The Role of IO Therapy in ​Advanced Non-Melanoma Skin Cancer

This roundtable video provides a comprehensive overview of aBCC and aCSCC. Experts discuss the current clinical treatment landscape, with a special focus on IO therapies. The session reviews key clinical trial data supporting IO therapy, highlighting its role in improving outcomes for patients with advanced disease.

This is Part 1 of 4:

• Part 1: The Role of IO Therapy in ​Advanced Non-Melanoma Skin Cancer
• Part 2: Identifying The Appropriate Patient for IO Therapy in Advanced Non-Melanoma Skin Cancer
• Part 3: Real-World Case Studies and Insights on IO Therapy for Advanced Non-Melanoma Skin Cancer
• Part 4: Operational and Logistical Considerations With IO Therapy for Advanced Non-Melanoma Skin Cancer

Dr Oliver Wisco: Welcome, and thanks everybody for joining us today. My name's Oliver Wisco, and I will be moderating this session with three amazing colleagues in the immuno-oncology space. And today, we'll be talking about integrating immuno-oncology therapy for advanced non-melanoma skin cancer. So, to start off, we'll do some introductions. My name is Oliver Wisco. I am a dermatologist and Mohs surgeon practicing at a clinic system called Dermatology Health Specialists focused on at-risk populations and also work in the academic setting. I'm going to hand it over to my colleague, Dr Hawkes. 

Dr Jason Hawkes: Hi, Dr Jason Hawkes, medical dermatologist and owner of the Oregon Medical Research Center in Portland, Oregon, where I also serve as principal investigator for immunology trials across dermatology. 

Dr Todd Schlesinger: Hi, I am Todd Schlesinger. I'm a private practice dermatologist, Mohs surgeon, and clinical investigator in Charleston, South Carolina. I practice with Epiphany Dermatology and also the Clinical Research Center of the Carolinas and also conduct immuno-oncology trials as well. 

Dr George Murakawa: Hi, I am George Murakawa. I'm a dermatologist in Troy, Michigan. My clinic covers from soup to nuts. I do Mohs micrographic surgery, complex medical derm, some cosmetics, some phototherapy, etc, etc. And we try to take the best care of people as we can. 

Dr Oliver Wisco: Great, welcome. Once again, thank you for joining us. So, today, we have three themes that we're going to be going over. First, we're going to be talking about the role of immuno-oncology therapy and the appropriate patients for that type of therapy. We're going to go over some real-world discussions on cases that we have seen throughout our clinical practice. We'll take a short break and then we're going to go into some operational logistical considerations when thinking about using this medication in our practices. And then, we'll end with some closing remarks. 

So, the objectives of this discussion is really to better understand immuno-oncology, how it's used, where's the appropriate use for certain patient populations—and as I said, talking about real-world cases and then also how do we actually do this? Because one of the biggest questions that we have when we start dealing with these complex therapies is actually implementing these medications when we have such difficult patients, difficult systems that we have to navigate. And it's wonderful to have people that have had such experience working with these medications. 

Alright, so first, talking about our theme number one, therapy for advanced non-melanoma skin cancer. And specifically, we'll be talking about basal cell carcinoma and squamous cell carcinoma, the keratinocyte carcinomas, and really identifying the appropriate patients. So, what I'm going to do is I'm going to hand it over to Dr Schlesinger, if you'd like to just give a little bit of a background about advanced non-melanoma skin cancer, advanced basal cell carcinoma, squamous cell carcinoma, defining what they are. 

Dr Todd Schlesinger: Yeah, so it's a great question. I think it's something that comes up every day in our clinical practices. How do we stratify these patients from our everyday low-, moderate-, and high-risk skin cancers that we see? And I think that the main, sort of, moniker that we've always talked about for the last number of years now is, is the patient a candidate for curative surgery and are they a candidate for curative radiation in those cases? And so, when you think about who's not a candidate for curative surgery, right? And so, you start to think about where these tumors are located, what are the risk factors associated with the tumors that you have? Is it histologically aggressive? Does the patient potentially have perineural invasion or other risk factors that we know from NCCN guidelines? So, when you're talking about a cancer that's so large in some ca--either way, that a patient would have to have a large reconstruction, a potentially disfiguring reconstruction, potentially a functional or aesthetically disfiguring surgery, and/or if you're talking about radiation therapy, are you talking about someone where radiating that patient would have high risk factors? 

Either they're not a candidate for radiation for whatever reason—that could be multiple reasons—or what's behind that target? So, if you're going to treat, for example, basal or squamous cell carcinoma located on the ear, and if you're going to give them enough radiation to actually cure that cancer, you may be destroying a lot of cartilage, potentially structures behind that. So, I think those are all things that come to consideration is, is the patient a candidate for those surgeries? And then, you have other things. And we—a few things to mention are whether a patient does have comorbidities as well, things like that that would come to mind. And the other main one that I think about is tumor burden, not only size of lesion itself, but may the number. Some patients will walk in your clinic with 20, 30 cancers, and what's their journey going to be like surgically? So, those are the things that I start to think about when seeing my patients in the clinic and starting to decide am I going to do surgery and/or radiation and/or combination or think about some other options? 

Dr Oliver Wisco: Jason, would you want to add anything coming from a unique perspective of being a specialist with immunology in the dermatology space? Is there anything else that you'd like to add to thinking about advanced skin cancers and how you would approach them? 

Dr Jason Hawkes: Yeah, I mean, we often talk about malignancy like some event happened and these cells go off and start spreading, growing. And though that's true, and we talk about the common risk factors—skin cancer exposure, radiation, type of radiation, we have these exposures. But I think what's really interesting coming from the immunology side is that we look at patients who have very, very high-risk skin cancers, right? There are immunosuppressed patients. There are organ transplant patients. And I think what that really sets from the fundamental understanding of skin cancers, that our immune system is protective, right? And we eliminate that immune surveillance against some of these cancers that we probably take care of a lot more than we actually see. And I think this really is that crossroads between the immunology and the malignancy, right? This is where derm meets oncology, and I think this is where this field's going. 

In some ways surgery is still pretty barbaric, right? Patients don't want to go in for a small area on the side of their nose and have their face reconstructed. And I think this is where we say, well, in those situations where they may not want to have that therapy or where that therapy is not an option, then we start to say, can we leverage the immune system to do some of the work that it normally would do if we could just tune it up a little bit, right? If we could turn on the immune system a little bit, teach it to attack these cancers, can we then have these other curative responses that we can get away from some of the tissue destruction that unfortunately is inevitable with surgery. 

Dr Oliver Wisco: It's exciting that we're starting to move to a world where we could be very targeted in our therapies. And this is really starting, really a very interesting introduction for the world of dermato-oncology, Dr Murakawa, I know that you have incredible experience in this space. I would love for—just to get your thoughts and also just even maybe paint a picture of what the landscape is for this newer therapeutic world. 

Dr George Murakawa: So, I think that in dermatology we've evolved significantly since the earliest days where we had just infliximab as our only infusion medication to progress to rituximab. Now, there’s atezolizumab to cemiplimab, and also with monalizumab, all medications that we use in dermatology. And the earliest medications like infliximab had the highest issues as far as using, infusion reactions. And now, these newer medications are much simpler, very quick to do, and very easy to handle. So, these are really exciting times for us. 

Dr Oliver Wisco: It is very exciting. I mean, we've gone from surgery, wide local excisions, to being more precise with Mohs surgery, the use of radiation, now these newer therapies. Todd, would you like to go over the current therapies that are approved for advanced basal cell carcinoma and advanced squamous cell carcinoma, the ones that we should be thinking about in this discussion? 

Dr Todd Schlesinger: Sure. So, in the immuno-oncology space, we have the two main players, cemiplimab and pembrolizumab, primarily the two ones that you would think of in this case. And you would think of cemiplimab for both basal cell carcinoma and squamous cell carcinoma, not only locally advanced but metastatic. And then, for pembrolizumab, only for squamous cell carcinoma. And so, those are the two main ones in the immuno-oncology space. Am I leaving any out? No, I think those are the ones. And as far as—did you also need to talk about the MOA? 

Dr Oliver Wisco: Oh yeah. We'll hop into that in just a little bit. 

Dr Todd Schlesinger: Okay.

Dr Oliver Wisco: Yeah. So, speaking of MOA, mechanism of action. Once again, being an immunology specialist, Jason, would you like to go over just the basics, mechanism of actions of the PD-1 inhibitors? 

Dr Jason Hawkes: Yeah, I think kind of from a background, this makes sense to dermatologists because we hear so much about these T-cell mediated disorders, right? Psoriasis, eczema, even B-cell mediated disorders where we talk about essential cell type as contributing to the inflamed aspect of disease. And so, this concept, I think, will make sense when dermatologists start to think about it. Because those T-cells, which are important for that immune surveillance, but also some of the complications we're going to see, they have an on-off switch, right? There are receptors and signals that activate T-cells. Those T-cells become active, and they start to attack other cells. In this case, might help with cancer surveillance. But we also have a check, right? A check and a balance because basically the difference between normal protection and disease is that uninhibited activation, right? When you turn on the immune system, but if you don't turn it off, it leaves the pathologic disease. 

So, not surprisingly, we know about the signals that can activate T-cells, but those T-cells also have receptors like PD-1, CTLA-4, and these are the off switches, right? These are the signals that the T-cells get from either a tumor or the tissue telling those T-cells to not be active anymore. So, it makes sense that we sometimes personify cancers like they're thinking this way, they're not. But what they do is they upregulate signals that can tell the T-cell to turn off or not be activated, right? So, that's one of the ways that cancers evade the immune response. So, these therapies are really blocking or cutting the brakes to turn off the immune response. So, you can turn it on just fine, but you can't shut it off. And the tissue or the cancer cells or the dendritic cells can't hit that receptor to turn off the response. So, it's like revving up the gas and eliminating your ability to turn off the immune response. And the hope is that by turning on the immune system, we can attack these cancer cells or these tissues that are involved and start to clear those cancer cells. 

The flip side to that is if that goes too much, we start to see some of the adverse events we'll talk about where we see excess inflammation. So, colitis, pneumonitis, right? We start to see skin rashes, itching. And that's all that unchecked, turned-on immune system because these antibodies are able to block that brake system. So, we can turn it on hoping the immune system will help clear the cancer. And this will get back into some of the management issues where we say, what do we do when those patients have some of these adverse events? We don't want to turn off the immune system. So, how do we do that in a balanced way to keep the immune system working for them against the cancer but also not immunosuppress them and then lose the benefits on the oncology side. So, this is really a delicate tightrope balance. 

Dr Oliver Wisco: It's fascinating, right? The ability to control the immune system to do the work for us, but also playing this interesting balance of balancing therapeutic benefit with adverse events. The oncology space has been doing this for over a decade, now really getting into the world of dermatology. George, I'd love to hear your thoughts about how important this is to our field. Where's this going? What are we going to be doing with this? 

Dr George Murakawa: You know, I think that it's an opportunity that we need to seize. Because we get these patients who have very significant disease, and it's very difficult to get them plugged in into the system, to get them approved, to make sure that they get taken care of and taken care of quickly. So, if you could do it within your office space, or your personnel, you've facilitated it so much quicker than you would otherwise. You can get them on medication. You get their imaging done quicker. You can also include your colleagues, your oncologists, your radiation oncologists, etc, etc. But you want to get the ball moving and that's very important for these patients. 

Dr Oliver Wisco: Yeah. Obviously, incredibly forward thinking in your clinical practice where you've had opportunities to directly use this medication. There's other opportunities with everything from teaming with an infusion center with very closely teaming with oncology. It's fascinating of how this can be used in so many different settings in an effective way. So, thinking about just the data about the therapeutics, particularly in the basal cell carcinoma space, Todd, I'd love for you to talk about Study 1620, which I know you were a part of, about talking about the effectiveness of PD-1 inhibitors with basal cell. 

Dr Todd Schlesinger: Yeah, so 1620 study was really an open-label study. So, unlike the registrational trials you normally think of for acne and psoriasis, whether you have double-blind and randomized placebo-controlled trials that are done in large numbers and times two, this is a small population. So, it's an open-label study. It was conducted, and what they were looking at, they was looking at patients who had been already treated with Hedgehog pathway inhibitor. And so, at that time, it was vismodegib. So, everyone that came in the study had to have been treated with vismodegib, and they had a different inclusion criteria. So, they either were treated with vismodegib and had intolerable side effects, and then they would be passed on to, okay, what do we do next? Or they were treated with vismodegib and didn't respond or became stable disease at one point, at which the question was, what do we do next with these patients? 

So, those are the kind of patients in the study. They were generally healthy, alright? Healthy patients with bad cancer. So, what does that mean? They weren't immunocompromised. They didn't have hepatitis. They didn't have HIV. They were not solid organ transplant recipients. And they were treated with cemiplimab at the standard dosing level—so, which is every three weeks, 350 milligrams given by IV infusion over 30 minutes. And that's the dosing schedule that we currently use. And we'll talk later about weight-based dosing, which was used back in the day. But this is a more recent study in a squamous cell study, which actually came before this one. So, in those cases, the patients were monitored for their outcome. And the way they were monitored, the primary endpoints were looking at complete response rate and then the partial response rate. And that's defined, it depends on where the tumor is coming from. If the tumor is internal, if it's metastatic, you look at RECIST criteria, which are internal measurements. And if the tumor is sitting on the surface of the skin, then you look at WHO criteria. So, there's different ways to look at it. And all the patients—and this covers both of those studies—were not only monitored by the investigators, they were also monitored by independent central review. So, it gave us 2 sets of data and of course safety. So, that's how this study was designed. It's not a big population, 130, 140 patients or so. 

Dr Jason Hawkes: And one other thing to add too is that, importantly, this is open-label phase II, right? So, what's nice is because then you know patients are on medication. So, in an interesting way, we think, oh, that's not good because you know they're on drug. But it helps you when you're managing side effects, right? So, ethically, it makes sense for this population because you can't put this group in placebo, right, because of the type of disease they have. And at the same time, we're able to watch them from day 1 and see what their response is knowing they're on therapy. So, we can really start to adjudicate some of the complaints they might have that are related or not related. So, there are situations where actually open-label is informative in different ways than the placebo-controlled trials, and in this situation it's very informative. 

Dr Oliver Wisco: Todd, do you want to comment just briefly about the findings? What the observed—or excuse me, objective response rates, and how should we interpret those results? 

Dr Todd Schlesinger: Yeah. So, I think we don't have much to go on because before we had basals—before we had this, we didn't have anything. Unlike squamous cell carcinoma, there were unapproved drugs being used. We'll talk about that later. But the overall response rate was in the 30% range. So, about 25% of the patients were partial responders, about 10% to 12% were complete responders. And what that means is those patients would not only have a complete clinical response by observing, but they also may, in cases, most cases, would have a biopsy or some kind of other method of determining that. And all that would be also looked at by independent central review. So, that really increases the stringency of this study and the response rate. It was interesting also that was seen over time, as you look at these patients, is some of the patients that were partial responders initially— And this is what we had to learn in the very beginning, because we really didn't have any experience with these medications, the short term, and what's going to happen in the long term, right? So, that data evolved over time, and that's some of those patients that were partial responders that eventually became complete responders. And that all depends on a number of specific factors that the patient may have. It could be previous scarring, previous surgery, previous radiation, the local tissue environment. So, all these things can affect how well these patients respond. And there's a lot we don't know yet. 

Dr Oliver Wisco: Right. So, metastatic basal cell carcinoma, about a 31%—oh, excuse me, locally advanced 31%, metastatic basal cells about a 21% response rate. On one, look at that, those seem really relatively low. But on the other hand, these are patients that we didn't have therapies for before. George, any thoughts about that and how we would explain to the audience and say it may be relatively low, but this is an interesting population. 

Dr George Murakawa: Well, these are not naive patients. They've all been on vismodegib, which in my hands, I've only seen 1 or 2 people who can really tolerate it without major issues. But everybody, everybody, complains of an intractable thirst, a lot of joint aches, a lot of hair loss, a lot of—people are pretty miserable. So, sure, we try to pulse them and give them 1 or 3 months at a time and 3 months off and, you know, they might get some response. But people don't tolerate Hedgehog inhibitors well. And that's why to see the kind of response, even after they've already been on medication, it's just amazing. And if we can jump over quicker, I'm sure it will be a much, much higher response rate. 

Dr Oliver Wisco: Absolutely. 

Dr Todd Schlesinger: I would just add, I agree with you on—you said you see the responses. I think in clinical practice, and this sometimes can happen, I think with Hedgehog as well, it seems to perform a little better than advertised, if you will. 

Dr Oliver Wisco: Right.

Dr Todd Schlesinger: So, we look at the study and see the outcomes in the patients. A lot of people respond more than you would think by looking at the data that you just mentioned. 

Dr Oliver Wisco: Right. And while there is relatively high adverse event rates, I mean, most of the time I see fatigue. That's still an adverse event rate or adverse reaction. So, obviously, Todd, you've been working extra hard. You've been involved with so many different studies in the oncology space. Do you want to talk a little bit more about the use of PD-1 inhibitors with cutaneous squamous cell carcinoma? 

Dr Todd Schlesinger: Absolutely. So, the squamous cell carcinoma study was called 1540. And, of course, this is the one that was conducted first, even though we're covering them in the opposite direction. 1540 very similarly enrolled a population of patients with both locally advanced and metastatic squamous cell carcinoma. A little bit different here though. We had—the initial group of patients here were treated with weight-based dosing. So, before they established by whatever methods, PK, whatever, that 350 milligrams every three weeks by infusion for 30 minutes was the proper dose. Some of the patients received weight-based dosing in their early groups in the study. And so, these just had sort of a rolling admission. Same idea, open-label, phase II, nonrandomized, nonplacebo-controlled study, multicenter study with the same idea, independent central review, same idea. Patients who were with bad cancer, squamous cell carcinoma, who were relatively healthy. Again, performance data. So also, I forgot to mention before, the ECOG performance data. The performance data means just their general ability to conduct activities of daily living was relatively good. So, these patients were relatively healthy generally. And, of course, we have more data for this. So, these patients now have about 4 years of data for us to look at. But again, the design similar, the safety was looked at in a similar way. 

Dr Oliver Wisco: George, would you like to comment at all about the response rates, side effects, everything from thinking about that study, but also just even thinking about your own clinical practice? 

Dr George Murakawa: You know, what we see clinically is that it stabilizes the squamous cell carcinomas relatively quickly. Within a couple of infusions, they're already stable. Now, it takes a few months before they really shrink and start to knock down, but it's quite impressive the response that we've seen with it. 

Dr Oliver Wisco: Yeah, my own clinical practice as well. I agree with you. Jason, is there anything else you'd like to add in terms of the response rates and how we would like to talk about these numbers? Thinking about, we just talked about basal cell’s response and how we should continue thinking about this therapy, knowing that we're not going to get perfect responses. 

Dr Jason Hawkes: Yeah, I mean, for the dermatologists, you just have to acknowledge the fact that this is totally different from all the other clinical trials that we do, right? So, when we take patients that are in psoriasis trials or atopic dermatitis or vitiligo, they're not refractory to therapy, right? Those are exclusions. These are often bio-naive or systemic-naive patients. They may have had therapies, but they wash out of therapies. I think just to highlight again the level of difficulty here, these are patients who are already in that upper 5%, 10% of cases, which are more difficult. And then, you have the level of, they've already, you know, as mentioned, the Hedgehog pathway, they've already failed some level of therapy. So, it's important that these trials, the level of difficulty’s a 10, right? And so, again, you can say, oh, these numbers don't seem that high, but this isn't applied to the run-of-your-mill cancer, right? These are difficult locations. They're difficult cases. They're refractory to first-line therapies that, before we got into these new targeted therapies. So, I think that's just really critical across the board is that comparator group, these are so much harder. So, you're operating in, and that makes sense, right? We're saying these are therapies for the very worst. 

Dr Oliver Wisco: Right.

Dr Jason Hawkes: So, you're starting on that end. Most of the trials we do in other inflammatory conditions are the opposite. We're like, we're cutting out sick people and saying, alright, now we're going to work forward and see how that works. So, I think that's a critical piece here. And then, also I think the safety profile adverse events I think is critical. And I think patients understand when you start to explain it. Like, the way this medication works, or these medications, is to turn on your immune system to attack the cancer, but that comes with collateral damage, right? Because we can't tell the immune response to just get the cancer. And so, you start to see other things spill out. You see pneumonitis. You see colitis. So, pruritus and rash, one of the most common symptoms. Then you mentioned this generalized fatigue, malaise, right? This generally not feeling well. And so, sometimes what's interesting from these trials too is you also see there can be these acute events. But even after therapy stops, some of these immune-related toxicities can persist for months or years even when the therapy's been stopped. And so, we're still learning in this area, but that's why the level of difficulty is so high. We're willing to have this tradeoff for potentially lifesaving therapies for when there's really no other option. So, that's a different context that we have to think about and not compare it to what we see in other clinical trial programs. 

Dr Todd Schlesinger: I was going to say, a couple more pieces I was thinking about when it comes to the outcome data. Number one, the response time for squamous cell carcinoma is a little shorter and generally that you might see a response faster than for basal cell. The other thing to think about is—and you don't see this as much with basal cell carcinoma—but with squamous cell carcinoma, sometimes you can see that early pseudoprogression. And you’ve got to be aware of that. Because sometimes these tumors will look like they're getting worse during their first few infusions where it’s either ulceration or whatnot could look worse. And that's where we have to really be careful and say, are we seeing pseudoprogression or are we seeing actual just response, immunotherapeutic response? Push through that. And that's just where it comes to, just kind of have to see these patients and see how they respond early and middle and late. 

The other thing about the squamous cell carcinoma data that's interesting is that they did different time cuts, data cuts off, which is every year or so there's a data cut. That again, similar to basal cell carcinoma, it is over a longer period. Now we're talking over 4 years of data that again, the patients that were the partial response moved a little bit and more into complete response over time. So, it's interesting how much we've learned from when we first started this and like, oh, what's this stuff going to do? What's going to happen to these people, right? And then, over time, seeing how they responded. Some people are able to stay on therapy long term, and other people have to go off early and move on to other things. 

Dr Jason Hawkes: Well, and these are first-generation therapies.

Dr Todd Schlesinger: That's right. 

Dr Jason Hawkes: So, we're working out the kinks. These drugs are going to get better and better. And there's a reason that this particular drug class is growing faster than virtually all other drug classes. So, there's this huge need from the oncology side. We're just starting, and we're learning so much. So, these are those crude first studies. And some of these right out of the gates have done a really good job. But they're going to keep getting better and better as we learn a little bit more on how to modify these and dosing and selection. So, I think this is the beginning of a story that will be pervasive in dermatology because we're going to see more and more therapies available. So, dermatologists, whether you use these medications or not, you're going to see them in use and you're going to have to help manage their toxicities to some degree because you can't practice without seeing these patients. 

Dr Oliver Wisco: Right. As dermatologists, we see the cutaneous side effects, right? We're now seeing if you're prone to psoriasis, you're going to get psoriasis. You're prone to atopic derm, you're going to get that. 

Dr Jason Hawkes: Well, and there’s—and importantly, there's preexisting diseases that worsen. 

Dr Oliver Wisco: Right.

Dr Jason Hawkes: And then, there's cases of de novo development. So, we have patients, particularly in the melanoma trials, that in their studies they go on to develop vitiligo. We see it, it's clear. So, the primary tumor has some impact on some of these disease-specific side effects. So, and those can be diseases they've never had. Or it could be, yeah, I've had this mild history of eczema and now it's going crazy. Or I never had psoriasis and all of a sudden I have psoriasis. So, it's also an opportunity to learn about, how do these diseases develop? We have no idea why somebody gets vitiligo or psoriasis. But, in these trials, we see all sorts of inflammatory conditions that we can also learn about what's maybe driving these to develop because we're changing something then turning on diseases or having worsening. So, I think dermatology-wise, we're going to learn more than just about the management of skin cancers here. 

Dr George Murakawa: I wanted to make a comment about some earlier stuff about the advanced squamous cell and basal carcinomas. I don't know if I mentioned earlier, I am also a Mohs surgeon. And a lot of times when you come into a case, you don't realize how bad it is until you get that first layer out. And once you get that first layer, you say “uh-oh,” and you're going to need to go way more extensive. You're going to find a lot more disease. You're going to upstage them. You're going to start doing imaging studies. You'll do Castle gene expression profiling. You'll start adding things. But you won't know that going into it. And so, a lot of these that seem really bad may not be as bad. But the ones that seem relatively innocuous, you can get some really nasty skin cancers there.

Dr Jason Hawkes: Yeah, so true. I was just thinking when you were talking about—I was a third-year derm resident, and I was working with one of the Mohs surgeons at the Huntsman Cancer Institute. And a little area here on the scalp, and I remember approaching 7, 8 o'clock and we have most of the skin exposed on the side. And sometimes the surgeons abandon therapy at that point in terms of surgery, like, we can't keep going, right? And I think that this is exactly the type of population where you can't always tell. There's some you see walk in the door and you're like, this is a problem. There's others where it doesn't look so bad. And then, you uncover it and there's this iceberg. And you saw the tip of it, and it's under. So, I think that this is an important point. 

Dr George Murakawa: Yeah. Or you do a recurrent one on the nose, then you know that whole face is coming off. 

Dr Todd Schlesinger: And I feel like the same thing applies to the adverse event management, right? 

Dr Oliver Wisco: Yeah.

Dr Jason Hawkes: Yeah.

Dr Todd Schlesinger: We've mentioned fatigue as a—I consider that to be a sleeper because older patients, you're basically trying to turn on an immune system that doesn't have much to give. So, it's like taking a 2-cylinder car that's 6 cylinders operating on 2, and you're hitting the gas and it just doesn't go anywhere, right? And sometimes those patients have issues with that. And then, the other thing about the adverse event management is—while we're thinking about ways to manage these patients and keeping them on therapy, the other thing you have to remember is that any one of these adverse events could be also a recurrence, a metastatic condition that could happen. So, each and every one of these things requires a thorough thought process and a potential workup for disease progression as well as the immuno-oncological adverse event. So, just things to think about as folks are managing patients or thinking about these patients and even involved in the multidisciplinary care of such patients. 

Dr George Murakawa: Fortunately for us, all the patients we've ever infused with cemiplimab, we have not had any issues. We have not had any adverse events. However, I've had patients come in from other people who are already treated, someone who developed Guillain–Barré, things like that. So, these things do happen and we're very cognizant of it. But, fortunately, if there's some wood for me to knock on, we've been pretty fortunate so far. 

Dr Oliver Wisco: Well, I'd like to say I've not been as fortunate as you working very close with multidisciplinary teams. I mean, I've seen the whole gambit from mild fatigue to endocrine abnormalities that are not reversible to even obviously the downstream effects of death. And so, they're not medications to take lightly. But, at the same time, I also don't think they're as bad as we think, especially when you understand what's going on. And I think you guys have pointed out so many important points. It's everything from thinking about the tumor biology, thinking about the underlying predispositions and recognizing this is very much a multidisciplinary approach, a disease process—excuse me, a therapeutic that touches all areas within dermatology. So, it's kind of exciting where we're going to go. 

So far, we've talked about cemiplimab. We've talked about its use with treatment-resistant Hedgehog inhibitors. And we've talked about cemiplimab in the space of advanced disease. There's another medication, which Todd had mentioned before, pembrolizumab. Jason, would you like to talk about one of the recent studies on KEYNOTE-629 and what—how we're thinking more about that medication in addition to cemiplimab for cutaneous advanced squamous cell carcinoma? 

Dr Jason Hawkes: Yeah, so it highlights a lot of the same concepts, which is that you have, I think very similar in terms of design, like we've talked about in inclusion. I think the patient population is still the patient population, right? So, I think it's that medications act a little bit differently. So, I think here it's looking at a different mechanism, right? Well, different therapy, I would say, that very similar mechanism. But again, looking at how we start to see that response in this same group. And I actually think you see a lot of the same features in terms of relative response. But I think here you basically start to see where the lack of response with the increased adverse event profile. This was a difficult study in terms of the outcomes. So, we didn't see what we talked about earlier. We struggled to see reaching these endpoints where we're really adding on top of it. We're starting to, starting to see that flip to the other side where toxicity becomes a problem. 

Dr Oliver Wisco: Yeah, we are thinking about these medications and thinking about the utility. There's obviously multiple therapies that are coming about. There will be multiple therapies moving on, benefits to different ways of approaching it. And even just thinking about the data. There's the follow-on study, 630, right? I, before this talk, was trying to look up this data, and I was racking my brain, I cannot find end results. I would love for you to comment about why I couldn't find that, Todd. Why is it that I couldn't find data on KEYNOTE-630? 

Dr Todd Schlesinger: Yeah, so one comment about 629 is also what we're missing—the missing piece we have for that is the duration response data that we have for 1540/1620, which is once you achieve a response, partial or complete, how long do they maintain that on therapy? So, that's one thing, 6 months, 12 months, whatever you have, that's missing. And then, so 630 was supposed to be that long-term-- Well, it's supposed to be that adjuvant study. So, what we have here is the 2 studies side by side, the C-POST study, which we'll talk about, the Regeneron neoadjuvant study or adjuvant study with radiation, and then 630, which were supposed to be sort of competing studies, right? But the patient populations were very different. So, what happened was 630 was abruptly stopped. It wasn't meeting the endpoints. They weren't seeing the differences between 2 populations. So, they discontinued that study abruptly around August or September of 2024. And there's different reasons. It hasn’t—nobody's really come out and said, hey, this is the reason why we stopped the study. 

But if you look at the populations, they're very different. The C-POST population, arguably C-POST patient population was higher risk. They had more factors, more lymphatic invasion, more risk factors that would make it more likely you would see a difference between the active population and placebo population, or non-treated population, in that study versus 630. And I think, in my opinion, that's the reason why 630 just wouldn't have been able to achieve the response rate the way it was designed. And you don't know that thing—you may not find that out until after the fact. You don't think about, when you’re designing a study and you have no idea what to put in, what kind of patients to put in, especially with studies like this that are on the cusp. So, that's, in my impression, what happened with that. And, of course, we're going to continue discussing C-POST data. 

Dr Jason Hawkes: Yeah, I think, what you're saying, what we were talking about earlier is you have this benefit and actually pretty decent tolerability, things we could manage. But then, I think here you start to see where that gap of benefit was small, but you see the toxicity, right? So, now, you're adding a potential adverse event but not the clinical benefit, right? So, I think a lot of reasons figure out why that was the case, but you have an input of what seems to be similar, but clearly something's different in the population or the design or even just the specific medication. But you eliminate that gap of improvement, but you still maintain the toxicity, right? The rash, the other components of it. So, I think that's the futility side of it, right? It's that, if you have this adverse event profile, but you can get a clear clinical benefit, then that's the benefit outweighing risk. And so, here, it's like you don't get the benefit, but you maintain the risk that comes with these types of therapies. 

Dr Oliver Wisco: Yeah, they're just tough. And these are just tough patients, right? So, these were sick people. They've had surgery, they've had radiation. You don't do surgery and radiation to somebody that has a small tumor, right? They already had very advanced disease. George, once again, having a lot of clinical experience infusing in your own practice—any more thoughts about adding onto these studies and how we are now starting to move in the next generation or the next evolution of use of these medications? 

Dr George Murakawa: I think that what we're going to have to figure out is what role will these have on tumors that seem pretty aggressive that we want to surgically treat but might be wise to preshrink it down, their tumors. So, patients with, which may appear to be an unresectable tumor, patient lesions, basal cells on the—that you feel the traction onto the orbital rim. You know that they have at least a 25% plus chance of not being cured and that they're going to have to go enucleation unless you pretreat them. So, there's a lot of things that—a lot of foci that we can go after, and it's going to be very important. 

Dr Oliver Wisco: And we talked about being surprised, middle of surgery. I don't think we do that very often. I think we do for the most part—or we should be doing this for the most part—a better job of pre-oping our patients. And your example of the tiny little squamous cell carcinoma that you end up taking half of their scalp or the patient that you initially did the pre-op on the patient and their squamous cell carcinoma was a centimeter. And then, they come back 1 month later and now it's 5 centimeters. There's certain things we just obviously are not going to be able to catch sometimes. And this is wonderful how we now have these options. Todd, I would love for you to talk a little bit more about neoadjuvant therapy. Where do you think we're going with this and what other spaces should we or—should we be approaching with the immuno-oncology space for skin cancer? 

Dr Todd Schlesinger: That's a great question. I think that everyone's question on their mind is adjuvant, neoadjuvant, perioperative therapy. So, neoadjuvant being what we do before surgery, adjuvant being we do after surgery, and perioperative what we do before and after surgery, right? So, I think that the open-ended questions are, what's going on with the biology? So, you've got the T-cells, the CD8 cytotoxic positive T-cells are in the tumor bed that surround the tumor. You've got the drug. Where's the drug going? Is it staying in place or not? So, the open-ended question is, okay, well do we do neoadjuvant therapy? Do we do immuno-oncology therapy and then surgery? Do we do surgery and then immuno-oncology therapy? And what's happening there? So, the theory behind that would be, the point is you would want to consider doing neoadjuvant therapy, which means that you're activating those tumor bed cell T-cells. And you're getting them into the tumor, and you're shrinking the tumor down, and you're causing that immune response, and then you’re doing surgery. 

And hopefully with that goal, with activating those cells in advance, you're helping to attack that tumor and then remove that tumor. You know, maybe shrinking it down to the point where it can become surgically manageable, right? On the other hand, you could think about adjuvant therapy where you're cutting the tumor out and then you're giving immunotherapy. But are we already—are we cutting out those important tumor-infiltrating lymphocytes that are in that tumor bed, and then cutting them out, and then trying to activate what's left? So, I think that's a big question. And I think the theory right now, I think the theory that most of us are thinking about now is that we should be treating in advance, doing surgery, and then potentially treating after. And then, maybe combining that with radiation postoperative as well. And those are the—that's where it starts to become fuzzy because radiation therapy is still extremely controversial: when we should use it, how we should use it, what settings we should use it. And then, the role of genetic expression profiling in helping decide the risk factors—not the risk factors, but the decision about what their expected response from radiation oncology treatments will be. And that's where we're at that point now. We're like, okay, when do we do the GEP testing? How much does that help us? And then, in stage does that help us decide whether we should be using radiotherapy? 

Dr George Murakawa: To go on with that, you know, if you have a Castle 2A expression on it, there's already a 20% chance that it's going to recur. And if you have a 2B, it's at least 50%. Is that, by itself, enough to give them additional therapy? Do we give them adjuvant or not? And these are really tough decisions to make. You know, whether they get radiation, whether they get cemiplimab or what have you. But these are numbers that you have to sleep on and worry and think about. You're going to continually image them, but when do we just pull the trigger? 

Dr Oliver Wisco: Right. I agree. Obviously, we follow guidelines, right? We think through what's the appropriate use criteria for Mohs surgery? What's the National Comprehensive Cancer Network guidelines? How do they guide us? But the reality is these are tumors in which we don't have great answers, right? So, in these scenarios, we have guidelines and we have options. We have to be very careful, right? We have to be mindful of the value equation, making sure that we're hitting appropriate outcomes with being very mindful of cost. But, once again, we don't have great answers in these spaces. 

Dr Todd Schlesinger: George made a huge point and he was—you made a huge point. And I think that point is: what's the expected recurrence rate? 

Dr Oliver Wisco: Yeah.

Dr Todd Schlesinger: So, I think that number, and that's fuzzy how we decide what the expected recurrence rate is, but I've seen that published in literature and floating around 20%. So, if your expected recurrence rate's higher than 20%, then you would consider doing radiation therapy postoperatively. If it's lower, then you wouldn't. But, again, the GEP testing is key, especially in the tumors that we consider to be low risk visually. This tumor is low risk, right? We look at it, but then we do GEP testing and it comes out high risk. Those are the patients that we normally wouldn't radiate, but we might think about in the setting of clear margins now. We've cut the tumor out. So, that's the big question, in the clear margin setting, what are we doing with radiation oncology? Now, if it's positive margin or we have nerve involvement, well now it's clear. 

Dr Oliver Wisco: Right.

Dr Todd Schlesinger: We radiate them. So, that's where the question, I think, is where we're at. 

Dr George Murakawa: And on the converse side, it's also true where I had one that I thought was so wicked and it comes back as a Class 1. And it's like, yes, I could leave them alone. 

Dr Todd Schlesinger: Yeah. There you go.

Dr Oliver Wisco: I also think about it similar to the melanoma space, right? Where now for stage 2B, stage 2C, where now even it's—so, it's node negative. We have no evidence of clinical disease. But now, there's an indication for immunotherapy just because we know the biological activity is higher for these patients. And even though we can't see that with our current ability to image or to stage, we know that's a higher rate of recurrence. And to your 20% thought process, I am interested to see how we move into that same space with keratinocyte carcinomas.