Background: Among patients with high-risk, locally advanced (LA) cutaneous squamous cell carcinoma (cSCC) who receive current standard-of-care surgical resection and adjuvant radiotherapy, ~40-50% develop local recurrence and regional metastasis (J Clin Oncol. 2018;36:1275-1283). Recent data suggest that programmed death 1 inhibitors such as pembrolizumab may provide a well-tolerated, effective, and durable response in patients with LA or metastatic cSCC. To evaluate the efficacy and safety of adjuvant pembrolizumab in patients with high-risk LA cSCC, the randomized, double-blind, placebo-controlled phase 3 KEYNOTE-630 trial (NCT03833167) will be conducted. Methods: After surgical resection and radiotherapy for high-risk LA cSCC, eligible patients will be randomly assigned 1:1 to intravenous pembrolizumab (400 mg Q6W) or placebo for up to 9 cycles (~1 year), with radiographic imaging at least every 12 weeks until year 2 and then every 6 months until the end of year 5 to assess treatment response. Eligibility criteria will include age ≥18 years, histologically confirmed LA cSCC with ≥1 high-risk feature at the primary site of malignancy, macroscopic resection with or without microscopic positive margins, completed adjuvant radiotherapy, disease free ≤28 days from randomization, and ECOG performance status 0-1. Treatment will be discontinued at disease recurrence, start of new anticancer treatment, unacceptable toxicity, intercurrent illness that prevents treatment, pregnancy, investigator or patient decision to withdraw, or administrative reasons that require treatment cessation. After the first disease recurrence, all patients who meet crossover or retreatment criteria may receive pembrolizumab 400 mg Q6W for up to 18 cycles. Adverse events will be monitored throughout the study and graded according to the NCI CTCAE, version 4.0. The primary efficacy end point will be investigator-assessed and biopsy-confirmed recurrence-free survival. Secondary end points will be overall survival, health-related quality of life, and safety. Recruitment is ongoing in 19 countries and will continue until approximately 570 patients are enrolled. Clinical trial information: NCT03833167