Researchers studied neoadjuvant immunotherapy to produce a pathologic response in patients with stage III/IV (M0) cutaneous squamous cell carcinoma of the head and neck in a pilot phase II experiment (CSCC-HN). Investigators presented the long-term results based on a pathologic response. Before surgery, patients with newly diagnosed or recurrent stage III/IV (M0) (AJCC 8th Ed) CSCC-HN were given two doses of cemiplimab 350 mg intravenously every three weeks. The primary outcome was the overall response rate (ORR) per RECIST v1.1. Secondary goals were safety, pathologic response, disease-free survival, and overall survival. About 7 (35%) of the 20 patients had recurrent disease, and 12 (60%) were in stage IV at the presentation time. There were no surgical delays due to neoadjuvant immunotherapy, which was generally well tolerated. About 7 (35%) patients had adverse effects (AEs), with 1 (5%) having grade 3 diarrhea and 6 (30%) having grade 2 AEs. The ORR calculated by RECIST was 30%. However, 85% (17/20) of patients had a pathologic response (50% viable tumour), with pathologic complete response (pCR) in 11 (55%) cases, major pathologic response (MPR, 10% viable tumour) in 4 (20%) cases, and pathologic partial response (pPR, >10% and 50% viable tumour) in 2 cases (10%). After surgery, patients with a pCR did not get the anticipated radiation. Despite surgery and adjuvant radiation or chemoradiation, patients who did not have a pathologic response (>50% viable tumor) either progressed and died (1, 5%) or had recurrence (2, 10%), despite surgery and adjuvant radiation or chemoradiation. None of the patients who obtained a pathologic response had recurred after a median follow-up of 34.5 months (7.7-42.7). In patients with advanced, resectable CSCC-HN, the pathologic response to neoadjuvant immunotherapy was lasting, as in other cancer types. The possibility of avoiding adjuvant radiation therapy in patients who obtained a pCR needs further exploration.