Individualizing First-Line Immunotherapy in Advanced cSCC: What Tolerability Trade-Offs Exist and How Do They Shape Real-World Use?

Solly Chedid: So, this is changing our patients just a little bit. So, we're looking now at an elderly or frail patient with multiple comorbidities. So, this patient is an 82-year-old gentleman with metastatic cutaneous squamous cell carcinoma. He has an ECOG performance status of 2. Now in both of the clinical trials, actually I think from all three clinical trials with Keytruda, cemiplimab, and Unloxcyt, all those trials specifically excluded patients with a performance status of 2.  

This patient has cardiovascular disease, and also for all three of those products, the patients with an active significant cardiovascular disease, those patients were excluded. So, we're talking about a little bit different patient population than was involved in the studies. But this patient also has respiratory disease.  

And at least in my patient population, who are heavy smokers, they present with new coughs all the time. So, I'm having to pause therapy repeatedly. And if we're pausing, if the patient's not receiving drug, are they really going to get the benefit? I'm not sure. But clearly the toxicity is life-threatening.  

And if you give the patient steroids and they wind up in the hospital, even if you are able to pull them back from having significant immune-mediated pneumonitis, that's still not potentially very deleterious to that patient's overall health trajectory. So, the fact that we have agents like Unloxcyt that prevent that from ever happening is really helpful.  

This patient also has a history of inflammatory arthritis. All of these agents were specifically excluded patients who are on active treatment for inflammatory conditions and required patients be on a dose-equivalent dose of prednisone 10 milligrams or less. And I believe for Unloxcyt, they had to have not received treatment within the preceding two years. So anti-PD-1 toxicity is ... Oh, sorry, Dr. Chandra.  

Sunandana Chandra: No, no. I think you're about to say that it is manageable, and I think that's true for the most part. You did make a point earlier, which I think is important that, in general, I think we in the hem-onc [hematology-oncology] community have gotten better at identifying these patients, hopefully earlier on. I think we can all agree that the earlier we think about perhaps are they having some sort of immune related reaction, the quicker we can act upon it and hopefully prohibit it from progressing to a more severe, more life-threatening immune related adverse event.  

So here, I don't know that the individual groups of patients who are treated with cemiplimab is that important. But I would take your attention to the gray bar, row number two, which talks about serious immune related treatment emergent adverse events. And there you can see that it ranges anywhere from about 5 to about 10%, no matter if they were locally advanced, no matter if they were metastatic, whether they were getting it every three weeks, et cetera, et cetera.  

Again, for this elderly frail patient population, that number is notable, but perhaps certainly not as high as we've seen it, for example, in our anti-CTLA-4 PD-1 treated patients in advanced melanoma. In the keynote data with pembrolizumab, I would urge you to look at row number two. Again, these are the serious grade 3/5 adverse events, and those were about 11.9 or about 12%.  

Individual IRAEs, in my mind, they're about the same... It's all the same profile. I always tell my trainees, and I'm sure you guys think of it very similarly, it's all the same itises, right? It's just a matter of how severe are they? How much are we having to interrupt therapy? How much are we having to introduce high dose steroids or even a second immunosuppressive such as mycophenolate, vedolizumab, infliximab, IVIG, et cetera, et cetera.  

Solly Chedid: Just a little pushback on that in terms of, I realize that hematologic toxicity, but aplastic anemia, aplastic anemia, sorry, pure red blood cell aplasia, ITP, those types of things, even for grade 1, probably pausing therapy. So, the fact that now Unloxcyt doesn't have grade 3, and in their study, they didn't report any of those, which is a good thing.  

And you could say that they're just relatively low in number in general, but not having those toxicities. Normally for grade 1, you could theoretically treat through grade 1 pneumonitis or grade 1 colitis under the caveat of as long as it's not rapidly accelerating, could potentially be grade 2 or 3 tomorrow. So, the fact that we have agents that appear a little safer with an underlying mechanistic rationale to be a little safer is reassuring to me as a clinician.  

Sunandana Chandra: But I think what's tricky is if someone is trending towards an ITP; we may not diagnose that upfront. We just notice a platelet drop. It might be a grade 1, grade 2, but it's not until maybe a little bit later in the course that we're like, "Uh-oh, this keeps dropping. It keeps becoming more severe. Perhaps it's not just a routine 'thrombocytopenia.'" Yeah.  

I think in general, I hope we can all agree that most of these immune related AEs are quite manageable. I do always, again, tell my trainees that the onus is really on us to have all these potential itises or all these potential immune related AEs on our differential, because I feel like if it's not on our differential, they might actually be quite easy to miss. And so, I also take it quite seriously when the ER doctor calls me or when their PCP calls me, et cetera, to also rediscuss all the possibilities that this could be.  

Thankfully, they are more rare, but certainly if they're not on my differential, I won't even think about it. But both with pembrolizumab and with cemiplimab, I think the toxicities are quite manageable. The number of patients that we have to actually discontinue therapy in are relatively, I think, quite low to modest. But I'm extrapolating a little bit here.  

As a melanoma and cutaneous medical oncologist, in the melanoma world, even when we discontinue therapy, sometimes the efficacy of these drugs remains and it can remain for months to years. And so, I don't take the discontinuation by itself as the only red flag to consider, because sometimes even if you discontinue, that anti-tumor immune response remains, and you can still see quite significant and durable benefits.  

Solly Chedid: Dr. Dasgeb?  

Bahar Dasgeb: So, talking about the adverse events, another hat I put on in our center is roughly 30% of my practice is management adverse events for our colleagues because skin is the most common adverse events and I end up managing some others. So, I really want to go back to this importance of the adverse events, because we may have actually something not only to discuss, but also, it may take us all the way back to the tumor itself.  

We already talked about PD-L2, so I wanted to get that out of the way, so I talk about this couple of more interesting things on a basic science front. So, PD-L1, it's not only expressed on the tumor. So, this is where I think one of the potential holy grails of investigating further for newer generation is. PD-L1 is also expressed on tumor associated macrophages in the microenvironment of the tumor.  

It's expressed on the dendritic cells that present antigens to the immune system. And also, it is in some natural killer T-cells. So, if PD-L1 is left, let's say we give PD-1 and PD-L1 is left intact on these cells; it's interesting. It's been shown that they can interact with a PD-1 on its own, cell-to-cell surface interaction.  

And that will, to some degree, inactivate, self-inactivate the immune system. So potentially one of the benefits of PD-L1 is also not only allowing not the eversion from the tumor to immune system, but it would allow us the immune system not to self-shutdown. And perhaps here we have another angle of the innate immunity, natural killer T-cells, dendritic cells, and macrophages to have a better ability to go after the tumor.  

So, this is one of the interesting aspects of the PD-L1. When it comes to these particular patients with pulmonary and cardiac, as I was discussing with you earlier before we started, the PD-L2 is a very significant self-preserving, self-tolerating mechanism, particularly in lung, how allow us, because when we breathe in air, a lot of antigen go in. And our lung, the endothelial inside our lung, but also macrophages, they use that PD-L2 mechanism to allow the lung to have a self-tolerance given that it's an organ when a lot of antigens go in.  

It's expressed there more than other organs in terms of self-tolerance and perhaps pneumonitis and inflammation in a patient with cardiovascular is debatable, but perhaps for pulmonary disease, given the importance of L2 in that organ and inflammatory aspects of that organ and preventing the autoimmune reaction in the organ, it could be something to consider, I would say, even in a naive patient because cosibelimab, there's still apprehension to use it in patients who are otherwise naive to immune system.  

It could be a good option given the importance in that. And from this, I want to go through actually interesting one layer. This would be one of the earlier aspects, much more on the frontline aspects of PD-L1. That PD-L1, not only its action in communicating with outside world cells, immune system, it has a cascade within. And this cascade within in PD-L1 is related to the metabolism of the tumor itself.  

And PD-L1 actually is believed to be implicated to allowing the cell to go on with its glycolysis metabolism. That if you're able to block the PD-L1, we can potentially also shut down the fuel system inside the cancer cells. So I'm not saying necessarily this particular drug, but I'm saying through the PD-L1 itself, we would be able perhaps to unlock so many different aspects from which we can attack the tumor that together and collectively can have a better result.  

Solly Chedid: It's fascinating how cosibelimab potentially with not inhibiting PD-L2 could potentially, that would explain why the data points to a little bit better safety profile. Could you speak to the potential, the Fc, the fact that it also-  

Bahar Dasgeb: Now it gets us to the innate immunity, which is very important; the antibody mediated cytotoxicity. I don't know why they somehow... Sometimes we traditionally, we do something and then it's just we keep going copying, copying. So, when the first PD-L1 was one of the adalimumab, which was earlier one, the Fc portion was intact, so cosibelimab continued, but our PD-1s, one of the differences is our PD-1 drugs, the Fc portion of the antibody is not functional.  

PD-L1 inhibitors, cosibelimab included; the Fc portion of the antibody is fully intact. It interacts with dendritic cells and natural killer cells, and it can unleash not only the natural killer cells to come into the picture, but also the antibody mediated cytotoxicity, another aspect of the immune system that potentially can be unleashed on the tumor.  

Solly Chedid: Cemiplimab is a fully human IgG4 anti-PD-1 inhibitor. So, it would theoretically, because it's fully human, would reduce the risk of infusion reactions. But it doesn't interact, as you stated, with the Fc region. Going back to the safety, so we have 14 minutes left. We need to give about 5 minutes for questions at the end. So can we go back and reiterate each of our points in terms of how... Let's start with the PD-L1 inhibitor, cemiplimab. Would you like to reiterate your perspective?  

Sunandana Chandra: Sure. I think at this time, I don't think that there's any doubt that targeting the PD-1 axis in these patients, whether they're locally advanced or metastatic cutaneous squamous cell carcinoma, is probably our first line go-to therapy. Certainly, people with solid organ transplants, et cetera, et cetera, I'm discounting those complexities.  

I think the next question is we have a number of drugs to think about and choose from, which is a great problem to have. So how do we make that distinction? In general, I think most of our experience with cosibelimab is quite limited. The trial was primarily x-US. And so, at this time we're dependent on trial data and just small numbers of patients that are being treated around the country.  

But I think efficacy-wise; they're probably quite similar. If you look at the... There's some differences between the phase 2 data with pembro and cemiplimab, et cetera. But in general, efficacy-wise, I think with cemiplimab, pembrolizumab, cosibelimab is quite similar, whether locally advanced or metastatic.  

I think the distinction, again, in my mind is really safety. Again, these are frail patients; they're elderly, they have logistics to think about because they often may not be able to drive, et cetera, et cetera. So, it's a very different patient population from many of the other cancers that we may treat. So, what can I do to keep them safe? What can I do to keep them on therapy, seeing a similar response rate, yet try to prevent some sort of immune related AE that would either require high dose steroids, which are not good for these individuals for various reasons that we all know, or that would require drug interruption.  

Of course, we've talked about that drug interruption and discontinuation doesn't always lead to negative outcomes, but it's something that we would try to avoid because we want our patients to benefit from these drugs. So, I think for me, that's a long-winded answer of what I think about when a patient like this walks through the door.  

Solly Chedid: So, you made an excellent argument for Unloxcyt. For cemiplimab, just as a pro towards it, the duration of follow-up has been substantially longer compared to Unloxcyt. From our Unloxcyt or PD-1 inhibitor, what are your thoughts in terms of why everyone should be Unloxcyt?  

Bahar Dasgeb: So, you perfectly befriended the PD-L1, so I'm just not going to repeat because it was such a beautiful collection of the adverse events aspects that you were discussing. So basically, everything you said and the fact that also considering that in this particular patient who had cardiovascular disease, not on a healthy heart, but an ischemic heart and a heart under stress, also there's been shown that PD-L2 is expressed to help with the decreasing the inflammation post-ischemia, which applies to this patient.  

Safety is very important. So even if at some point proven efficacy, the same, although some of the earlier comparison with cemiplimab might show a slight advantage for this and all of the other aspects is that if anything, I think that could be potentially, both adalimumab and cosibelimab, a leap forward to look at the immune system a little bit deeper to start layering this onion skins layer by layer.  

We started with PD-1, PD-L1, and I hope very soon we all get together to talk about the other inhibitors from all completely different categories.

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