Background: Combination of immune checkpoint inhibitors and targeted therapy may produce durable and deep response in a higher proportion of pts with BRAF V600–mutant unresectable or metastatic melanoma. A recent report from the randomized, double-blind, placebo (PBO)-controlled Part 3 of the Phase 3 COMBI-i trial (NCT02967692) failed to show a statistically significant progression-free survival (PFS) benefit (hazard ratio (HR) of 0.82 (95% CI, 0.66‒1.03, p=.042)). Here, we report 3-year OS data from COMBI-i part 3. Methods: Eligible pts were randomized 1:1 to receive either S+D+T (n = 267; S 400 mg IV Q4W + D 150 mg orally BID + T 2 mg orally QD) or PBO+D+T (n = 265), until progression or unacceptable toxicity. Although the primary endpoint of PFS was not met, exploratory OS and safety analyses were performed. OS was summarized descriptively using Kaplan–Meier methods and HR was estimated using a stratified cox regression model. Results: As of October 19, 2021 (median follow-up, 42.8 months), the median OS was not reached in S+D+T arm and was 40.4 months with PBO+D+T (HR 0.796; 95% CI, 0.615‒1.029). There were 113 (42.3%) deaths in the S+D+T and 126 (47.5%) in the PBO+D+T. Estimated 2-year and 3-year OS rates were 67.7% (95% CI 61.6‒73.1) and 60.1% (95% CI 53.8‒65.8) with S+D+T vs 61.9% (95% CI 55.6‒67.5) and 52.9% (95% CI 46.6‒58.9) with PBO+D+T, respectively. An OS benefit was observed with S+D+T in these prespecified subgroups – Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (HR 0.50; 95% CI, 0.32‒0.8), age ≥65 years (HR 0.58; 95% CI, 0.36‒0.94), PD-L1 negative ( < 1%) (HR 0.62; 95% CI, 0.42‒0.91), sum of lesion diameters ≥ 66 mm at baseline (HR 0.63; 95% CI, 0.43‒0.91) and metastatic sites ≥ 3 (HR 0.66; 95% CI, 0.47‒0.94). Adverse events (AEs) irrespective of study treatment relationship were observed in 99.3% of pts in S+D+T vs 97.3% in PBO+D+T. The most common AEs (in > 30%; all grades) were pyrexia, diarrhea, and nausea. Grade ≥3 treatment-related AEs (TRAEs) occurred in 56.9% vs 35.2% of pts treated with S+D+T vs PBO+D+T, respectively. Dose reductions of D and T due to AEs were more frequent in the S+D+T arm than PBO+D+T arm (47.2% vs 25.4% and 45.7% vs 25.4%, respectively), contributing to a lower relative dose intensity; the TRAEs leading to discontinuation of all 3 study drugs occurred in 13.5% vs 8% of pts, respectively. Conclusions: Results from this landmark 3-year OS analysis from COMBI-i- part 3 was consistent with the primary analysis, while the PBO+D+T showed a higher OS rate than previously observed for D+T alone in COMBI D/V studies, with a longer median follow-up. Subgroup analyses showed that ECOG PS 1, age ≥65 years, negative PD-L1 status and high tumor burden were associated with better OS in S+D+T in terms of HR. Clinical trial information: NCT02967692.