Background: The PD-1 inhibitor cemiplimab was approved in 2018 for treatment of locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable with surgery or radiation. This approval was based on the results of the phase 2 EMPOWER-CSCC-1 trial, which demonstrated an objective response rate of 47% with a significant number of these patients experiencing a durable response. However, patients with high risk cSCC that are able to undergo curative intent surgery are not candidates for checkpoint inhibitor therapy but still experience high rates of recurrence and/or systemic progression even when offered adjuvant radiotherapy. In light of data using checkpoint inhibitor therapy in the neoadjuvant setting in other cutaneous malignancies, we hypothesized that cemiplimab therapy would improve surgical outcomes and reduce long-term recurrence rates in patients with high-risk resectable cSCC if used in the perioperative setting. Methods: Winship 4851-19 is a single arm pilot study of cemiplimab in the neoadjuvant and adjuvant setting for high-risk resectable cSCC (NCT04428671). In the neoadjuvant phase, patients receive three doses of cemiplimab every three weeks followed by standard of care surgery. Radiation may be offered when clinically appropriate at the discretion of the investigator. In the adjuvant phase (following surgery +/- radiation), patients receive cemiplimab every three weeks to complete one year total of treatment. Eligible patients must have surgically resectable histologically proven high risk cSCC defined as: nodal disease with extracapsular extension or one node ≥20mm; in transit metastases > 2cm from primary lesion; T4 head and neck primary tumor; perineural invasion; or recurrent cSCC with concurrent ≥N2b nodal disease, size ≥4cm or bony invasion, or poorly differentiated histology. Patients cannot have received prior immunotherapy and must have a ECOG performance status of 0 or 1. Primary objective is to establish pathologic response rate. Secondary objectives include assessments of local and distant recurrence and overall survival rates. We also plan to evaluate the immune profile of fresh tumor and blood to assess the impact of neoadjuvant cemiplimab on the tumor microenvironment and circulating immune responses. To date 5 of 20 patients have been enrolled; this sample size was selected based on feasibility and ability enroll within a timely fashion. Clinical trial information: NCT04428671