Background: As monotherapies, the BRAF inhibitor dabrafenib (D) and the MEK inhibitor trametinib (T) demonstrated superior progression-free survival (PFS) v chemotherapy in pts with BRAF^V600 mutant, metastatic melanoma (MM). Resistance develops in most pts, and oncogenic toxicities (e.g., cutaneous squamous carcinoma (cuSCC)) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects in the Phase I/II study of D+T v D (NCT01072175), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01584648) was conducted to confirm the superiority of D+T over D in pts with BRAF^V600E/K mutant MM. Methods: Pts were randomized 1:1 to receive D (150 mg twice daily) + T (2 mg once daily) or D+ placebo (P) as first-line therapy. Eligible pts were ≥18 years and ECOG performance status ≤1, with histologically confirmed unresectable stage IIIC or IV, BRAF^V600E/K mutant cutaneous melanoma. The primary endpoint was investigator-assessed PFS; secondary endpoints were overall survival (OS), ORR, duration of response, and safety. Cross over was prohibited. The study has 95% power and a one-sided α=0.025 to detect a PFS hazard ratio (HR) of 0.59. Results: From May 2012 to Jan 2013, 423 pts were randomized (211 to D+T, 212 to D+P). Median follow up was 9 mo (0-16 mo). HR for investigator-assessed PFS was 0.75 (95% CI: 0.57, 0.99; p=0.035), in favor of D+T with a median PFS of 9.3 v 8.8 mo with D+P. The confirmed ORR was 67% (complete response [CR] 10%) for D+T and 51% (CR 9%) for D+P (p=0.0015). HR for interim OS was 0.63 (95% CI 0.42, 0.94; p=0.023), in favor of D+T (40 v 55 deaths). Rates of AEs were similar for both arms. More pts had AEs leading to dose modifications with D+T v D+P. Increased incidence (51% v 28%) and severity (grade 3, 6% v 2%) of pyrexia occurred with D+T v D+P. Fewer cutaneous hyperproliferative events occurred with D+T v D+P (CuSCC 2% v 9%; hyperkeratosis 3% v 32%). Conclusions: D+T demonstrated a significant improvement in PFS compared to D+P in pts with BRAF^V600E/K mutant MM. Clinical trial information: NCT01072175.