Individualizing First-Line Immunotherapy in Advanced cSCC: How Should Pivotal Trial Data Guide First-Line Treatment Selection?

Solly Chedid: Talking about the treatment landscape for advanced cutaneous squamous cell carcinoma. So systemic immunotherapy options for advanced cutaneous squamous cell carcinoma are not amenable to immediate curative surgery and/or radiation therapy. So, the approval process so far in 2011, ipilimumab was first approved and then Opdivo was approved for melanoma, not squamous cell obviously. And then cemiplimab was FDA approved for cutaneous squamous cell carcinoma that was not amenable to immediate surgery radiation. And then pembrolizumab was first approved for cutaneous squamous cell carcinoma. And then neoadjuvant PD-1 for cutaneous squamous cell carcinoma was first reported by Libtayo or cemiplimab. And then it did subsequently get adjuvant therapy approval. And then just December of last year, Unloxcyt was also approved for locally advanced and metastatic cutaneous squamous cell carcinoma.  

So cemiplimab and pembrolizumab are listed as preferred. Cosibelimab is listed as another recommendation as 2B. I believe that it's because it doesn't have a control arm. So mechanistic rationale for the checkpoint inhibitor subclass is for the anti-PD-1 agents, broad blockade of the PD-1 receptor inhibition interactions with both PD-L1 and PD-L2 ligands. The anti-PD-1 ligand causes selective inhibition of the PD-L1 that leaves the PD-1 and PD-L2 signaling intact. There's also a retained Fc region which can contribute to potential antitumor activity. Hopefully we can talk on that in just a second. How do you guys feel about the actual mechanism of action for both agents?  

Sunandana Chandra: I mean, so all these drugs target the PD-1 axis, which has been proven, I think, without any doubt to be quite efficacious in locally advanced and metastatic cutaneous squamous cell carcinoma. I think the question is as we have more follow up, as the data matures, as we have more safety data with the newer drug of cosibelimab, are there going to be any differences between the three drugs? That's how I think about it.  

Bahar Dasgeb: The way that the tumors are capable of evading the immune system in general are a very interrelated, complicated onion-like layer, layer, layer of processes. PD-1 axis to be one of many. I think with PD-L1 agents, we have moved one step forward on peeling off this onion of being able to not only be more precise of blocking PD-L1 and leaving PD-L2 a little bit untouched, but also as we discussed later, to be able to a little bit get help from not only the innate immunity, but the antibody because the PD-L1 agents, cosibelimab included, do have an intact Fc portion that can get antibody-mediated cytotoxicity. So, this way we're having two or three layers of onion peeled until one day we would be able to have a much more effective and a higher cure rate. So, for that reason, I look at the PD-L1 as one step leaping forward towards going above and beyond, looking at it in a simplified one aspect processes, which is in reality a very, very complicated interaction between the tumor cells and our defense system.  

Solly Chedid: So, for my simplistic brain—so, PD-L1 and PD-L2 both essentially do a double negative. They inhibit the inhibition of the immune system against the cancer, but Unloxcyt also has potentially a theoretical additional benefit of having the Fc portion, which allows for direct binding to the cancer and direct immune activation against the cancer as well. So, we're going to go through two rounds. The first round is a patient with a good performance status and no significant comorbidity. And for this patient, this is a 60-year-old gentleman with an ECOG performance status of zero who's immunocompetent, who presented with a bulky locally advanced cutaneous squamous cell carcinoma of the scalp that was not amenable to curative surgery or radiation therapy. So, Dr. Chandra?  

Sunandana Chandra: Yes. So, let's talk about the anti-PD-1 efficacy data. So, the EMPOWER trial in cutaneous squamous cell carcinoma, the EMPOWER-1, looked at both metastatic and locally advanced cutaneous squamous cell carcinoma patients. It was a little over 160 patients. All of these patients received cemiplimab, 350 milligrams every three weeks. And obviously those who are immunosuppressed, those who had autoimmune disease requiring active immunosuppressives, and those who were solid organ transplant or even heme transplants were not allowed. At Northwestern, we actually participated in this trial. So, they looked at the data in aggregate. They looked at both locally advanced and metastatic, which is a little bit different from what some of the other trials did. But here in aggregate, the objective response rate was almost 50%. I think it's notable for these patients who tend to be frail, who tend to be a little bit more elderly. A complete response rate of about 17%, I think, is quite remarkable. Median progression-free survival was almost two years at 22 months, and median overall survival was not reached. Of the 160 plus patients, about 10% had to discontinue due to treatment-emergent AEs. Next slide please.  

So, in contrast, the KEYNOTE-629 study that looked at pembrolizumab in both recurrent and metastatic cutaneous squamous cell carcinoma; you see here that the median progression-free survival actually has not been reached. Remember it was about 22 months with cemiplimab and then the median overall survival has not been reached. Both of these are in the locally advanced cohort. In the metastatic or recurrent cohort, the median progression-free survival was about 5.7 months, and the median overall survival was about 23, 24 months. Again, both of these are anti-PD-1 antibodies. Now they defined locally advanced a little bit differently, so it's a little bit tricky to compare and to actually do cross-trial comparisons, but I think it gives you a sense of the activity of these drugs.  

Solly Chedid: But if we were to do a cross-trial comparison.  

Sunandana Chandra: Yes. Yes. But if we were to do a cross-trial comparison, I think here you see that with all three drugs, pembro [pembrolizumab], cemi [cemiplimab], both anti-PD-1s as well as cosi [cosibelimab] or cosibelimab, which is an anti-PD-ligand-1, the follow-ups have differed. Obviously, longest follow-up with pembrolizumab followed by cemiplimab, and then cosibelimab is the new kid on the block that we're all trying to learn about now that it's available for our patients with new efficacy and new safety data. Next slide, please.  

Solly Chedid: Dr. Dasgeb.  

Bahar Dasgeb: So, I just want to start to say that although we are here both to take a various side and look at this issue from these two different angles, at the current moment, it is acknowledged that there is no true right or wrong answer. Having said that, we're here just to look at these two from two different points of view. And perhaps the real answer is all of the above, that one day we would have an agent that could foster various mechanisms and apply. But having said that, I would like to start, since this is a debate, the counterargument of this is with two more simpler answer and then a little bit if you allow me to get a little bit deeper because the point of us getting here and deeper is not necessarily what is the state of the affair today, but we hope to do what would be the right path moving forward.  

And if we can get there, then perhaps a little bit deeper view to that would be, and the fact that also my background is more translational basic, so allow me to go to the area where I'm more comfortable than the clinical data, if it's okay. Which is good. We are coming from not only two different aspects, but also two different views to the diseases. So, one is in science and technology; maturity has a weight, but also on a retrospective look. Always when we come up with the first iteration of any problem we tackle, it does not necessarily mean that that was the ultimate and the perfect one. And as time passes by, the time has shown for the industrial age of past 200 years that the next iteration will be better and more effective. So, from that point of view, I will take the maturity data with a grain of salt that had we come together. If we come together five or 10 years from now, this potentially could flip.  

That's one. Going to the efficacy data, the numbers are there, and I allow you just to look at these numbers. So, this has been shown to be an efficacious treatment for the metastatic and locally advanced diseases. In this clinical trial, both patients were included. One may argue that locally advanced to begin with have a better prognosis anyway and they perhaps helped. But then I want to take this clinical and acknowledging that and go a little bit deeper in. We already talked about wonderfully PD-1 inhibition, but would allow me to discuss... Can we go to the next slide? To discuss safety data and get this safety data. So, I'm not going to go through these numbers because these are there and cosibelimab and other PD-L1s have shown to have perhaps better immune-related adverse events, but I want to use this data to bring two points for this healthy patient who doesn't have otherwise comorbidities.  

PD-L1, when it's inhibited, it allows the PD-L2, which is mostly expressed on healthy tissues. And this is how one of the many mechanisms that we develop self-tolerance and that our immune system doesn't go after our own self. So perhaps by allowing the healthy tissue to preserve that evasion from the immune system, maybe this is one of the reasons that the adverse events, the immune adverse events have been shown to be slightly more favorable. And if that would be one out of many reasons for PD-L1, well, if you have a drug that could potentially cause less reasons to delay or halt treatment to address potentially immune adverse events would be a good start.  

Additionally, this is just because this drug is new, and right now, I learned from my colleague from Northwestern that she's trying to add it to our formulary. So, I actually was lucky to be able to put this drug on our formulary very early in early June. So, I do have a relatively large cohort on this medication. I do have a good proportion of naive patient, healthy naive patient, and also patients with comorbidity or failed otherwise other drugs. I just want to take this moment to say on a very small data, very small data, I have seen a slightly faster result on cosibelimab. I don't want to put it here as just because this drug is new. I just wanted to share with everyone as something that I come back and will take this word back when I have more patients.  

Solly Chedid: How do you feel about the fact that there's no grade four, no grade five, and relatively speaking, relatively few grade three side effects? I can't put them up side by side with cemiplimab, but the grade three toxicity appears relatively modest.  

Bahar Dasgeb: That's completely true. And that exactly goes back to the fact that...  

Solly Chedid: Exactly what you just said. 

Bahar Dasgeb: Yeah. Let's say consider efficacy similar. For one second, we put that parameter out of our discussion. Imagine efficacy similar. The fact that you potentially can have less halt in treatment for adverse events. I mean, of course, four and five are very serious ones, and that would be a significant halt. But even sometimes for grade three or grade two, we do have a short term of halt. And I just want to know here to emphasize that when we have the efficacy data and the survival rate out of clinical trial, in that data, we don't include those patients who come out of clinical trial. But in daily life for any adverse events, we do have halts that otherwise. So, in reality, all these times we take off of medicine to address some adverse events is perhaps an impact on an overall survival because it wasn't in a clinical. So, you're absolutely right. That would be a plus, which I would attribute it to many reasons, perhaps PD-L3 included.  

Solly Chedid: Yes, Dr. Chandra?  

Sunandana Chandra: Well, I was going to say, I think it's also notable that the numbers, if you look at the patient numbers, the number of patients evaluable for safety in cosi [cosibelimab] was almost 200 patients. Whereas for pembrolizumab and cemiplimab, it was somewhere over 160 patients that we're comparing. So again, I think there is something to this safety data in terms of potentially our patients tolerating this slightly better.  

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