Real-world overall survival after PD-1 failure in advanced cutaneous squamous cell carcinoma.

e21570 Background: Anti–PD-1 therapy Cemiplimab is standard first-line systemic treatment for advanced cutaneous squamous cell carcinoma (cSCC). However, optimal therapy following PD-1 failure is not well defined. We compared overall survival (OS) outcomes for patients who failed anti-PD-1 therapy and were subsequently treated with ipilimumab (anti-CTLA-4) versus cetuximab-based regimens (anti-EGFR ± chemotherapy) in a large real-world cohort. Methods: We conducted a retrospective cohort study using the Epic COSMOS database. The cohort included patients with advanced cSCC who progressed on first-line anti-PD-1 therapy. OS was estimated using Kaplan–Meier methods and compared between treatment groups using log-rank testing. Associations between baseline characteristics and survival were evaluated using univariable Cox proportional hazards models with false discovery rate (FDR) correction. Results: The cohort included 251 patients with a median age of 74.0 years; 73.7% were male, 93.0% were White, and 48.2% had a history of tobacco use. The median Charlson Comorbidity Index score was 10.0. The median OS (mOS) was 52 months (95% CI [37.3-NR]). In the univariate analysis of prognostic factors, a higher Charlson Comorbidity Index was the only factor significantly associated with worse survival (HR 1.09, 95% CI [1.04–1.15], FDR = 0.001). Age, sex, race, BMI, tobacco use, and residence were not significantly associated with outcomes. Out of 251 patients, 26 received ipilimumab, and 225 received cetuximab-based regimens, with 168 receiving cetuximab alone and 57 receiving it in combination with chemotherapy. There was no statistically significant difference in survival among the treatment groups (log-rank p = 0.54). The 48-month overall survival probabilities were 48.1% (95% CI 24.5–68.3%) for ipilimumab, 46.6% (95% CI 33.3–58.8%) for cetuximab monotherapy, and 40.4% (95% CI 20.0–54.0%) for cetuximab plus chemotherapy. Conclusions: In this real-world analysis of patients with advanced cSCC progressing on anti-PD-1 therapy, OS did not significantly differ between those treated with ipilimumab and those receiving cetuximab-based regimens. Comorbidity burden was the primary driver of survival outcome. Given the retrospective design and limited sample size of the ipilimumab cohort, prospective studies are warranted to better define optimal sequencing in this setting.