Nonoperative management of locally advanced resectable cutaneous squamous cell cancer of the head and neck with PD-1 blockade.

6111 Background: Head and neck cutaneous squamous cell carcinoma (cSCC) is common, increasing in incidence, and highly immunogenic. Neoadjuvant PD-1 blockade with cemiplimab has demonstrated substantial efficacy prior to surgery; however, its role as a definitive nonoperative strategy in resectable disease remains poorly defined. Methods: We conducted a single-institution retrospective study (2018–2023) of patients with locally advanced, resectable stage III/IV head and neck cSCC treated with cemiplimab. Patients received either neoadjuvant cemiplimab followed by surgery or cemiplimab monotherapy without surgery. The primary endpoint was objective clinical and radiologic response rate. Secondary endpoints included disease-specific survival (DSS), progression-free probability (PFP), histopathologic response, and exploratory genomic biomarkers. Results: Seventy-three patients were included: 52 received cemiplimab monotherapy (median age, 78.8 years) and 21 received neoadjuvant cemiplimab (median age, 73 years). In the monotherapy cohort, complete response occurred in 68.6%, partial response in 9.8%, stable disease in 5.9%, and progression in 15.7% (median treatment duration, 10 months). Two-year DSS and PFP were 90% (95% CI, 80–100) and 82% (95% CI, 72–94), respectively. In the neoadjuvant cohort, radiographic response was observed in 66.7% and pathologic complete response in 38.1%. Two-year DSS and PFP were 95% (95% CI, 86–100) and 78% (95% CI, 62–100), respectively. DSS and PFP did not differ significantly between cohorts. Tumor-infiltrating lymphocytes (TILs) were higher in complete and partial responders than in patients with stable or progressive disease (p=0.005, q=0.02), with absent TILs more frequent in non-responders. Tumor mutational burden (TMB) was greater in complete (55.7) and partial responders (14.9) than in patients with progressive disease (4.9; p=0.02, q=0.04). Conclusions: In the largest reported series to date, cemiplimab monotherapy achieved durable disease control and oncologic outcomes comparable to neoadjuvant cemiplimab in selected patients with resectable, locally advanced head and neck cSCC, supporting further study of definitive immunotherapy as an organ-preserving strategy.