Background: RELATIVITY-047, a global, randomized, double-blind, phase II/III study, met its primary endpoint of progression-free survival (PFS). Relatlimab and nivolumab (RELA + NIVO) as a fixed-dose combination (FDC) demonstrated a significant PFS benefit (median PFS was 10.1 months [mo]; 95% CI, 6.4–15.7) with RELA + NIVO vs. 4.6 mo (95% CI, 3.4–5.6) with NIVO; hazard ratio (HR) 0.75 (95% CI, 0.6–0.9; p= .0055), with a manageable safety profile, compared to NIVO alone in patients with previously untreated metastatic or unresectable melanoma (Lipson EJ et al. J Clin Oncol 2021;39[15_suppl]:9503P). Here we report updated PFS and the first disclosure of secondary endpoints, overall survival (OS), and overall response rate (ORR). Methods: Patients were randomized 1:1 to receive RELA 160 mg + NIVO 480 mg FDC or NIVO 480 mg alone, given intravenously every 4 weeks, as previously described (Lipson EJ et al. J Clin Oncol 2021;39[15_suppl]:9503P). The primary endpoint of PFS per RECIST v1.1 was assessed by blinded independent central review (BICR). Secondary endpoints were OS and ORR by BICR, to be tested hierarchically. The OS boundary for statistical significance was p < .04302 (2-sided) based on 69% power for a target HR of 0.75. Results: Patients (714 patients) were randomly selected to receive RELA + NIVO (355 patients) or NIVO (359 patients). Median follow-up was 19.3 mo. Updated median PFS was 10.2 mo (95% CI, 6.5–14.8) with RELA + NIVO vs. 4.6 mo (95% CI, 3.5–6.4) with NIVO (HR 0.78; 95% CI, 0.6–0.9). Median OS was not reached (NR; 95% CI, 34.2–NR) with RELA + NIVO vs. 34.1 mo (95% CI. 25.2–NR) with NIVO (HR 0.80; 95% CI, 0.6–1.0; p = .0593). OS rates at 12 mo were 77.0% (95% CI, 72.2–81.1) vs. 71.6% (95% CI, 66.6–76.0) and at 24 mo were 63.7% (95% CI, 58.1–68.7) vs. 58.3% (95% CI, 52.7–63.4) with RELA + NIVO vs. NIVO, respectively. Subsequent systemic therapy rates and types were generally similar between treatment groups. Confirmed ORR per BICR was 43.1% (95% CI, 37.9–48.4) with RELA + NIVO vs. 32.6% (95% CI, 27.8–37.7) with NIVO. Complete responses were observed in 16.3% of patients on RELA + NIVO vs. 14.2% on NIVO. Grade 3/4 treatment-related adverse events (TRAEs) were observed in 75 (21.1%) patients on RELA + NIVO and 40 (11.1%) on NIVO. There were four treatment-related deaths in the RELA + NIVO group and two in the NIVO group. TRAEs (any grade) leading to treatment discontinuation were observed in 54 (15.2%) patients on RELA + NIVO and 26 (7.2%) on NIVO. Conclusions: RELA + NIVO continued to demonstrate a PFS benefit vs. NIVO alone in patients with previously untreated metastatic or unresectable melanoma, consistent with the primary analysis. RELA + NIVO demonstrated a 20% reduction in risk of death and numerically improved OS rates vs. NIVO, although statistical significance was not reached for this secondary endpoint. ORR was higher with RELA + NIVO vs. NIVO. The safety profile of RELA + NIVO remained manageable with no new or unexpected safety signals. Clinical trial information: NCT03470922.