Background: Previous analysis of COMBI-d (NCT01584648) showed that D+T compared with D monotherapy improved ORR (69% [95% CI, 62%-75%] vs 53% [95% CI, 46%-60%]; P = 0.0014), reduced risk of progression (HR, 0.67 [95% CI, 0.53-0.84]; P = 0.0004) and death (HR, 0.71 [95% CI, 0.55-0.92]; P = 0.0107), and increased 2-y OS rate (51% vs 42%) in BRAFV600–mutant melanoma. Methods: In this phase 3, randomized, double-blind study, pts with histologically confirmed unresectable stage IIIC or IV, BRAF V600E/K–mutant melanoma were randomized 1:1 to receive frontline D 150 mg twice daily (BID) + T 2 mg once daily or D 150 mg BID only. The primary endpoint was PFS; secondary endpoints were OS, ORR, duration of response, and safety. Whole-exome sequencing was used to assess somatic mutations and copy number changes in pretreatment tumor (mean target coverage [MTC], 170×) and matched normal blood samples (MTC, 100×) collected from > 140 pts to further characterize BRAF V600–mutant melanoma and explore whether individual gene changes or genetic profiles were associated with treatment benefit. Results: A total of 423 pts were randomized to D+T (n = 211) or D (n = 212). As expected, initial genetic analysis of 130 pts showed that BRAF was the most frequently mutated gene (V600E, 83%; V600K, 15%). Additional mutations were observed in genes related to tumor suppression (TP53, PTEN, CDKND2A) and resistance to MAPK pathway inhibition (MEK1, MEK2, NRAS, NF1, RAC1), and amplifications were observed in BRAF and MITF. Overall mutation rate was higher in V600K vs V600E pts (median mutations per sample, 1701 vs 419; P< 0.0001). Updated genomic analysis, including OS and mutation rate association, and efficacy and safety results, including 3-y OS, will be presented. Conclusions: Preliminary genetic analyses showed additional mutations related to tumor suppression and MAPK inhibitor resistance were present in pts with BRAF-mutant melanoma, with a higher overall mutation rate in V600K-mutant tumors. Updated genetic analysis and 3-y efficacy and safety analysis will be presented. Clinical trial information: NCT01584648