Background: Melanoma (Mel) accounts for the majority of skin cancer-related deaths. Most patients (pts) with a newly diagnosed Mel have resectable disease and are potentially cured by surgery. However, regional nodal and/or distant relapses can occur after curative-intent resection. Postoperative adjuvant therapy with immune checkpoint inhibitors improves relapse-free survival (RFS) and distant metastasis-free survival (DMFS) of pts at high risk of Mel. Fianlimab (anti-LAG-3) and cemiplimab (anti-PD-1) are both high-affinity, fully human, IgG4 monoclonal antibodies (MAbs) that combined have shown high clinical activity in pts with advanced Mel in a phase 1 study. Additionally, combination of relatlimab (anti-LAG-3) and nivolumab (anti-PD-1) have shown superiority over nivolumab for PFS in advanced Mel. These observations provide a rationale for use of fianlimab and cemiplimab combination in high-risk adjuvant Mel. Methods: Our study (NCT05608291) is a three-way, double-blind, phase 3 trial to compare fianlimab + cemiplimab to pembrolizumab in the adjuvant therapy (Rx) of high-risk, resected Mel. The primary objective is RFS, and the secondary objectives are overall survival, safety, pharmacology, and immunogenicity. This international trial will be conducted at 200 sites. Pt eligibilities: (1) ≥12 years of age; (2) Stage IIc, III or IV (all M-stages) and histologically confirmed Mel, completely resected ≤12 weeks prior to randomization; (3) no prior systemic anti-cancer Rx or radiation Rx for Mel in the previous 5 years; (4) no evidence of metastatic disease on staging investigations; and (5) an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1 (for adult pts), Karnofsky PS >70 (pts >16 years) or Lansky PS >70 (pts <16 years). Study arms (all Rx every 3 weeks intravenously for one year): A. fianlimab (1600 mg) + cemiplimab (350 mg); B. fianlimab (400 mg) + cemiplimab (350 mg); C. pembrolizumab (200 mg) + saline/dextrose placebo. The placebo controlled trial will enroll about 1530 pts, randomized 1:1:1 to Arms A:B:C, treated for up to 1 year. The trial will stratify by disease stage (stage IIIA vs IIC-IIIB-IIIC vs IIID-IV [M1a/b] vs IV [M1c/d]), and geography (North America vs Europe vs Rest of World). The primary endpoint is investigator-assessed RFS. The secondary endpoints include efficacy (overall survival, DMFS, melanoma-specific survival), safety [treatment-emergent adverse events (TEAEs), interruption or discontinuation of drugs due to TEAEs], pharmacokinetic (concentrations of fianlimab and cemiplimab in serum over time), immunogenicity (anti-drug Abs and neutralizing Abs in serum against fianlimab or cemiplimab), and patient reported outcomes. The first analysis will be performed when 242 RFS events have been observed. Clinical trial information: NCT05608291.