Background: Combined BRAF/MEK inhibitor therapy is standard of care in advanced BRAFV600-mutant melanoma. COLUMBUS Part 1 evaluated ENCO 450 mg once daily (QD) + BINI 45 mg twice daily (BID;COMBO450) vs VEM 960 mg BID or ENCO 300 mg QD (ENCO300) in patients (pts) with advanced BRAFV600-mutant melanoma. The primary study endpoint was progression-free survival (PFS); median PFS was 14.9 vs 7.3 mo for COMBO450 vs VEM; hazard ratio (HR): 0.54 (2-sided P< 0.001). Here we report a planned analysis of overall survival (OS), a secondary endpoint of the study. Methods: Pts with advanced/metastatic BRAFV600-mutant melanoma, untreated or progressed on/after first-line immunotherapy, were stratified by disease stage, Eastern Cooperative Oncology Group Performance Status and prior first-line immunotherapy. Pts in Part 1 were randomized 1:1:1 to COMBO450 (n = 192), ENCO300 (n = 194), or VEM (n = 191). Tumor responses and progression were assessed by blinded independent central review. An analysis of OS was planned after 232 events in the COMBO450 and VEM arms combined. Results: As of data cutoff,105, 106, and 127 events contributed to the OS analysis in the COMBO450, ENCO300, and VEM arms, respectively; median follow-up across arms was 21.5 mo. Median OS was 33.6 mo (95% CI, 24.4-39.2) with COMBO450, 23.5 mo (95% CI, 19.6-33.6) with ENCO300, and 16.9 mo (95% CI, 14.0-24.5) with VEM. Risk of death was reduced with COMBO450 vs VEM (HR, 0.61 [95% CI, 0.47-0.79]; nominal 2-sided P< 0.001). Updated median PFS was 14.9 mo (95% CI, 11.0–20.2) with COMBO450, 9.6 mo (95% CI, 7.4–14.8) with ENCO300, and 7.3 mo (95% CI, 5.6–7.9) with VEM. PFS was longer with COMBO450 vs VEM (HR, 0.51 [95% CI, 0.39–0.67]). Updated response rates, safety data, and information on 2nd-line therapy will be presented at the meeting. Conclusions: The best-in-class median PFS of 14.9 and median OS of 33.6 mo suggest that COMBO450 is a promising new regimen for treatment of BRAF-mutant melanoma. SPONSOR: Array BioPharma Inc. Clinical trial information: NCT01909453