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Background PD-1 blockade achieves response rates of ~50% in unresectable/metastatic cutaneous squamous cell carcinoma (CSCC) with durable responses lasting >6 months in 60% of patients. Here we present primary results from a phase 2, multicenter, open-label study of neoadjuvant cemiplimab in patients with high-risk, resectable CSCC ( NCT04315701).Methods The NeoPOWER study enrolled patients with resectable CSCC, according to 1 of the following categories: 1) high-risk localized CSCC (tumor diameter >2.0 cm, depth>6mm, poorly differentiated histology, or perineural invasion), 2) recurrent CSCC after prior surgery/radiation, or 3) regionally advanced CSCC (in-transit, subcutaneous or nodal metastases). Patients received cemiplimab 350mg IV every 3 weeks for 3 cycles, then underwent definitive surgery; no adjuvant therapy was administered. The primary endpoint was pathologic partial response (PPR); secondary endpoints included pathologic complete response (PCR), objective response rate (ORR), 12 month progression free survival (PFS) and toxicity.Results Among 35 patients enrolled, the median age was 72 yrs (range 41-95), 74% were male, 63% were white; all patients (100%) were ECOG 0 or 1. There were 18 (51%) patients with high risk localized CSCC, 3 (9%) with recurrent CSCC, and 12 (34%) with regionally advanced CSCC; 40% of patients had nodal involvement. Most patients (91%) received all 3 cycles of cemiplimab; 28 patients (80%) completed definitive surgery. The median duration of follow-up was 9.9 months (0.7-28.5). At the time of reporting, 28 patients (82%) had completed study treatment; 2 (6%) stopped due to progression, 2 (6%) discontinued due to toxicity, and 1 patient withdrew consent after 1 cycle of therapy. Among 29 patients with available pathology, the overall PPR rate was 89.7%, including PCR for 72.4% and near PCR (NPCR) 10.3%. The RECIST ORR was 58.8%, with 50.0% partial response (PR) and 8.8% complete response (CR); 29.4% had stable disease (SD). The 12 month PFS rate was 82%; median progression free and overall survival were not reached (NR). TRAE included low-grade fatigue (22.9%), increased AST (11.4%), anorexia (8.6%), pruritus (8.6%), and maculopapular rash (8.6%). There were no grade 3-5 TRAE reported.Conclusions Neoadjuvant cemiplimab for 3 cycles prior to surgery is well tolerated and highly effective with PPR 89.0% and PCR 72.4% in resectable CSCC, despite a lower clinical/radiographic RECIST ORR of 58.8%. Neoadjuvant PD-1 therapy should be considered a potential new treatment paradigm for patients with high risk localized, recurrent or regionally advanced, resectable CSCC.Acknowledgements This investigator-initiated clinical trial was supported by Regeneron Pharmaceuticals. The authors gratefully acknowledge Regeneron and their clinical trials research team for their support, including the provision of study funding and investigational drug supply.Ethics Approval This clinical trial was approved by the Institutional Review Board (IRB) at the University of Southern California. The study was conducted in accordance with the ethical standards of the IRB and the principles outlined in the Declaration of Helsinki. The official IRB approval number for this study is HS-19-00848. Written informed consent was obtained from all individual participants prior to their enrollment in the trial.