoadjuvant strategy ever since it first came out. Let’s begin back with that, Jason.

DR LUKE: So absolutely. So we also at the meeting had the 3-year update from the Phase II adjuvant study of pembrolizumab versus pembrolizumab plus the individualized neoantigen therapy. And so very quickly to explain what is this for the audience who might not be following this, the concept here is that we can take the patient’s tumor and then sequence the tumor, and then bioinformatically identify what are the unique mutations that are in the patient’s cancer and predict which of the proteins that would come from that mutation would actually bind to MHC proteins and thus be presented to the individual patient’s immune system.

And so that’s what the schema on the upper left shows. And then in the trial it’s pretty simple. It was a 2:1 randomization for more patients to get the individualized neoantigen therapy.

So at the meeting — because it’s already been disclosed and published in The Lancet that there was a huge benefit to this vaccine, cancer vaccine, as opposed to pembrolizumab alone. And what we saw at the meeting was the updated data at about 3 years, which continued to show a 19% difference in relapse-free survival for these high-risk Stage III patients, as well as an improvement in distant metastasis-free survival, which would — continued to be maintained at about 20% difference between the arms.

And so these were reassuring data to suggest that this is an approach that maintains its effect out over a longer period of time. And a Phase III clinical trial to definitively show this difference is rapidly accruing right now, and many of us are very excited about these data potentially impacting practice as recently as 1 to 2 years from now.

And so in addition to that, at the meeting we saw some updated data on some other therapeutic approaches. One of them is around LAG3 targeting, which is now the third checkpoint that’s come into clinical practice. And so for those who aren’t aware, again, I put a little schema picture. LAG3 is like PD-1. It’s another receptor that gets expressed on exhausted immune cells in the tumor microenvironment.

And we had update to this trial, RELATIVITY-047, which compared nivolumab versus nivo and rela. And what we saw in the study was updated data, again, showing the sustained benefit in terms of the primary endpoint of relapse-free survival. And it was also noted that the overall survival, going on now 4 years, showed a difference between 51 and 33 months. And in the trial that actually didn’t meet statistical significance, and yet I think most of us believe that that’s a clinically significant — clinically important difference, such that actually in my practice, for the most, part I’ve shifted over to using nivo and rela in treatment-naïve patients who come with metastatic disease.

And that’s for context. It has to be put alongside some other data from another LAG3 molecule that’s now coming into clinical trials — or coming into registration intent trials, which is the molecule fianlimab. So the audience will be aware of cemiplimab as the PD-1 antibody, but now this LAG3 fianlimab is being combined with it.

And these are data actually from last year’s ASCO Meeting, and it’s a little small in the table, so apologies on that. But the take-home point was in front-line PD-1-naïve melanoma the response rate to this PD-1 and LAG3 combination was over 60%, which numerically looks to be even higher than nivo plus rela albeit, of course, we have trial-to-trial comparisons here, which are somewhat fraught.

But the reason to be aware of that is this is moving forward. There’s a Phase III clinical trial comparing cemiplimab plus fianlimab versus anti-PD-1 antibodies alone that’s accruing patients now, and I think most of us feel very confident this is going to be a positive study out over time as well.

Finally, I’ll breeze through. The audience will be aware that we recently had the first approval of adoptive cell transfer in solid tumors with lifileucel, which is the tumor-infiltrating lymphocyte product. And this was — data was updated at the meeting. This is from the JCO paper that really underpinned the approval.

And what we saw was from this cohort of patients in the treatment-naïve setting, which were receiving TIL plus pembrolizumab in a Phase II setting, which set up the Phase III that’s ongoing for this combination. And what we saw is that the response rate in this group of patients was 60% and that the response was very, very durable, so 30% complete response rate, and all of the responders seemed to be durable out over time.

And so TIL obviously is a complicated therapy. You see on the upper left the process. Of course you have to resect the tumor, get the lymphocytes out and grow them up and then bring the patient back with lymphodepletion to give them the cells and high-dose IL-2. But this is promising. I’m not sure how much this is going to impact on the standard of care immediately, but it’s something certainly to be aware of because this is now approved for patients with refractory disease.

And as I alluded to, there’s an ongoing Phase III confirmatory trial in the front line of pembro versus pembro plus TIL. We’ll have to keep an eye out for that because this is underpinning the approval of TIL for refractory disease, and so we all hope this is a positive trial, even though in my practice it’s hard for me to imagine using this in the front line. We do need this trial to be positive to make sure that we have this available for patients out into the future.

DR LOVE: Alright. Well, there’s so much to talk about there as well. And before we get into the things that Jason just talked about, Nikhil, this is always a great opportunity for people to ask questions, cases they have, et cetera. Here’s another question from Susanna. “Other than ulceration, LVI, mitosis, et cetera, how do you decide when to offer sentinel lymph node biopsy for a thickness of 0.8 to 1.0 mm? Does it matter where the draining lymph node basin is?” Nikhil.

DR KHUSHALANI: I don’t think it really matters where the draining lymph node basin. I do know that technically sometimes it is difficult on a lymphoscintigraphy to identify the draining basin when we are operating on the head and neck. At least that’s what we have seen in clinical practice. Virtually everywhere else it’s fairly easy to map and define. I think sentinel lymph node biopsy remains very important from a prognostic standpoint and certainly in selected cases from a therapeutic standpoint. I think it’s one of the biggest advances that we have seen in melanoma surgery in decades through the MSLT-I and MSLT-II. And it really has allowed us to risk-stratify patients and even de-escalate from surgery.

So I think for our patients, typically anybody above — with a thickness, tumor thickness of 0.8 mm and thicker will get sentinel lymph node mapping regardless of whether it’s ulcerated or non, and then if it’s thinner than that there are selected criteria that were just highlighted that we would certainly consider for use as well.

DR LOVE: So Nikhil, a quick follow-up from Thoy in the chat room. “Can you please talk about criteria for adjuvant radiation for Stage III melanoma?”

DR KHUSHALANI: So that’s a moving target, and there’s — the data behind adjuvant radiotherapy is primarily to optimize regional control. We do it here at Moffitt on a case-by-case basis. We will certainly consider it in selected cases with a multitude of involved nodes, with extensive extracapsular extension, but given that our adjuvant systemic therapy has dramatically improved, I mean I think I can almost count on my fingers how many patients we’ve treated now with adjuvant radiotherapy. There are selected recurrences that we see post sentinel lymph node biopsy, so patients who’ve had a positive sentinel lymph node, are getting adjuvant therapy, and then relapse in that same regional basin because 40% of patients who have a positive sentinel node will still relapse in that nodal basin as the primary site. And if those patients have significant evidence of in-transit disease that is resected we would certainly consider those patients for adjuvant radiotherapy. But that’s becoming uncommon.

DR LOVE: So let’s get back to the mRNA thing, Jason. First of all, do you see single-agent response rates to this? And also, can you talk about exactly the process of what happens if a patient’s going to be treated with it? Like CAR T, like what are the points — what leads up to their getting the treatment?

DR LUKE: Yup. Great question. So on this question of single-agent response I think the answer is that we don’t actually really know. There were Phase I clinical trials done in highly-refractory metastatic patients where these were — INTs were made. That’s certainly not the optimal setting to potentially see an antitumor response, because in fact the minimal residual disease setting is almost certainly the optimal place to try to look at the impact of a vaccination strategy.

So I think the jury is out. I think right now what we see is a combination with anti-PD-1 looks most attractive, but it is possible that if we were able to select patients better, even in earlier stages of disease, we might want to consider the INT alone without the pembro. But that’s an emerging area of research over the next few years.

To your question about how does this work logistically/mechanistically, so a patient would come in, and they would have their surgery with the melanoma removed. Like how you do for ordering genomic sequencing you then would request that the tumor be sent, and it would be shipped off to the study sponsor, where they would undergo whole-exome sequencing, as well as actually transcriptional profiling of RNA sequencing. And they’re going to look for aberrations compared to the patient’s own genome. So in addition to that they’re going to have the patient’s own normal cells, and they’re going to compare those 2 sequencing tests to try to look for differences.

Once those differences are identified, then, though, they are put into a computational pipeline to try to predict will these new, normal proteins actually bind to immune molecules that would be presented to the immune system in that same patient. And that’s the kicker, right? So that’s why this is truly a personalized individual vaccine approach. And that process takes about 4 weeks as it stands currently, which is why you offset this. In the trial you start the pembro anyway, and then you start the vaccine by about dose 2 to 3, because that’s when it gets to be ready. And then they vaccinate with that over the course of I think it’s 6 vaccinations out over time.

And so that’s then given concurrently with pembro as the patients come in, and it actually is quite easy. Just giving the vaccine is just as simple as you might expect it would be, and so far we don’t seem to see any side effects that are any greater than what would be expected for pembrolizumab alone.

So the big part is that early piece about identifying and actually getting the tumor specimen and sending it off. And I will caution for community practitioners, those of us that do academic medical oncology in cutaneous — we have specialized coordinators who actually help us find all the samples because patients who get biopsies in the community, they might go to this hospital, and then it gets shipped off to that path department, then they go and have surgery over here. It’s now always quite so straightforward where exactly is the specimen. And this will be something that in your practice you need to make sure you have your nurses understanding this workflow so that they actually can request these samples in a timely fashion under the assumption we eventually move to a model where this is the kind of treatment that’s being given.

DR LOVE: So what about studies in metastatic disease? Is this going to be studied, or only in the microscopic adjuvant situation, Jason?

DR LUKE: So absolutely it will be. In fact, another company has a very similar study to what you’re alluding to, actually already ongoing. And with this medicine we’re thinking about how to do that study. I think part of what’s difficult is that I think the advantage that we’re going to see is really going to be that overall survival or event-free survival, and that’s hard to measure in a metastatic trial.

The great thing about an adjuvant trial is you get a whole year to actually follow the patient, right, whereas in a metastatic trial you’re going to scan the patient in 2 months. That means the impact of the therapy has to be readily obvious in that 2-month period. If the impact of the therapy doesn’t happen for 6 months, then it’s just harder to pick up in metastatic disease. So I think we will see it move there eventually, but I think for sure the adjuvant setting is where it will be going first.

DR LOVE: So Jason, you suggested that maybe this is going to be available in the next couple/few years. I have this joke, oncologists wake up in the morning, and they check their phone, they see what’s approved, and then they decide how to apply it to their practice. Any thoughts about whether it might be this year?

DR LUKE: There are rumblings about discussions with the FDA, but I’m not privy to the exact conversations. I just know that that is an ongoing conversation.

I will caution that while we’re extremely excited about these data, we do have to remember that the Phase III has to be positive, and in fact it has to be really positive. So these Phase II data that we talked about are more than a 50% improvement relative to pembro alone.

There are a bunch of other adjuvant trials that are ongoing right now. And so eventually it’s going to matter to see what actually are the hazard ratios in all these trials, because we talked about LAG3, there are LAG3 adjuvant trials, and if it turns out that the benefit looks very similar between the LAG3 adjuvant trial and the individualized neoantigen therapy, well then why bother doing all this extra work for the vaccine when you could just pull it off the shelf and use this one. So to extent we need to see the data before we know how pervasive or how much of an impact on clinical practice this is going to be.

DR LOVE: Alright, Nikhil, here’s another one. This is from Rosanna in the chat room. Here’s an easy one for you. “Which patients do you pick nivo/rela versus nivo/ipi? How do you approach first-line therapy?” That’s a basic question but getting a little complicated.

DR KHUSHALANI: I’d say that’s a great question because number 1, there’s been no head-to-head comparison between the 2, and there are — there have been some attempts at overlaying these studies. Dirk Schadendorf has attempted to do that and actually showed that very elegantly. So just to put it into perspective, from a clinical standpoint I still utilized ipi/nivo at standard dosing, so I’m talking about ipi 3/nivo 1 every 3 weeks for 4 doses followed by nivolumab. For patients who have metastatic melanoma to the brain, regardless of BRAF status, the asymptomatic patients definitely get ipi/nivo. The ones who are symptomatic and BRAF mutant we’re preferentially steering them towards an ongoing trial, SWOG 2000, that just closed as of 2 days ago they announced that they had met their national accrual.

So ipi/nivo for brain mets. I also use it for patients who have high-volume disease with high LDH, and I certainly consider using it for patients with metastatic mucosal or metastatic acral melanoma that traditionally doesn’t respond as well to monotherapy. For virtually everyone else it is nivo/rela in the front-line setting, and I’ve found that these patients respond very well to nivo/rela, as well, and certainly with a far more tolerable toxicity profile. Though I don’t think that should be underscored because it does cause hepatotoxicity. It does cause GI toxicity. It certainly has cardiac toxicity, at least anecdotally we have seen cases of myocarditis with nivolumab plus relatlimab, and certainly adrenal insufficiency.

DR LOVE: Jason, anything new in terms of prediction of benefit from immunotherapy? We’ve had TMB, et cetera. Anything particularly useful in melanoma?

DR LUKE: Well, unfortunately I think the answer is yes but no. I think there are many elegant multidimensional modeling papers that are published in Nature and Science about getting lots of biomarkers together. But for the clinical practitioner who has a patient who shows up in front of them and doesn’t own a supercomputer that can turn things around in 5 seconds, in reality the answer is probably not really, because we know that PD-L1-positive patients will do better, but so do PD-L1-negative patients, they do okay. So right now I think, unfortunately, we just don’t have really great biomarkers that are clinically useful in melanoma.

DR LOVE: So one more question back to you, Jason, again, from Ed in the chat room. It’s too complicated for me to repeat, but basically I think what he wants to know is what do you see in terms of Phase III trials in first-line therapy of metastatic disease. There’s so many different options. There’s so many new strategies. What are some of the Phase III strategies you think you see coming over the next few years? Such a complicated field.

DR LUKE: Yeah. And so I think we’re all expecting there will be at least 2 LAG3 combinations that get approved, so which one you would choose, I mean we don’t know that yet. We also are learning about the data now for this PRAME CD3 T-cell engager, or bispecific molecule, which looked pretty promising at ASCO, and a Phase III trial of that in the front line is ongoing. We have this data now for TILs plus pembro.

So I think a lot of it’s going to actually become — say we zoom 3 to 5 years from now, is how did the patient originally present. Because if the patient originally presented with Stage III disease and got ipi/nivo and then went on to metastatic disease, that’s going to be a very different patient who actually was — in the unfortunate minority but who had Stage I melanoma and yet somehow still progressed to metastatic disease. Because for the former patient who had refractory disease to ipi/nivo you’re probably going to want to transition to something like adoptive cell transfer or a completely different mechanism, whereas the patient who went from Stage I all the way to Stage IV, that patient’s going to have the full gamut of all of these different options, and there probably risk/benefit/upside, et cetera, will be how we think about things. But it’s only a good thing that we have so many options for patients, right?

DR LOVE: Really good thing.

Optimizing the Management of Nonmelanoma Skin Cancers — Dr Khushalani

DR LOVE: Alright. Well, let’s move on now and get into nonmelanoma skin cancer, before we talk about what happened at ASCO and what’s been going on, just to take a breath. And particularly from the point of view of the community-based general medical oncologist, as we were alluding to before with melanoma, Nikhil, any thoughts in terms of some of the issues that docs face with these cancers and questions you get from them, and maybe let’s say myths or misperceptions out there?

DR KHUSHALANI: I think there are several. Number 1 is there’s certainly far more education now that these tumors are nonmelanoma skin cancers, I’ll even put them as a bucket of keratinocytic cancers and Merkel cell carcinoma, are responsive to immunotherapy. And so in the appropriate patient immunotherapy is now the standard of care for these patients with advanced disease.

The medical oncologist tends to see a lot of these patients in their locally advanced and/or in the minority metastatic setting after they have already exhausted options of surgery, often disfiguring surgery, particularly in the head and neck area. And I think a lot of what we see now in cSCC can be borrowed from paradigms of what we’ve seen in desmoplastic melanoma of the head and neck, where patients underwent extensive disfiguring surgery but recognized now that these patients respond very well to anti-PD-1 therapy.

The nuanced part of this is that many of these patients with locally advanced disease have diminished social support systems. These patients often present with large, neglected tumors, but the size of the tumor really should not matter because some of these respond so beautifully to immune checkpoint inhibitor therapy, and the before and after pictures are almost staggering to observe. And I’ve shown some of these at previous seminars, as well.

So I think it’s important to have a multidisciplinary team and not just the surgeon, the radiation oncologist and the medical oncologist, but I think our advanced practice professionals, our APPs, nurse practitioners, physician assistants, are so important in their management. Social workers, our nurses, and certainly, if necessary, our psychologists, as well, because to get these patients through therapy is certainly, I think, a little bit more challenging than we see with say a melanoma patient.

I think Merkel cell has also turned around, again an immunogenic tumor, despite having 2 etiologies, both virus or ultraviolet related. And I think that is a cancer that is increasing in incidence, so we need to be aware of it. And then basal cell with hedgehog inhibition and then with immunotherapy now, certainly more treatment options for these patients as well.

DR LOVE: Anything you want to add to that, Jason, particularly the issue that Nikhil brought up in terms of the social constructs that a lot of these patients have, and trying to work your way through that?

DR LUKE: Yeah. And the only thing I’d add to that is that in addition to folks that have these bit tumors often these develop in older folks, and so even if it isn’t a case that’s it’s extremely neglected the patient’s operating understanding of the overall scenario sometimes is less than other patients, and making sure that the whole family’s engaged and that there is support for that patient I think is another real important part of that.

The only other thing I’d add is I think what we’re going to see is with the efficacy of immunotherapy a crash of all of these treatments into the perisurgical space, and we’re going to talk about some of that here. But that’s really where all of this is probably going in nonmelanoma skin cancer as well.

DR LOVE: So Nikhil, before you get into the data, I’ve got to ask from Blanca in the chat room “Use of immunotherapy in Gorlin syndrome.” Remind us what Gorlin syndrome is too.

DR KHUSHALANI: So Gorlin syndrome is essentially Gorlin-Goltz syndrome, which is a form of hereditary basal cell carcinoma. So these are patients who have a germline patch mutation and therefore are prone to developing BCCs at a very early stage in life and not 1 or 2 but a multitude of them over their lifespan. And they also develop additional features, including other tumors such as meningioma, for example, as well as cysts that develop over a period of time. So it becomes really important to have multidisciplinary approaches for this. And recently in an initiative was launched where a group of experts came together for precisely this very question, to answer clinical and pragmatic questions on how do you address management for Gorlin syndrome, because over a period of time these patients have surgical fatigue. There’s only so much that you can operate on these patients with the multitude of basal cells that they experience.

I have treated patients with Gorlin syndrome with immunotherapy successfully, but the key issue becomes how long do you treat them for. Do you actually try to extend the interval between treatments? Rather than give it every 3 weeks, for example cemiplimab, should you actually give it with longer intervals of time? We don’t have great data to support that, but it certainly would not be an unreasonable strategy. And then certainly consideration to intermittent dosing or pulse dosing of hedgehog inhibition because of the significant toxicity of these agents. Most of these patients will not tolerate it for a chronic period of time.

DR LOVE: So Jason, I’ve never seen the chat room blow up like it is today. The heaviest question that I don’t even understand enough to ask, but Susanna comments “Basal cell, locally advanced. I’ve treated to date 4 patients with vismodegib, and each one benefited. Ladies don’t like hair loss. When would you pick ICI versus vismo for locally advanced?”

DR LUKE: Yeah. So this is a great question, and I think it really comes down to a patient-specific consideration. The labeled indication for cemiplimab after hedgehog is intolerant to hedgehog, and I think that that flexibility was intentional. And so to that point there are going to be patients who really for various reasons can’t tolerate the toxicity of hedgehog inhibition, and I think it’s very reasonable to transition quickly or even jump over hedgehog inhibitors in the right patients, but it’s not to discount. Hedgehog inhibitors really do work really, really well, and so finding a way to get patients access to a drug that works really well I think is important, but there’s no doubt that for some patients it’s pretty tough or not the right treatment.

DR LOVE: Alright. Just 1 more from the chat room, and then we’ll get back. I’m going to throw this back to you, again, Jason. This is from Priya, who’s always in our chat room there. So she says, “Just driving back from” — she’s listening in her car, I guess — “just driving back from a new consult that she just saw in metastatic uveal melanoma in the hospital. HLA typing pending. Any role for ipi/nivo?” Jason.

DR LUKE: Potentially, yes. I mean, it’s bad to hear that the patient’s in the hospital. That’s probably not a very good sign.

So in uveal melanoma we know that it’s a very different disease than cutaneous melanoma. You’d think it’s a different cancer if they weren’t both called melanoma. Those patients tend not to be particularly responsive to checkpoint blockade, but having said that they’re not really particularly responsive to anything, unfortunately, right? So in standard practice now HLA profiling for A201 is the standard of care, and for patients who are A201 positive in their germline, I guess it’s important to point out, not in the tumor but in the actual patient, tebentafusp is approved, so the gp100 CD3 bispecific molecule.

For patients, though, who are not A201, which is more than half the population, in the absence of something better we do give those patients ipi/nivo. We only really expect a response rate in the range of about 10% to 20%. And frankly speaking in somebody who’s already in the hospital, presumably due to the cancer, that’s going to be a tough situation, right? Because the data both for tebentafusp and for ipi/nivo, as much as it is, is really in patients who have low-volume disease and no symptoms. So this is a really, really hard population to treat. If they have gotten enough of a liver metastases burden that they’ve actually landed in the hospital, these patients unfortunately are pretty tough to treat.

DR LOVE: Quick follow-up from Faye. Will there be adjuvant uveal melanoma therapy, Jason, coming along?

DR LUKE: Yeah. It’s a really good question. The answer is maybe. I’m not sure yet. And so the thing about it is the tebentafusp data are quite impressive. I mean many of us worked on this since the very first Phase I trials, and yet the drug is really not advantageous for adjuvant administration because it’s dosed weekly. So the idea that you would have to give weekly therapy in the adjuvant setting is a little problematic. They are thinking about designing a trial in that space.

It’s also worth noting there’s been discussion about using the PKC inhibitor adavosertib, which is probably not a molecule everybody here’s been following super closely. But that’s also been looking somewhat interesting in uveal melanoma because uveal melanoma has high signaling through PKC. And that’s something that we might see come out relatively soon, but those would be trials that we’d just be initiating. We’re talking about years from now in terms of when that might be clinically relevant in practice.

DR LOVE: I was just flashing on PKC versus KFC for dinner.

One more case before we get into this, okay? I have to do this. One more. Okay. So Nikhil, Rosanna has an 80-year-old patient with squamous cell of the back, resected, but recurred at an isolated site, supraclavicular, treated with pembro for a year. No other site of recurrence, resected, showed squamous cell on the resected lymph node, would you continue immunotherapy or monitor? Of course she says, “Would you check cell-free DNA?” And actually she already checked the cell-free DNA, and it’s negative.

DR KHUSHALANI: Okay. So from the description it appears that the patient received quasi preoperative pembrolizumab and then was resected to NED status. At this point I would just observe. I would not offer any additional therapy. The only caveat would be in the resection of the supraclavicular node, if there was evidence of extracapsular extension, I would consider postoperative radiation to that site. But outside of that I would not do anything else. I would observe and cross-sectional imaging every 3 to 4 months.

DR LOVE: Alright. One more quick one. Go ahead.

DR LUKE: Just real quick on that one. The ctDNA is an emerging story that I think is really important in oncology, but it’s not clear what it means yet in cutaneous oncology. The lesions that we deal with are much smaller, and so the fact that it was negative of course is reassuring, but it doesn’t mean that it’s not there. And so even in melanoma, in Stage III melanoma, we’re only able to pick up ctDNA currently with the technology about 15% of the time. So that unfortunately means the technology is not really good enough to be relevant in cutaneous malignancies yet.

DR LOVE: Yeah. It’s really hard to stop the tsunami of interest in this, but you’re right. I mean, it needs to be practical.

Alright. One more from Hasan, Jason. “In starting nivo/rela do you continue both on progression? Can we de-escalate to nivo after maximal response?”

DR LUKE: So no. So if we’re using nivo/rela then we use nivo/rela. It’s administered as a coformulation, that’s the commercial product, so there really — there is no data for the idea of like doing an induction with PD-1 and LAG3 then dropping the PD-1. And what I would suggest from my practice, and Nikhil can comment if he thinks, I haven’t actually noticed that there’s really a difference in my practice between using nivo/rela versus nivo. Numerically it’s in the trial that, but I haven’t noticed that, so the continuous dosing is not really the issue there.

In terms of treatment beyond progression, inasmuch as that’s practically a thing, then I would approach that the same way I approach other immunotherapies. I wouldn’t drop one of the drugs or necessarily try to switch. An open question in our field is what about ipi/nivo after nivo/rela or vice versa. So far, the data we have to that effect is not especially promising, but we need larger data series to really more fully understand it.

DR LOVE: Alright.

DR KHUSHALANI: I agree completely with what Dr Luke just said.

DR LOVE: I do, too. It makes it unanimous. But, of course, who cares what I think?

Anyhow, let’s talk a little bit about what happened at ASCO, Nikhil.

DR KHUSHALANI: Certainly. So again, this is now just switching gears to nonmelanoma skin cancer, and essentially what we’ll talk about is long-term data for anti-PD-1 therapy. Just to remind patients why this works — I mean to remind our colleagues why this works, keratinocytic cancers have a high tumor mutational burden.

And what you see here on the right side is response rates in proportion to a higher median number of coding somatic mutations, so the tumor mutational burden. And you can see cutaneous squamous cell carcinoma on the top right there, very high TMB. Again, typified on the left side, and most of these are in the light blue, which is C to T transitions typical for a UV damage-related tumor that cSCC is.

And this was the EMPOWER study that led to the approval of cemiplimab for advanced cSCC. And just a quick primer, cohorts 1 and 2 were essentially weight-based dosing for metastatic cohort 1, locally advanced cohort 2, and then the fixed based — fixed dose, which was 350 mg every 3 weeks intravenously, which is now the FDA approved dose. And in these 193 patients the response rates were 45% to 50%.

And what you see at the bottom was progressive increase over time with the complete response rate. So these are tumors that over a period of time, usually an average of about 9 months, that’s when they tend to hit their CRs as opposed to at 3 to 6 months. So it’s important to keep that number in mind.

Similarly, pembrolizumab is also approved, and this was based on KEYNOTE-629: 159 patients, 2 arms, locally advanced or recurrent metastatic. Slight differences in the definitions between these 2 trials, EMPOWER and the KEYNOTE-629, but suffice it to say that the front-line response is essentially similar. And at ASCO this year we saw an update, which was now very impressively at a median follow-up that exceeded 5 years. And what I’ve highlighted in red is what changed from the previous data set that was published in 2021, so 3 years ago.

So what we now have is the complete response rate in locally advanced disease has improved to 22%, in metastatic disease is 12%. We now have reached median progression-free survival of 14 and a half months for locally advanced disease. Unfortunately, in the metastatic setting we don’t do as well. And it is very impressive to note that at 5-plus years of follow-up we still don’t have the median overall survival for patients treated with pembrolizumab for locally advanced cSCC. So just to recap this, this is the PFS, you can see here very clearly, across these two settings.

Patients do have toxicity. It’s important to recognize these early because 11% to 12% of patients will require steroids for toxicity, and about 9% of them will discontinue their treatment due to toxicity, but importantly no new safety signals for this very long follow-up. And so I think in my mind the takeaway here is anti-PD-1 monotherapy with either cemi or pembrolizumab can provide very deep, durable responses for unresectable advanced cSCC.

I think it’s important to compare this to the pre-IO era. At that point in time the median survivals were less than 1 year for our patients, and now we have median survivals that are technically not yet reached, at least in terms of PFS, and OS is actually getting closer to 3 years. So I think we’ve made some really impressive gains.

So now the unanswered question is do we have better biomarkers of response, and do we need to explore combination immunotherapy, déjà vu from melanoma, should we actually take that to our keratinocytic cancers?

There was a very interesting poster utilizing PET/CT as a prognostic biomarker at ASCO. Admittedly a retrospective study, a small study, 53 patients, but essentially these investigators from Australia looked at baseline PET/CT scan for cSCC in patients who were starting immune checkpoint inhibitors, and at least 1 more PET scan. And just the punchline here was that patients who had a complete metabolic response their 12-month progression-free survival was 100%, and those who had progression of disease unfortunately did not do too well, so all of them essentially very rapidly progressed. So if you have an early PET scan that demonstrates lack of response or progressive disease maybe it is time for these patients to switch to an alternate line of therapy rather than continuing anti-PD-1 monotherapy.

DR LOVE: So before we continue, just a couple of questions before we finish out the talk and the meeting here. One thing was I was thinking about Jason. We have a variety of checkpoint inhibitors available, anti-PD-1/PD-L1, and everybody kind of has the feeling that essentially the equivalent, we follow the data, if there’s a trial that uses one agent that’s the one we use. But I’m just kind of curious whether you think inherently there might be some differences in efficacy or tolerability between these agents, that we’re just maybe not able to see because we’re not comparing them directly. For example, if you had a checkpoint inhibitor that was 20% better than another one would we even know that at this point?

From your point of view are they all kind of similar? Or either practically or clinically do you think there’s any maybe that are more — have more favorable profiles?

DR LUKE: What I’d say to that is that it might be the case that if we had prospective trials with thousands of patients in them to compare we might see minor differences between them. My read, though, is that the clinical data for anti-PD-1 agents, so pembro, nivo, cemiplimab, dostarlimab, they all look basically overlapping and very similar.

There is more variability in the PD-L1 agents, and so that’s where it gets a little more complicated. In cutaneous malignancies we don’t worry about that as much because we basically give nivo/pembro/cemiplimab, but that’s what I would kind of say on a high level.

The question about combos then makes that much more complicated, right, because then the second agent, of course, is going to also have an impact. So what I’d say is that in monotherapy I would prefer a PD-1, but once it becomes a combo I think you just have to take the data as they are.

DR LOVE: So one other general question before we finish out the talk, Nikhil, related to autoimmune toxicity. A lot of tertiary centers, like the ones you all work in, have teams that deal with autoimmune toxicity. People out in the community don’t have that. Anything you want to say about, again, I’m not going to say errors, but myths or misperceptions that people have in the community in terms of — obviously there’s a huge experience in oncology with checkpoint inhibitors, but there are a lot of docs that touch these patients, not just medical oncologists, ER docs, hospitalists, et cetera. Any comments as you see people dealing with autoimmune toxicity?

DR KHUSHALANI: Well, I think the key here has to be education, both on the part of the patient and the provider, 2-way communication, because of the essentially ubiquitous use of immune checkpoint inhibitors. I mean, we are just seeing the focus here on cutaneous, but these drugs are used in lung cancer, they’re used in a variety of GI cancers. Virtually any solid tumor that you have and selected hematologic malignancies these drugs are being used.

So I think all providers, it’s almost incumbent on them to recognize what these toxicities may be and how to mitigate them through early communication and triage. Yes, we are a little spoiled here at our centers because we do have teams, including inpatient dedicated teams that take care of these patients with immune toxicity. But I think it’s very easy to reach out to any one of us, communicate with us. We’d be more than happy to help. But telling the patient what to look out for and when to call becomes so important so you can nip a Grade 1/Grade 2 diarrhea right away rather than getting it escalated to Grade 3.

DR LOVE: And as you say, these issues come up in all the solid tumors, or most of them, at least at this point. But you guys have the most experience, so it’s always great to talk to you about that.

And just one other thing before we finish out with this talk here, Jason, relates to prior autoimmune disease. We were talking about this in a webinar the other day in lung cancer, and the general oncologists were saying how often they see people with prior history of GI or other autoimmune problems. Anything in particular that you keep your eye out for, Jason? We hear the idea of if they’re not being treated for it that should give you a little bit more comfort.

DR LUKE: Yup. And I think also the question about how urgent is it that you might lose the opportunity to offer it, right? So we run into patients a lot that have that, and you really have to sometimes talk to them about something bad here might happen, but if we don’t treat the cancer then of course we know something bad is going to happen, and I think that’s really where informed consent comes in. And really giving the patient the ability to know what to expect and trying to intervene as early as possible if you do treat those patients, as Nikhil was just mentioning a little bit ago.

DR LOVE: Alright, Nikhil, I’m going to skip the question in the chat room about immunotherapy in people with organ transplants. They just keep throwing these great questions out. But let’s just get through the data first.

DR KHUSHALANI: Sure.

DR LOVE: Nikhil.

DR KHUSHALANI: So I’ll quickly run through neoadjuvant déjà vu for cSCC. And all of us are fairly familiar with the multicenter study of 79 patients. These were high-risk Stage II to Stage IV resectable cSCC. They got 4 doses of neoadjuvant cemiplimab and then underwent curative intent surgery and then at investigator discretion received postoperative radiotherapy or postoperative cemiplimab. The primary endpoint was pathologic complete response rate, which is very impressive at 51%, and major pathologic response rate of 12%. So again, to refresh folks’ memory, this is tumors that have less than 10% viable cells at final pathology.

A lot of questions that I’ve been asked is how would you translate this into the community. Are community pathologists well versed with these neoadjuvant-treated patients in assessing what degree is viable, what degree is fibrosis? I think that’s a learning curve, and there are now guidelines out there, at least in melanoma through the International Neoadjuvant Consortium, in how to accession these tissues, and again, communication with pathology becomes important.

So this is a paradigm that we use very, very commonly, and what’s really important here is that the 24-month event-free survival for those patients receiving neoadjuvant cemiplimab was very high, 85%. In those patients who had a path CR there were no relapses at the last check. So we anticipate that more data with this will certainly come out.

At ASCO we saw a smaller, single-arm, single-institution study from the University of Pittsburgh, neoadjuvant pembrolizumab. Very similar patient population. So 2 cycles followed by surgery, and again, a very high pCR rate.

To just paraphrase what Dr Luke mentioned earlier, the median age of these patients is noticeably older. So when you look at some of this data you will notice that many of these patients may have concurrent cardiovascular morbidity, and there have been some deaths related to myocardial infarction, which may not be related to study drug therapy or the immune checkpoint inhibitor, but rather to the physiologic condition of these patients. So we have to be careful, particularly when we are starting to talk about combination therapies for these patients.

This was a really interesting trial called the DESQUAMATE study, which was also from Australia, saying given how well we have done with systemic therapy in the neoadjuvant setting can we actually eliminate planned surgery or postoperative radiotherapy after giving 4 cycles of pembrolizumab. So very innovative. If patients had a complete clinical and PET-negative radiographic response, they also had mapping biopsies performed. If all of that was negative, no surgery or radiation. They were just observed. If they had a less than complete clinical response they underwent the surgery as planned and then received risk-adaptive postoperative therapy based on the path response. So again asking the question can we eliminate a couple of these modalities. And the answer here in a small study was yes.

In almost two thirds of patients either surgery or radiation or both eliminated. And I certainly think this is very intriguing. We do a lot of this in clinical practice, but these authors actually were able to demonstrate prospectively that this is certainly feasible, essentially saying that we need immunotherapy for these patients, and we may not need anything else. Longer follow-up is certainly needed.

There are 2 trials. One has already completed accrual for high-risk cSCC, postoperative pembrolizumab versus placebo. A large study, 500-plus patients, and C-POST, which is adjuvant cemiplimab versus placebo, is getting close to the finish line, so we anticipate data from these studies over the next couple of years.

Just a quick reminder on basal cell. We all know about hedgehog inhibitors. Somebody brought up that question earlier. This is simply the longer-term final analyses data from vismodegib on the left and sonidegib on the right. And as you can see, the locally advanced response rate for BCC to hedgehog inhibitors is about 60%, essentially on both sides.

And many of these responses can be quite durable, but the problem, as somebody mentioned earlier, is these drugs are hard to tolerate. Real-world discontinuation. Virtually every patient by 12 months will have some interruption of therapy. Dysgeusia, fatigue, hair loss, which can be a big issue, particularly, can be permanent in some patients.

So cemiplimab demonstrated efficacy in this patient population of locally advanced BCC who were either intolerant or who had progressive disease on hedgehog inhibition. The response rate is not trivial, 32%, with a median progression-free survival of almost a year and a half, so certainly is now approved in this indication and has also demonstrated efficacy for metastatic basal cell after hedgehog inhibition.

We have selectively used this in the front-line setting, per label, because for patients who had hedgehog inhibitor may not be appropriate. And again, patient preference. We can certainly consider this. And the group at Johns Hopkins had suggested that the response in the front-line setting, again a small study, was about 46%, and some of those patients, again, 1 out of 5, very small numbers, were salvaged with nivolumab plus relatlimab.

And some of the other therapies of interest, this is my last slide, is intralesional RP1, which is essentially a genetically modified herpes virus. In CERPASS the data were not publicly released, but this was a press release back in December of last year where they demonstrated that the combination of RP1 plus cemiplimab did not meet its primary endpoint relative to cemiplimab alone, but those patients are still being followed to see if there’s any change over time.

ARTACUS is the same drug, RP1 intralesionally, in transplant recipients since they typically cannot receive immune checkpoint inhibition. That’s still ongoing.

There’s a trial of intralesional IL-1 with TNF immunocytokine for basal cell. And at Moffitt we have a study of a very interesting compound, IFX-Hu2.0, that my colleague Dr Brohl presented, that’s being taken to a larger study, where after this agent intralesionally there was adequate priming when the patients then got repeat response to immune checkpoint inhibition after being refractory to that previously, particularly for Merkel cell.

So I think a lot is changing. These are therapies of interest in nonmelanoma skin cancer, and we’ve come a long way since the original chemotherapy days. I’ll stop there, Neil. Back to you.

DR LOVE: So Nikhil and Jason, thank you so much for working with us today. I think I need to take a nap after all the stuff you guys have been just talking about and just digest it a little bit.

Audience, thank you for coming. Come on back next week, same time, same place. I think I’m going to ask Dr Gubens what he thinks about the NADINA study. He’s going to talk about immunotherapy in lung cancer. Of course, neoadjuvant and adjuvant IOs in lung cancer is hot and heavy nowadays, so we’ll see what he thinks.

Be safe, stay well and have a great night. Thanks so much, Nikhil.

DR LUKE: Thank you.

DR LOVE: Thanks, Jason.

DR KHUSHALANI: Appreciate it. Thank you.