Real-World Case Studies and Insights on IO Therapy for Advanced Non-Melanoma Skin Cancer

This video presents real-world patient cases from each of the three expert speakers, illustrating the practical use of IO therapy in treating aBCC and aCSCC. Each case highlights key factors influencing therapy decisions, from diagnosis through treatment and post-treatment monitoring, providing valuable insights into individualized patient management.

This is Part 3 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: I’d like to now move into our next theme, theme 2, real-world case studies and getting very personalized insights from each of you. I'd love to start with you, Todd, having a lot of experience in this world, particularly having such experience in the original studies. Love to hear your thought process or even whatever cases you have for us to discuss how we should be thinking about this as an audience within the broader field of dermatology. 

Dr Todd Schlesinger: Yeah, so in my cases, so a lot of the study patients primarily were vismodegib patients. And they all had to be on that. But in the real world, I think the case that comes to mind is, really, a relatively young patient came in with basal cell carcinoma that we measured in body surface area. So, this is not the average. We're talking about what’s the BASI score, for example, the basal cell surface and area index. That doesn't exist. But yeah, BSA. So, the patient really had about 12% BSA covered in basal cell carcinoma; a large lesion on the chest, a large fungating exophytic lesion on the left arm. Came to the waiting room, the bleeding and all this stuff. So, to me, it was a relatively easy decision in that case because not everyone would think about, “Okay, immuno-oncology first line, let's do it,” right? 

But in this case, it actually was an easy decision. The patient could easily have been treated with a Hedgehog pathway inhibitor as well. But I felt that since I'd seen the responses, I knew what the drug could do. We went ahead and started him immediately on cemiplimab. Relatively healthy, so, there wasn't any comorbidities to be concerned with. And the patient responded very well and continues to respond well. So, we saw early on, after 3 to 5 cycles, an immense shrinkage of the tumor, just falling away of that exophytic mass to the point where I think after about 6 to 9 cycles every 3 weeks, the areas became flat, erythematous. Patient really didn't have a lot of issues with adverse events— I think a testament to his being young. And there's a sweet spot, I think. Very young patients, hmm. Older, very older patients, there's not as good—it’s almost like a bell curve. So somewhere in that middle. Same thing with weight; somewhere in the middle, they do well. If they’re very overweight or very underweight, it's not as good for the patients for outcome goals. So, this guy was a classic case of, just did very well on that kind of therapy. One of those hands-down, easy decisions to make, and seeing a great outcome. 

Of course, I can cover other cases that were very different decision-making processes. Another one I just think of, and this, I'm not going to get into this one too much, is again, we talked a bit earlier about those patients that have multiple tumors. I have patients that come in sometimes with 25, 30 tumors, you know, basal cell carcinomas. None of them, many of them candidates for Mohs surgery or whatnot, but just the overall tumor burden. So, you're talking about, say, a 50-, 60-year-old patient coming in with—a fair skin patient with 30 basal cell carcinomas. That person's looking at a 5-year journey of cutting those all out. So, those are two things I think of on the basal cell side, which are patients who I thought would be a reasonable candidate for immuno-oncology medication. 

Dr Oliver Wisco: Interesting that you went to cemiplimab prior to Hedgehog inhibitor therapy, which obviously there's rationale to do that. Have you done that with other patients, and can you take me through a little bit more of your thought process? Personally, for the patients that I've seen, a lot of those that I've put on Hedgehog inhibitors really hate the fatigue, the hair loss, and the significant cramping. 

Dr Jason Hawkes: The taste changes, too. 

Dr Todd Schlesinger: Dysgeusia.

Dr Jason Hawkes: It doesn't always resolve, right? There's a thought that it would happen during therapy, but even when you stop therapy, it doesn't always resolve. 

Dr Oliver Wisco: Right.
 
Dr Todd Schlesinger: So, I think about it. And it's a great question. So, when I think about those 2 drugs, right? And we have the 2 approved drugs, vismodegib and sonidegib. They're very different. So, those 2 drugs, vismodegib being the older one, sonidegib being the newer one—the PK, the pharmacokinetic profiles of those drugs are very different. And the way you think of it, and this can't necessarily be connected directly to the outcomes, is the volume of distribution. So, vismodegib in our body has a volume of distribution that's approximately the same as the number of liters of blood we have. Whereas sonidegib has a volume of distribution over 9,000 liters. Now, what does that tell you? That tells you that that drug is going farther. And it's also much more lipophilic, loves fat. 

So, where is the fat? In the dermis subq, right? So, we think that drug theoretically might be getting better into the dermis than vismodegib, but we don't know for sure if that really connects well. But we've, again, what I mentioned earlier, we've gotten smart at dealing with those medications. So, the bottom line is, I try to use them, and I try to keep them on as long as I can, right? Because there are adverse events for immuno-oncology and may not want to expose the patient to it. They may not want to have it. So, that means giving them pretreatments of various supplements, they get them. Giving them a nutrition consult, so that way they know what to do, what to expect. Talking to them about the hair loss, neuropathy. And then, using aggressive dosing schedules, different dosing. And when I mean aggressive, I mean aggressive under, which means every-other-day dosing. Maybe 10 days a month, maybe every-other-week dosing. Things like that, that we already know that the patient's going to have a side effect, but I want to keep them on longer. 

So, I might start them on 2, 3 months of daily dosing and then immediately just automatically drop them down to a lesser dose. Especially with soni, knowing that profile. So, I try not to just throw them on the medication with the knowledge that they're going to have an adverse effect and I'm going to take them off immediately. I'm going to try to utilize that medication to the fullest extent I can and manage those side effects in the best way I can before switching. Or in some cases, like this guy I mentioned, he was a hands-down winner for immuno-oncology drug from day 1 just because of the amount of tumor the patient had. And that was a discussion that was still carried out: “Hey, you have option A, option B,” you know? 

Dr Oliver Wisco: Along those lines, have you guys had any experience with thinking about the tumors in terms of their subtype? So, basal cell carcinoma, I find that larger nodular basal cells respond pretty well to Hedgehog inhibitors. But certain subtypes, more aggressive subtypes, infiltrative, or even if I see keratinizing features, I find that those were more treatment resistant. Have you had that experience as well? The feeling of our tumor board is a little bit of a concern of Hedgehog failing, significant side effects, and then having limited ability to move to the next step. So, to your point earlier— 

Dr Todd Schlesinger: So, you're talking about Hedgehog pathway and you're talking about—

Dr Oliver Wisco: Yeah. 

Dr Todd Schlesinger: I think the basal squamous, yes. When you're starting to see those, what we call collision tumors— 

Dr Oliver Wisco: Mm-hmm.

Dr Todd Schlesinger: where you have the 2 types, I think that does lower your chance of getting a good outcome with a Hedgehog pathway inhibitor. And, again, that would mean—now, when it comes to immuno-oncology medications, I don't think the subtype matters as much. I still think they'll respond, even morpheaform basal cell carcinomas. I think that what matters differently there is the prior therapies to some extent, not whether they failed a Hedgehog pathway inhibitor because of lack of response or side effect. They usually do about the same. But if a patient has extensive scarring, prior surgeries, multiple surgeries, prior radiation, you start to think about that tumor bed and whether you've got a bunch of cancer cells wrapped up in the scar. And so, can the drug actually even get to them? So then, in the studies that also showed the patients that had the extensive scarring going in, some of those patients didn't have long-term responses. 

Dr George Murakawa: Yeah, I think the other thing is it's surprising how sometimes the histologic subtype really doesn't matter as far as how aggressive it is. The ones that seem relatively innocuous as far as the nodular basal cell could be incredibly aggressive. That the whole, if it's recurrent, the whole scar has to come down because it's all through it. And then, they just push down and deep into the dermis and extend way beyond what you would expect from just a run-of-the-mill–looking nodular basal cell. 

Dr Jason Hawkes: Well, this highlights just how much we don't understand about looking at a cancer under the microscope and predicting what it's going to do in the future, right? There are some clear features. We see things like perineural invasion, and you mentioned some of these other, the morpheaform. Some of those are helpful. But this one, it's a good example of where just looking at the architecture histologically doesn't really tell you the patient journey, right? So, I think it highlights a gap that we still have, even though we've gotten much, much better. We still have a gap on, again, these predictive features based on objective characteristics. 

Dr Oliver Wisco: Dr Hawkes, I'd love to move on to you. I’d love to hear your insights and your experience. 

Dr Jason Hawkes: Yeah. So, I'll take us to the other end of the spectrum, which is we start with patients who are presenting with the primary oncology complaint in dermatology or dermatology surgery. And then, trying to decide, is this a good candidate? But the other end that I think dermatologists need to be aware of is the fact that in your office, you might end up seeing a patient who was put on for another reason by another provider. It could be a non-dermatologic malignancy. And I'll share a case that came in. It was about a 58-year-old Hispanic male came in. Both of his sons were there. He'd had a really aggressive tumor, a GI tumor, and he had intractable itching. He had widespread erythema, some involvement of the flexural areas, and he's just miserable. He had a little bit of hair loss. And so, he was doing pretty good in terms of his tumor. 

But walking into the dermatology office, these are the intersections that even the general dermatologist may have, right? And interesting, after I saw this patient, I talked to the oncologist and I said, “You should have given me a heads up. It would've been helpful. But let's talk through what your thoughts were.” And I think when we start to look at how these adverse events are managed from these medications, so again, separate from the primary tumor response, we have the secondary toxicity. And management, to date, has been these usually IV steroids, right? They try to do IV for the fast response, and they'll often pulse these a couple of times to see if they can get these patients under control. But it's interesting, when you go through the guidelines, the next step is then to move on to something like a TNF inhibitor, right? Well, both steroids and the TNF inhibitors are broad-acting immunosuppressants. 

So, TNF alters 4,000 genes. So, what's happening is we're being forced to manage some of these cutaneous toxicities, also involving hair, for example. And by giving them things like steroids or TNF inhibitors, we're actually suppressing the immune response. And so, we've got this activated immune response. We start to see attack on the tumor. We get attack in the cutaneous toxicities. And then, the response is, well, let's shut it down, right? Let's give them things like IV steroids or TNF inhibitors. But now, we're pushing them back the other way where now we're eliminating what we are trying to do. So, you and I have talked a lot about this, this balance of immunoactivation versus immunosuppression. 

And I think where this is going to be very interesting, and I think there are people out there leading the field like Mario Lacouture in New York and others in Europe who have really taken on this group is—is there a balance there? Can we manage these patients with selective therapies towards things like itching or psoriasis or rashes and try to move them back towards clearing of the adverse event while still allowing them to maintain their oncology goals? Because one of the key factors in this area is that the cutaneous toxicities or other toxicity, right, colitis, the real risk is that you run to discontinuation of therapy. So now, we're letting these toxicities or adverse events basically remove our ability to continue treating these patients. So, that's why it's critical that the dermatologist not say, “Oh, I don't use these drugs,” right? Because we want you to be partnered with either individuals like yourself and the group here who's using the medications, but also the local oncologists who may be using it to say, we want to find ways to help you as a specialty so that these patients can stay on this medication. 

And this particular medication, or this patient, we used dupilumab because there are a lot of features. He had itching, he had flexion involvement. The biopsies are often nonspecific. They can show an interface dermatitis or a lichenoid dermatitis, spongiosis, eosinophils, kind of that nonspecific feature here. But we looked at the clinical picture. We used dupilumab. And the thought there is we can block IL-4 and -13. We can take away some of the drivers of the itching and some of the components of the rash, which mimicked an atopic or an eczematous-type eruption. And this is a patient that had a very, very good response. It's not immunosuppressive. We were able to take away itching, had a dramatic improvement in the rash. But most importantly for this patient, he was able to stay on the immunotherapy so they could keep progressing their oncology goals. 

And I think this is an area that hasn't been taught well in our specialty. It's new. It's going to become more and more important. And I think the dermatologists are going to form partnerships in these multidisciplinary teams to find ways to manage toxicities to keep them on therapy. And then, allow either the surgeon or the oncologist to keep pushing forward in the objectives of trying to get the tumor clear. So, this is a good example where we can now leverage some of the other advances being made in these other conditions to also be used in combination with some of these therapies to try to help take away. Because think of things like type 17 or type 3 inflammation or type 2 Th2 inflammation as not really being critical for tumor response or tumor surveillance. So, we can maybe hit part of these components and disrupt the immune drivers of these toxicities while not interfering with the response from the malignant cells. So, I think this is a good example of where we can be useful in this particular area. 

Dr Oliver Wisco: I love that you brought up Th2, Th3, Th1. Thinking about the 17 pathway. This is a discussion for another time, but I'd love to hear your thoughts more about how that might spill over to the other organ systems as we start treating certain disease processes that are a Th1-, Th2-predominant type of disease. Does that actually—is that the same type of immune response we're seeing in the other organ systems? If you want to comment just briefly on that, but— 

Dr Jason Hawkes: Yeah, I think bottom line is that we've just started looking at these patients, right? It's much easier to biopsy the skin than biopsy your colon or a liver, for example, or even the lung. So, one of the advantages we have as our specialty, which has always appealed to me, is the fact that we have ready access to tissues, right? So, you can go in and you can take out a proportion of the colon or the GI system, but you can't really get to the pituitary gland. You can't get to some of these other areas. So, we can start to learn from easily accessible skin. Easy to do a biopsy, easy to start looking at profiling, that we can start to see, are we seeing these patterns, right? Why do—what's the link between hair loss and rash and itching and fatigue? And I think we're just starting there. So, I think groups are starting to put this together. 

I was in New York. We started collecting some of these samples in collaboration with Memorial Sloan Kettering, where we started to say, can we start to look at the molecular profiles and then understand? And how does that match what might be happening in the lung or the GI system, for example? So, I think we're just starting that area. But it's a very important area to tease out. And hopefully, it helps inform some of the therapies. We say, these patients who get colitis, for example, these therapies are going to be helpful. People who start getting more itching, these therapies are going to be helpful. And we're getting things that work for just itching. Think about nemolizumab blocking the IL-31 receptor. That's itch, right? So, can we start to leverage some of these newer therapies coming out for other indications to help us in this particular area? 

Dr Oliver Wisco: George, I’d love to hear about your case. 

Dr George Murakawa: Okay, so this person had a recurrent basal cell carcinoma. It was periorbital, went on his nasal sidewall. Originally went to plastics who cut it out, cut it out, and cut it out. I think he missed 4 times. Saw me about 2 or 3 years later, and we did Mohs on it. We thought we had him cleared out, but I told him he's got a really high chance that this is going to recur, because I took it all the way down to the orbital rim, cleaned up everything. And sure enough, about 6 months or a year later, he recurs. And I know that the whole scar is going to be involved. He's just no longer a surgical candidate. We offered him up vismodegib, and he couldn't tolerate it. So, we had to do a lot of insurance manipulation games. So, finally, he's on cemiplimab. You can palpate the area. It used to be rock hard, because you knew all that scar tissue and everything had tumor in it. Now, it's soft as a baby's butt, you know? And you can just see how it's regressed so much. 

I have two squamous cell carcinoma patients that come to mind right away. Both of them had neural involvement. So, one of them, below his ear, he had ptosis, facial drop. Another one, the supraorbital nerve. And that, his whole eye was pretty much swollen shut. So, both of them were on it. The first one, the ear guy, it shrunk down tremendously. Did fantastically well over about 6 months. But he was elderly, and at the end it became really hard for the family to bring him and to do that. So, he ended up wanting to go into hospice care. But, his eye had improved quite a bit, the swelling, the edema. It still had some facial distortion but improved tremendously. 

Second one, I just started recently, has both nerve involvement and it's in the retroorbital area as well. He's on, he's gotten about 2 or 3 doses. His tumor has recurred. So, you can see that it's still back there, but his eye now is open. He can move his eyes. He could do stuff again. So, the main part may not have quite shrunk down yet, but it's not expanding from where the area was. But the other symptoms are doing much, much better. And I assume that he's just going to keep going and doing better. So, those are my cases.