Choosing Between PD-1 and PD-L1 Inhibition in Advanced Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, and while most cases are cured with surgery or radiation, a meaningful subset become locally advanced or metastatic and are no longer candidates for either.¹ Immune checkpoint inhibition has transformed the treatment landscape across cutaneous malignancies broadly,² and three checkpoint inhibitors are now approved by the Food and Drug Administration specifically for advanced cSCC: pembrolizumab, cemiplimab, and cosibelimab.

Each has its own evidence base. The approval for pembrolizumab rested on the KEYNOTE-629 trial, where objective response rates ranged from about 34% in recurrent/metastatic disease to 50% in locally advanced disease, with grade 3-5 treatment-related adverse events in roughly 6%-12% of patients.^3,4 Cemiplimab, the first checkpoint inhibitor approved in this setting, has shown objective response rates of about 47%-50% in long-term follow-up, with grade 3 or higher treatment-emergent adverse events in roughly 25%-46% of patients.^5,6 Cosibelimab, a programmed death-ligand 1 (PD-L1) inhibitor and the most recently approved of the three, was the first anti-PD-L1 therapy approved for this indication.⁷ Its pivotal and long-term studies reported objective response rates of 47%-55%, with grade 3 treatment-related adverse events in a small proportion of patients and no grade 4 or 5 immune-related events reported to date.^8,9

Mechanistically, programmed death-1 (PD-1) inhibitors such as pembrolizumab and cemiplimab block both the PD-1/PD-L1 and PD-1/PD-L2 interactions, while the PD-L1-directed cosibelimab leaves the PD-1/PD-L2 axis intact.¹⁰ None of the three agents have been studied head-to-head, so the efficacy and safety results should not be read as direct comparisons.

With three approved options and no comparative trial data, clinicians say the decision increasingly rests on individual patient factors. Omid Hamid, MD, Director of the Cutaneous Malignancies Program at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, described this kind of individualized approach in a recent Oncology Learning Network commentary: “When I look at these patients who are older and may have multiple comorbidities…the idea that, with cosibelimab, some of the visceral organ preservation from immune-related toxicities are available—that makes this therapy one that I may lend myself towards more than the PD-1 inhibitors. And this is based on individual patients. There is no one-size-fits-all.”

Pembrolizumab and cemiplimab remain well-established options in their own right, and no current guidance recommends one of the three agents over the others across the full cSCC population. As additional real-world data and clinical trials mature for all three therapies, the emerging model is not a single preferred agent, but an individualized match between a patient's age, performance status, and comorbidity burden and the specific evidence available for each approved therapy.

1. Burshtein J, Schlesinger T. Cosibelimab: a novel therapeutic for advanced cutaneous squamous cell carcinoma. J Clin Aesthet Dermatol. 2025;18(11):21-23.
2. Petty AJ, Emge DA, Cardones AR. Advances in targeted and immunotherapy for high-risk cutaneous malignancies. Oncol Res. 2026;34(3):2. doi:10.32604/or.2025.073383
3. 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
4. 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
5. 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
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 of groups 1, 2, and 3, and primary analysis of fixed-dose treatment group 6. J Am Acad Dermatol. 2025;92(1):68-77. doi:10.1016/j.jaad.2024.06.108
7. Lee A. Cosibelimab: first approval. Drugs. 2025;85(5):695-698. doi:10.1007/s40265-025-02164-2
8. 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):e007637. doi:10.1136/jitc-2023-007637
9. 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
10. Idris OA, Westgate D, Saadaie Jahromi B, Shebrain A, Zhang T, Ashour HM. PD-L1 inhibitor cosibelimab for cutaneous squamous cell carcinoma: comprehensive evaluation of efficacy, mechanism, and clinical trial insights. Biomedicines. 2025;13(4):889. doi:10.3390/biomedicines13040889