Patients With cSCC Generally Tolerate Immunotherapies but Should Know About Common Adverse Events: Todd Schlesinger, MD

In part 2 of an interview with The American Journal of Managed Care^® (AJMC^®), Todd Schlesinger, MD, continues his discussion on topics from his 2026 Winter Clinical Miami presentation by examining the role of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors in treating cutaneous squamous cell carcinoma (cSCC).

Specifically, he highlighted differences in mechanisms of action among the 3 approved immunotherapies for cSCC: cemiplimab (Libtayo; Regeneron), pembrolizumab (Keytruda; Merck), and cosibelimab (Unloxcyt; Checkpoint Therapeutics, Inc.). To conclude, Schlesinger discussed how clinicians can choose between these treatments while considering the potential adverse events associated with each.

Read part 1 of the interview here.

This transcript has been lightly edited for clarity.

AJMC: Could you elaborate on the differences in the mechanisms of action among the 3 approved treatments for cSCC?

Where the drug binds, the antibody binds. In cosibelimab, it binds to the PD-L1 ligand on the surface of the cell, which is on the tumor cells. Cemiplimab and pembrolizumab both bind the PD-1 receptor on the surface of the T cell.

There's a theory going around that if you block the PD-L1 ligand, you're leaving PD-L2 [programmed death ligand-2] alone and available to be bound. That way, if you block PD-1, that will block the action at PD-1 and PD-L2. If you block just PD-L1, you leave PD-L2 open and available, which may theoretically alter the side effect profile.

You also have a theoretical additional bispecific action of cosibelimab, where the Fc [Fragment crystallizable] receptor is thought to interact with the natural killer cells to induce antibody-dependent cellular cytotoxicity, which is more of a natural way of killing tumor cells with natural killer cells, which are the body’s immune surveillance cells that float in the blood and help to kill off tumor cells before they actually get going. That is all theoretical and may impact the adverse event profile mechanistically, but we just don't know yet.

A lot of this is just based on theoretical data that comes over from Checkpoint Therapeutics, which is the company that introduced cosibelimab into the world. It has now been wholly purchased by Sun Pharmaceuticals, so we'll learn more as time goes on and hopefully study the mechanism of action in more detail so that we can understand how these drugs are interacting with our patients and better utilize them in the future.

AJMC: How do you choose among the approved options on a case-by-case basis?

As far as the choice goes, cosibelimab is just arriving on the market now. There have just been a few patients who have been infused with that medication post-marketing use in the US in the last few months or so, so we'll see how things go.

Cemiplimab has been around since 2018, when it was originally approved for squamous cell and then basal cell carcinoma, both locally advanced and metastatic.

For squamous cell carcinoma, we have the 3 choices. Pembrolizumab really hasn't been used as much lately. The data numbers are probably a little lower for that one as far as the outcomes go.

Cemiplimab and cosibelimab are relatively similar. Cosibelimab looks like it may have a slight advantage in outcomes as far as efficacy goes and maybe a safety advantage, because it has no grade 4 or 5 adverse events and a smaller number of grade 3 adverse events. Although, it does have a higher rate of infusion reactions than cemiplimab on the label.

Cemiplimab, however, has been around for a long time. We have lots of experience with it. It's probably almost 8 years of ongoing data. For cemiplimab, we certainly have long-term data and very comparable outcomes. We know the safety profile well, so that's also an excellent choice.

I think it comes down to the patient's comorbidities, because cosibelimab has a slight difference when it comes to the grade 4 and 5, or most severe, adverse events. It may be a choice we think of in patients who have had comorbidities, possibly organ transplants, viral infections, HIV, hepatitis, HPV, or other things that we would think of as comorbidities that would maybe slow us down from thinking of immunotherapy; we don't want to make those things worse.

The early data we have shows that you can actually use these drugs in those populations when they're carefully managed and selected. In reality, it's going to come down to a very individual patient decision and a multidisciplinary team decision, in many cases. These patients typically are seeing multiple doctors for their specialty and for their condition, which is actually the most appropriate way to manage them.

So, individual decision, but I think we'll see that cemiplimab is still a very solid performer and does very well. Hopefully, we'll see improving results from all these drugs over time as we treat more patients and learn how to use them more effectively.

AJMC: Regarding the safety profile, what adverse events do patients typically experience, and how are these managed?

The safety profiles are comparable. Of course, we only have about 2 years of data with cosibelimab vs 8 or more years of data with cemiplimab and ongoing data with pembrolizumab as well. If you look at the labels, you'll see that cosibelimab does not have grade 4 or 5 adverse events listed. It has a low rate of grade 3 adverse events.

The most common adverse events that you see with all these drugs are going to be pneumonitis, usually a dermatological immune-related, immune-mediated reaction, which usually presents as a rash. You will also see fatigue, usually GI [gastrointestinal] symptoms, as well. Things like that commonly happen with these medications. Thyroid, as well: either hypothyroidism or hyperthyroidism. You can also get some central pituitary gland dysfunction, called hypophysitis. You can also get some blood abnormalities; lipocyte depletion and things like that can happen, as well.

Fortunately, most of those are well tolerated. The most common way to manage those more common side effects is going to be with oral steroids, given that you have also made sure that the patient’s cancer isn't recurrent or the symptoms aren't coming from recurrent cancer or disease progression of the actual underlying carcinoma.

Typically, steroids are used, usually mid- to high-dose oral steroids like prednisone, and, of course, discontinuation of the medication, or holding the medication, for grade 3 adverse events until they're managed. For grade 4 adverse events, you would typically not restart the medication. For certain indications, you may decide not to restart. For example, pneumonitis can recur quite easily, so some physicians aren't comfortable restarting immunotherapy in a patient who’s had pneumonitis, which can present as a cough or shortness of breath.

There's also a host of rarer adverse events that can happen, and these can affect any system in the body. They can actually occur after the medications have been stopped and possibly months after they've been discontinued. More rare adverse events affect the heart, nervous system, eyes, and things like that.

Their safety profile, you have to think about, is affecting everywhere the immune system touches, which is anywhere in the body. So, it can affect any system. However, most patients tolerate the medications well with careful monitoring, which includes lab monitoring before each infusion. Patients should generally do well, but clinicians should just be aware of the adverse event profile.

Reference

Schlesinger T, Miller DM. Checkpoint choices in cutaneous squamous cell carcinoma (cSCC): case-based exploration of the role of PD-1 and new PD-L1 inhibitors. Presented at: 2026 Winter Clinical Miami; February 27-March 1, 2026; Miami, Florida.