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Background Cemiplimab was approved for treatment of metastatic cutaneous squamous cell carcinoma (CSCC) based on the EMPOWER-CSCC-1 trial. A phase II study of 79 patients receiving four doses of neoadjuvant cemiplimab for resectable CSCC showed a major pathologic response (MPR) rate of 64%. In a synchronous study we hypothesized that peri-operative cemiplimab would lead to high response rates and excellent recurrence-free survival (RFS).Methods Winship4851 is a single-arm phase II study of neoadjuvant and adjuvant cemiplimab for high-risk resectable CSCC defined as: nodal disease with extracapsular extension or one node ≥20mm; in transit metastases; T4 head and neck (H&N) tumor; or recurrent CSCC ( NCT04428671). Patients received three doses of cemiplimab every three weeks followed by surgery and 18 adjuvant doses of cemiplimab until recurrence or toxicity. Adjuvant radiation was offered at the discretion of the investigator. Primary endpoint was pathologic response rate. Secondary endpoints were safety and feasibility, RFS and overall survival (OS). The study was approved by Emory University’s IRB.Results Fourteen patients were enrolled; the median age was 73 (range 53-87) and 13 (92.8%) were males. Thirteen (92.8%) had H&N disease; one had axillary nodal recurrence. All patients completed neoadjuvant therapy except one who developed grade 2 arthralgias, and all patients underwent planned curative-intent resection. Rates of complete, near-complete, and partial pathologic responses were 57.1%, 21.4%, and 14.3%, respectively, with major pathologic response (MPR) rate of 78.5%. Four patients underwent adjuvant radiation, two with MPR and two with non-MPR. All four of these patients were treated by the H&N team; the remaining 10 patients treated by the cutaneous malignancy team did not undergo radiation. Median time to adjuvant cemiplimab was 32 days (range 15-50) in patients that did not undergo radiation. At median follow up of 33.4 months, one patient with pathologic non-response experienced recurrence and died; one patient died without disease. Three-year RFS and OS rates were 92.3% and 85.7%. One patient experienced grade 3 pneumonitis that developed after adjuvant treatment was complete. Patients with MRP had significantly higher increase in HLA-DR+ CD38+ CD8+ T cells from baseline compared to pathologic non-responders ( figure 1).Conclusions Peri-operative cemiplimab is safe and well-tolerated and leads to excellent pathologic responses with only three neoadjuvant doses of cemiplimab. Use of adjuvant radiation was disease-team dependent and in this small study did not appear to correlate with recurrence. Further studies assessing the impact of adjuvant radiation and/or systemic therapy are warranted.Trial Registration NCT04428671Ethics Approval The study was approved by the Emory IRB (approval number IRB00115160) and participants gave informed consent to take part in this study.Abstract 527 Figure 1Fold change by response: cycle 1 vs. cycle 3