Background: Fianlimab (anti-lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti- programmed cell death-1 [PD-1]) are both high-affinity, fully human, IgG4 monoclonal antibodies (Abs). Concurrent blockade of anti-LAG-3 and anti-PD-1 has shown enhanced efficacy (increase in progression free survival [PFS]) in advanced melanoma (Mel). We previously presented data from a phase 1 study showing a 63.8% objective response rate (ORR) across two separate cohorts of advanced PD-(L)1 naïve metastatic Mel patients (pts) treated with fianlimab plus cemiplimab with an acceptable risk-benefit profile. Methods: This is a randomized, double-blind, phase 3 study to evaluate fianlimab plus cemiplimab compared to pembrolizumab in pts with previously untreated unresectable locally advanced or metastatic Mel (NCT05352672). This study will be conducted globally, at approximately 200 sites. Key inclusion criteria are: (1) ≥12 years of age; (2) histologically confirmed unresectable Stage III and Stage IV (metastatic) Mel (3) no prior systemic therapy for advanced unresectable disease, prior (neo)adjuvant therapies are allowed with treatment/disease-free interval of 6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) valid LAG-3 results; (6) 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); and (7) anticipated life expectancy of at least 3 months. There are 4 arms to the study: (1) Arm A: fianlimab (1600 mg) + cemiplimab (350 mg) every 3 weeks (Q3W), intravenously (IV); (2) Arm A1: fianlimab (400 mg) + cemiplimab (350 mg) Q3W, IV; (3) Arm B: pembrolizumab (200 mg Q3W, IV) + saline/dextrose placebo (placebo); (4) Arm C: cemiplimab (350 mg Q3W, IV) + placebo. The trial is expected to enroll approximately 1590 pts. The primary endpoint is progression-free survival. The key secondary endpoints are overall survival and objective response rate. The additional secondary endpoints include disease control rate, duration of response, safety, pharmacokinetics of cemiplimab and fianlimab, and immunogenicity (incidence and titer of anti-drug Abs and neutralizing Abs). The study is currently open for enrollment. Clinical trial information: NCT05352672.