Immune Checkpoint Inhibition in Advanced cSCC: Perspectives From Clinical Practice

In this expert commentary, Omid Hamid, MD, examines the evolving treatment landscape for advanced cutaneous squamous cell carcinoma, including considerations for selecting among PD-1 and PD-L1 inhibitors. He discusses how disease setting, comorbidities, performance status, and the potential for immune-related toxicities can inform individualized treatment decisions, illustrated by a clinical case involving an older patient with locally advanced disease.

Hello, I'm Dr Omid Hamid, co-director of the Cutaneous Malignancies Program at The Angeles Clinic & Research Institute, a Cedars-Sinai affiliate in Los Angeles, California. Welcome to this KOL commentary series hosted on the Oncology Learning Network. Today, we're 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 personalize care for our patients. My practice is an academic and community hybrid practice. That is, we do an extensive amount of clinical trials and multidisciplinary care of cutaneous malignancies, including cutaneous squamous cell carcinoma. I see a significant amount of advanced cutaneous squamous cell carcinoma. As you know, squamous cell carcinoma of the skin is a very high incident tumor, but the majority are manageable with surgery or radiation.

Once those cases become either recurrent or they become locally advanced, that means in an area they've grown where they're not amenable to surgery or radiation, or they become metastatic, those are the patients that come to me for options. As we have developed more immunotherapies for cutaneous squamous cell carcinoma, at times I may not see those patients with locally advanced or metastatic disease at the initial input for therapy, but will see them once they have a need for a novel therapy and they have failed a treatment with a standard therapy. So, the transition point at which patients become candidates for systemic therapy, for me, is that point where they are multiply recurrent, having failed radiation or surgery, unable to be taken care of by radiation or surgery, despite the fact that they're just focal, that is in areas where they can cause deformity or morbidity, locally advanced where they cannot be treated with just one surgical procedure alone, or metastatic, which is that they've left the local area and gone elsewhere in the body.

Choosing the right therapy for these patients who are locally advanced, metastatic, or multiply recurrent with cutaneous squamous cell carcinoma is hard. The benefit is that we're at a time where we have three approved options, including cosibelimab, cemiplimab, and pembrolizumab. These three immune checkpoint inhibitors are similar in many ways and different in others. Choosing therapy could be as simple as evaluating what therapy is available, that is, for example, on a clinical protocol or for an indication, and it can be as complicated as having to review the incidence of toxicities and make decisions based on a full history. Let me give you an example. We're currently at a time where there is an approved option for adjuvant therapy for cutaneous squamous cell carcinoma to prevent recurrence and to help with morbidity, and that is only cemiplimab.

In other settings, like locally advanced or metastatic, all three drugs are approved, and at times, the indication to use one may be higher than the other. Personalizing therapy in this fashion is difficult, as these drugs have not been reviewed head-to-head, but some of the data behind PD-L1 targeting and not PD-1 targeting lends us to consider possibly the use of cosibelimab in those patients who may have an increased risk or toxicity. And then this is... Based on individual patients, there is no one-size-fits-all. There is no similar to this similar to that, and that's another reason why I like my practice. We are a multifaceted practice with surgical oncologists, radiation oncologists, palliative care, and social work, and medical oncology and radiation oncology also come in to discuss the pros and cons of therapy. So, a complicated decision tree, but one that we are grateful to have multiple options for.

At this point, all three of these drugs are approved for this one indication of advanced, multiply recurrent, metastatic, not amenable to surgery or radiation patients, that it's important to look at each one of them one by one. So, what are the specific characteristics I think of? I think of age, performance status, and other comorbidities. Obviously, no head-to-head trials makes it difficult to say one is over the other, but if you go back to the early times when we were doing phase 1 trials with PD-1 inhibitors and PD-L1 inhibitors, there's always been this idea that they have a decreased incidence of toxicity, and that is due to their interactions where PD-L1 blockade blocks PD-1, PD-L1, but allows the PD-1, PD-L2 interaction to continue. Now, this is a lot of molecular discussion, but we believe that in the setting of stress or inflammation, PD-L2 is overexpressed on normal tissues as a protective mechanism, and it allows that interaction with the T-cell to become immunosuppressive.

Therefore, you don't see as many immune-related toxicities. Now, what's striking to me in the data from cosibelimab is the fact that their grade 3 toxicities were very minimal and very manageable. And for me, that's an important point to make, that the immune-related adverse events seen were dermatological. There were no grade 4 and no grade 5 toxicities. When you review the data in cutaneous squamous cell carcinoma, what struck me most was low toxicity followed by an efficacy that is similar to PD-1 inhibitors, and that's something that's novel and new that we really hadn't seen before. I look forward to updated data that'll be presented at future meetings, including the European Society of Medical Oncology and other immunotherapeutic meetings, to see how this data matures over time.

A very, very germane recent clinical example that I was brought to was a patient of mine who showed up. He's 84 years old. He's got some cardiac issues from longstanding heart disease. There was a question of whether he had polymyalgia, which his rheumatologist said he didn't have. He had some symptomatology, and this gentleman had a squamous cell carcinoma that had recurred and moved to the parotid area, and was causing a lot of pain, some functional issues, and was really growing in a rapid fashion, and it was locally advanced. Now, the patient was on blood thinners, and this tumor was located in a very, very intricate area, so surgery was out of the question. And we discussed radiation as a first line, the risk of fibrosis and ineffectivity, and the inability to then go back in surgically, if there was a good response, made us steer towards an immune checkpoint inhibitor.

Given my experience and the data with toxicities, this is where I really thought it was best to utilize a PD-L1 inhibitor like cosibelimab. And we talked to the patient, his spouse, in a very comprehensive fashion about why I thought that this would be better for him and how we would manage toxicities if it showed up. They agreed, and we moved on to utilizing this drug. The PD-1 PD-L1 interaction has been a longstanding interest for immunologists and immunotherapists. We understand that the interaction between both of them, the PD-L1 on the tumor, the PD-1 on T-cells, is important for immune inactivation, and antibody therapies that target either can cause a resolution of the immunosuppression. It's important to understand that the PD-L1 mechanism has been looked at for an extended period of time, even from the beginnings of PD-1 antibody development. And this safety is important as the PD-1/PD-L2 interaction remains. For me, this is important as I think about the clinical choices made for patients.

With cosibelimab, one could think that, "Well, there might be decreased efficacy," but as we have looked into this, we found that there are multiple other ways that this drug works towards stimulating the immune system and eradicating the tumor. One is through antibody-dependent cellular cytotoxicity. The other is through stimulation of another subset of immune cells and K cells. And then the third is the traditional way that checkpoint inhibitors work. Safety is an important rationale for the selection of therapy in fragile and comorbid populations, and that's extremely important for me.

As the oncology community gains more familiarity with cosibelimab, I see its role evolving in many different ways. Number one, I think it is a valid option to consider for patients who you want to avoid significant immune toxicity. Number two, I think we'll begin to understand how to target PD-L1, and what the benefits of this drug are with off-target and K cell and ADCC. And number three, here we have another player, another pharmaceutical partner who is willing to look at novel combinations and support the growth of this drug in cutaneous squamous cell carcinoma through clinical trials. As we come to the end of our time together, I really want to say that these breakthroughs have been made through clinical trials, and always, my first thought is for clinical trials and a way to increase efficacy, decrease toxicity, and get us to where we want to be for our patients.

That's greater survival and decreased morbidity. To me, 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. I look forward to future data in relation to these immune checkpoint inhibitors and cutaneous squamous cell carcinoma. Please visit Oncology Learning Network for more education about the CSCC treatment landscape. Thank you for watching.

1. Bartley B, Rosenberg A, DeBusk L, et al. Efficacy and safety of cosibelimab for advanced cutaneous squamous cell carcinoma: an expert consensus panel. J Drugs Dermatol. 2026;25(5):413-420. doi:10.36849/JDD.9954. 
2. Burshtein J, Schlesinger T. Cosibelimab: a novel therapeutic for advanced cutaneous squamous cell carcinoma. J Clin Aesthet Dermatol. 2025;18(11):21-23. 
3. Clingan P, Ladwa R, Brungs D, et al. Efficacy and safety of cosibelimab, an anti-PD-L1 antibody, in metastatic cutaneous squamous cell carcinoma. J Immunother Cancer. 2023;11(10). doi:10.1136/jitc-2023-007637.
4. Grob JJ, Gonzalez R, Basset-Seguin N, et al. Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629). J Clin Oncol. 2020;38(25):2916-2925. doi:10.1200/JCO.19.03054. 
5. Hughes BGM, Muñoz-Couselo E, Mortier L, et al. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial. Ann Oncol. 2021;32(10):1276-1285. doi:10.1016/j.annonc.2021.07.008. 
6. Hughes BGM, Guminski A, Bowyer S, et al. A phase 2 open-label study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1): final long-term analysis. J Am Acad Dermatol. 2024;92(1):68-77. doi:10.1016/j.jaad.2024.06.108. 
7. Idris OA, Westgate D, Saadaie Jahromi B, et al. PD-L1 inhibitor cosibelimab for cutaneous squamous cell carcinoma: comprehensive evaluation of efficacy, mechanism, and clinical trial insights. Biomedicines. 2025;13(4). doi:10.3390/biomedicines13040889.
8. Lee A. Cosibelimab: first approval. Drugs. 2025;85(5):695-698. doi:10.1007/s40265-025-02164-2.
9. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341-351. doi:10.1056/NEJMoa1805131. 
10. Ruiz ES, Muñoz-Couselo E, Montaudié H, et al. Efficacy and safety of cosibelimab in advanced cutaneous squamous cell carcinoma: results from a pivotal open-label study with a median follow-up of ≥2 years. J Am Acad Dermatol. 2025;94(1):48-56. doi:10.1016/j.jaad.2025.09.009.