In Rural and Community Practice, Tolerability and Access Shape Immunotherapy Choice in Advanced Cutaneous Squamous Cell Carcinoma

Advanced cutaneous squamous cell carcinoma (cSCC) often affects older patients with other health conditions. In one real-world cohort of patients aged 70 and older, the median age was 81.8 years and a third had an Eastern Cooperative Oncology Group performance status of 2 or higher.¹ Three checkpoint inhibitors are now approved by the US Food and Drug Administration for the indication: pembrolizumab, cemiplimab, and cosibelimab.²   

For community oncologists, geography adds another layer. David Portnoy, MD, a medical oncologist at the West Cancer Center and Research Institute in Memphis, Tennessee, described his practice in a recent Oncology Learning Network commentary: “…this is a pretty rural part of the country…a lot of our patients may not have the best access to local specialty care. 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.”  

Each approved agent has its own evidence base, drawn from separate, noncomparative trials. Pembrolizumab produced objective response rates of 34%-50%, with grade 3-5 treatment-related adverse events in roughly 6%-12% of patients.^3,4 Cemiplimab showed response rates of 47%-50%, with grade 3 or higher treatment-emergent adverse events in roughly 25%-46%.^5,6 Cosibelimab showed response rates of 47%-55%; in long-term follow-up, grade 3 immune-related adverse events occurred in 2.6%-3.6% of patients, and none were grade 4 or 5.^7,8 Adverse-event definitions differ across these trials.  

Real-world results can run lower. A Dana-Farber cohort of 61 patients with advanced CSCC reported a best overall response of 31.5%, versus 48% in published trials.⁹  

Dr Portnoy described a recent patient who was 82 years old with heart disease and cirrhosis. His large ear-region tumor was growing into cartilage; dermatology judged it too large to resect without removing much of the ear, and radiation oncology worried about hearing loss and inadequate treatment of a thick lesion. Because of the patient's comorbidities, Dr Portnoy recommended cosibelimab, concerned that high-dose steroids for an immune-related adverse event would be hard for him to tolerate. He framed treatment selection this way: “Which one will the patient most likely be able to stay on and tolerate?” That is one clinician's judgment in one patient, and Dr Portnoy himself notes that the three agents have never been compared head-to-head.  

Managing toxicity outside academic centers has its own challenges. In a rural Maine community setting, 25% of 465 patients treated with programmed cell death 1/programmed cell death ligand 1 inhibitors across tumor types developed new immune-related adverse events, 7.3% were hospitalized, and 15% permanently discontinued treatment.¹⁰  

For now, the choice rests on performance status, comorbidities, and the ability to tolerate both treatment and an adverse event, alongside practical factors such as travel and local expertise. As Dr Portnoy explains, “The ability to tailor therapy to the individual patient's comorbidities and performance status is becoming our most important clinical skill.” 

1. McLean LS, Lim AM, Bressel M, Thai AA, Rischin D. Real-world experience of immune-checkpoint inhibitors in older patients with advanced cutaneous squamous cell carcinoma. Drugs Aging. 2024;41(3):271-281. doi:10.1007/s40266-024-01095-z  
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. 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.  
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-2023-0076378.  
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. Hanna GJ, Ruiz ES, LeBoeuf NR, et al. Real-world outcomes treating patients with advanced cutaneous squamous cell carcinoma with immune checkpoint inhibitors (CPI). Br J Cancer. 2020;123(10):1535-1542. doi:10.1038/s41416-020-01044-8  
10. Bhatlapenumarthi V, Patwari A, Harb AJ. Immune-related adverse events and immune checkpoint inhibitor tolerance on rechallenge in patients with irAEs: a single-center experience. J Cancer Res Clin Oncol. 2021;147(9):2789-2800. doi:10.1007/s00432-021-03610-w