Immune Checkpoint Inhibition in Advanced cSCC: Perspectives From Clinical Practice

My name is David Portnoy. I'm a medical oncologist at the West Cancer Center and Research Institute in Memphis, Tennessee, and my practice focuses on the treatment of patients with cutaneous malignancies. Welcome to this KOL commentary series hosted on the Oncology Learning Network. Today, we are discussing the evolving treatment landscape for advanced cutaneous squamous cell carcinoma, specifically how we navigate the choice between PD-1 and PD-L1 inhibition to personalized care for our patients. To start, let me tell you a little bit about my practice and the kinds of patients we see. So, as I mentioned before, we are based out of Memphis, Tennessee, and we cover a pretty wide area. We see patients obviously from Western Tennessee, but we also see patients from Northern Mississippi, Eastern Arkansas, Southern Missouri, and sometimes even from Northwestern Alabama. And this is a pretty rural part of the country, so we see a lot of people who have spent a lot of time outdoors. And a lot of our patients may not have the best access to local specialty care. And as a result, we tend to see a disproportionate number of patients with neglected and locally advanced or metastatic cutaneous squamous cell carcinomas along with other skin cancers.

In addition, our patients went on treatment when they have adverse reactions because of the nature of being in a community practice in this area, they may not have access to specialists to help treat their adverse effects who have a lot of experience with checkpoint inhibitors. Because many of our patients live in rural settings, access to specialties such as dermatology can be limited, and this often leads to patients presenting with larger and more advanced skin cancers.

The treatment landscape for metastatic and locally advanced cutaneous squamous cell carcinoma has drastically changed in the last few years after having many years of really no good options. So now we are lucky enough to have three approved options for our patients. We have cosibelimab, cemiplimab, and pembrolizumab, and all of them can be useful, and I think there are certain advantages to each one. I think the main advantage of pembrolizumab is that it can be given once every six weeks.

So, for patients who have difficulty coming to the office, that can be a more convenient choice. Cemiplimab is another PD-1 inhibitor that is approved for the treatment of patients with metastatic cutaneous squamous cell carcinoma. One of the advantages of cemiplimab was that there is data showing its efficacy in the neoadjuvant and adjuvant setting. In contrast, a clinical trial of pembrolizumab in the adjuvant setting, the KEYNOTE-630 trial was negative. Cosibelimab is the newest checkpoint inhibitor for the treatment of metastatic cutaneous squamous cell carcinoma. Unlike the other two drugs, this is a PD-L1 antibody. It also has a functional FC domain that appears to mediate antibody-dependent cytotoxicity and complement dependent cytotoxicity. So, it seems to have multiple mechanisms of action. Most notably, it has a much different side effect profile from the PD-1 inhibitors. So, in patients where you're really concerned about their ability to tolerate the immune-related toxicities of checkpoint inhibitors, cosibelimab is a really attractive choice.

When trying to determine which of these checkpoint inhibitors would be the right one for a patient with locally advanced or metastatic cutaneous squamous cell carcinoma, there are a few things we need to take into consideration, but most notably, we need to look at the patient's performance status, comorbidities, and ability to tolerate treatment, and also the ability to tolerate an adverse event should it happen. So, the average patient with metastatic cutaneous squamous cell carcinoma tends to be older. In population-based studies of patients with locally advanced or metastatic cutaneous squamous cell carcinoma, the median age is usually in the late 70s or early 80s, and these patients tend to have multiple comorbidities. Studies looking at older patients receiving checkpoint inhibitors have traditionally shown that the incidence of adverse events is no different in older patients than it is in younger patients. However, I do become concerned that their ability to tolerate the adverse events is going to be worse than in a younger patient who may have fewer comorbidities. So, the likely to develop an adverse event may not be different in older population. The ability to tolerate one would be different.

Because cosibelimab has a different mechanism of action as a PD-L1 inhibitor and also may mediate its effects through antibody-dependent cytotoxicity and complement-dependent cytotoxicity, we see a lower rate of immune-related adverse events. Cosibelimab similarly showed very low rates of immune-related adverse events in the pivotal trial. Even with extended follow-up, fewer than 4% of patients had grade three immune-related adverse events, and there were no grade four or grade five immune-related adverse events in these patients.

So let me give you an example of a patient I recently saw who I felt that cosibelimab was the best option. He was a patient who was 82 years old, has some heart disease, also happens to have cirrhosis, and he comes in with a large squamous cell carcinoma in the right preauricular region, but growing into the cartilage of the ear. He'd been referred to us by dermatology, felt that the lesion was really too large to resect, and really to resect this lesion with negative margins would've required taking a large portion of the ear. It really looked like it was unresectable. Radiation oncology was concerned that with radiation therapy, there could be some hearing loss, and also the lesion was quite thick and they just were concerned that radiation would not adequately treat this lesion. So, this was really a patient who, even though he didn't have metastatic disease, was really a good candidate for systemic therapy.

So, we were talking about the different checkpoint inhibitors, and I recommended cosibelimab just because of his comorbidities, just concerned that his ability to tolerate an immune-related adverse event would not go well, and it'd be very hard to have to put a patient like this on high dose steroids for an extended period of time and cope with this, and I think it would make it very difficult to treat him long-term. These checkpoint inhibitors have never been compared head-to-head, but they all have similar overall response rates in their individual studies. So, the decision really comes down to which one will the patient most likely be able to stay on and tolerate. And in a situation like this, I think cosibelimab provides the best opportunity for this patient.

When deciding which checkpoint inhibitor to use and leaning towards cosibelimab, a lot of it has to do with its mechanism of action. Cemiplimab and pembrolizumab are PD-1 inhibitors. Cosibelimab is a PD-L1 inhibitor. In addition, cosibelimab appears to have other mechanisms of action. It has a functional FC domain that appears to induce antibody dependent cytotoxicity and complement dependent cytotoxicity. So, it allows us to attack the squamous cell carcinoma from multiple angles.

Now that we have three checkpoint inhibitors to use, the question becomes, well, how do we employ them and what's going to be the role of cosibelimab in this setting? Pembrolizumab has been around for years. We're all very comfortable with it. Cemiplimab is newer than pembrolizumab but has been around for several years. We've been using it. We've seen that it has efficacy in the adjuvant and neoadjuvant setting. But cosibelimab, it's the newest one. We are still trying to really get used to using it as a community, but I think with time we're going to see it become more and more widely used. In the community setting, I think there's a real advantage to this, which is that when patients have adverse events from any treatment and we need to enroll specialty care, there often needs to be a lot of education of the specialists that we're referring our patients to because they're not used to dealing with patients who are on checkpoint inhibitors. Because cosibelimab has such a lower rate of inducing immune-related adverse events, it becomes a lot easier to administer for our patients. It's clear that as our toolkit grows, the ability to tailor therapy to the individual patient's comorbidities and performance status is becoming our most important clinical skill. Please visit Oncology Learning Network for more education about the CSCC treatment landscape. Thank you for watching.

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