Comorbidities Take Center Stage in Selecting Immunotherapy for Advanced Cutaneous Squamous Cell Carcinoma

Three immune checkpoint inhibitors are now approved by the US Food and Drug Administration for advanced cutaneous squamous cell carcinoma (cSCC): pembrolizumab, cemiplimab, and cosibelimab. With no head-to-head trial comparing them, clinicians say the choice increasingly comes down to the patient in front of them, not the drug label.¹ 

Autoimmune and inflammatory disease is one factor moving to the front of that conversation. Patients with conditions such as psoriasis, psoriatic arthritis, or inflammatory bowel disease have historically been excluded from immune checkpoint inhibitor trials. A 2024 systematic review and meta-analysis of more than 23,000 such patients across cancer types found a pooled flare rate of 36% and new immune-related adverse events in 23% after checkpoint inhibition, though most were low-grade, and tumor response rates did not differ from those of patients without autoimmune disease.² That evidence gap leaves clinicians relying heavily on individual case experience. 

Bahar Dasgeb, MD, a dermato-oncologist who treats complex and advanced cutaneous carcinomas, described that experience in a recent Oncology Learning Network commentary, recalling two treatment-naive patients with locally advanced cSCC: “One of them had psoriatic arthritis, on anti-psoriasis medication, on an immune modulator. And the other one had colitis, inflammatory bowel disease, also on an immunomodulator…I put both of them on cosibelimab. And during the course of treatment, which is still ongoing, the psoriatic arthritis and inflammatory bowel disease have not gotten worse.” 

Each of the three approved agents has its own efficacy and safety data from separate, noncomparative trials. The registration trial for pembrolizumab reported objective response rates of 34%-50%, with grade 3-5 treatment-related adverse events in roughly 6%-12% of patients.^3,4 Cemiplimab has shown objective response rates of 47%-50% in long-term follow-up, with grade 3 or higher treatment-emergent adverse events in roughly 25%-46% of patients.^5,6 Pivotal and long-term studies of cosibelimab 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.^7,8 None of the three agents has been formally studied in patients with preexisting autoimmune disease. 

Dr Dasgeb also pointed to a structural difference in her commentary: cosibelimab retains a fully functional fragment crystallizable (Fc) region, which she says allows it to engage natural killer cells and complement in addition to blocking programmed death-ligand 1 (PD-L1). This is a dual mechanism that the Fc-modified programmed death-1 (PD-1) inhibitors pembrolizumab and cemiplimab do not share.⁹ Whether that translates into a meaningfully different clinical profile, in comorbid or older patients or otherwise, has not been established prospectively. 

Age shows a similar pattern. A US-led, multicenter, international cohort study of 928 patients aged 80 and older found immune-related adverse events in 41.3% (grade 3-4 in 12.2%), similar across age subgroups, though discontinuation for toxicity was more than twice as common in patients 90 and older; the authors described checkpoint inhibitors as “generally well tolerated” in this population.¹⁰ A 2026 multidisciplinary expert consensus panel focused on cosibelimab concluded that its reported safety profile may make it a reasonable consideration for older adults or patients with significant comorbidities.¹¹ For now, the emerging approach is not a single preferred agent for these populations but individualized selection weighed against the specific, and still limited, 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. Lopez-Olivo MA, Kachira JJ, Abdel-Wahab N, et al. A systematic review and meta-analysis of observational studies and uncontrolled trials reporting on the use of checkpoint blockers in patients with cancer and pre-existing autoimmune disease. Eur J Cancer. 2024;207:114148. doi:10.1016/j.ejca.2024.114148 
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. 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 
8. 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. 2026;94(1):48-56. doi:10.1016/j.jaad.2025.09.009 
9. 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 
10. Nebhan CA, Cortellini A, Ma W, et al. Clinical outcomes and toxic effects of single-agent immune checkpoint inhibitors among patients aged 80 years or older with cancer: a multicenter international cohort study. JAMA Oncol. 2021;7(12):1856-1861. doi:10.1001/jamaoncol.2021.4960 
11. 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