Progression patterns and clinical outcomes in patients with cutaneous squamous-cell carcinoma following anti-PD-1 therapy failure.

[BACKGROUND] Anti-programmed cell death protein 1 (PD-1) therapy is the cornerstone for managing advanced cutaneous squamous-cell carcinoma (CSCC). Nevertheless, many patients experience treatment failure. Limited data exist regarding outcomes following anti-PD-1 failure. This study investigates progression patterns and clinical outcomes in CSCC patients post-anti-PD-1 therapy.

[PATIENTS AND METHODS] We conducted a retrospective analysis of CSCC patients treated with anti-PD-1 at the Dana-Farber Cancer Institute. We evaluated clinicopathological features and outcomes. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method. CSCC-specific mortality was estimated using cumulative incidence. Multivariate regression was used to investigate prognostic factors.

[RESULTS] Among 238 patients receiving immunotherapy, 72 exhibited anti-PD-1 failure with a median age of 72 years; 22% were female and 29% were immunosuppressed. Median follow-up was 23 months [95% confidence interval (CI) 19-37 months] and median duration of immunotherapy was 3 months (range 1-44 months). Progression after anti-PD-1 failure occurred as local (21%), locoregional (37%), or distant metastatic (42%). Primary resistance was observed in 62.5%, while 37.5% developed secondary resistance. Patients with primary resistance exhibited a significantly lower tumor mutational burden (TMB) (P = 0.03). Among 61 patients receiving subsequent treatment, cetuximab-based therapy and local treatments each were administered in 31%. Complete and partial responses were achieved in 5% and 25%, respectively, while 6% had stable disease, 28% progressed, and 36% were non-assessable. Median OS was 44.1 months (95% CI 17.4 months-not achieved) and median EFS2 (time from starting subsequent treatment post-anti-PD-1 until recurrence, progression, or death) was 7.1 months (95% CI 3.2-12.2 months). CSCC-specific death was 50% at 5 years (95% CI 30% to 67%). Prior chemotherapy was associated with poorer OS (hazard ratio 2.87, 95% CI 1.03-7.98, P = 0.04).

[CONCLUSIONS] In this cohort of patients with CSCC, distant metastatic and locoregional progression were the predominant patterns following anti-PD-1 failure, with lower TMB linked to primary resistance. Prior chemotherapy was associated with poorer OS. Select patients benefited from subsequent treatments, including cetuximab and local therapy.