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Background The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. Methods In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. Results At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P = 0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combinationtherapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P

Aim: BRAFi (D) and MEKi (T) each demonstrated superior progression-free survival (PFS) vs. chemotherapy in pts with BRAF V600E/K mutation-positive metastatic melanoma (MM). However, the emergence of disease resistance and development of cutaneous squamous cell carcinoma (cuSCC) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects as shown in the Phase I/II study of D + T combination therapy vs. D monotherapy (NCT01072175) and the Phase III study of D + T combination therapy vs. D monotherapy (NCT01584648), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01597908) was conducted to establish superiority of D + T combination over V with respect to overall survival (OS) in pts with BRAF V600E/K mutation-positive MM. Methods: Pts were randomised 1:1 to receive D (150 mg twice daily [BID]) and T (2 mg once daily) vs. V monotherapy (960 mg BID) as first-line therapy. Eligible pts were ≥ 18 years old and had an ECOG performance status ≤ 1, with histologically confirmed, unresectable stage IIIC or IV, BRAF V600E/K mutation-positive MM. The primary endpoint was OS; secondary endpoints were PFS, ORR, duration of response, and safety. Crossover was prohibited. A pre-specified interim OS analysis was performed when 77% (222/288) of the total number of expected deaths, required for the protocol-specified final analysis, were observed; the study could be stopped for efficacy if the one-sided P value was Results: From June 2012 to Oct 2013, 704 pts were randomised (352 to each arm). IDMC recommended stopping study based on an interim analysis which demonstrated an OS benefit that crossed the pre-specified efficacy stopping boundary for D + T combination. Rates of adverse events were generally similar for both arms and consistent with data from previous trials. Full efficacy and safety results will be presented at the meeting. Conclusions: D + T demonstrated a significant improvement in OS compared with V in pts with BRAF V600E/K mutation-positive MM. Disclosure: C. Robert: has received fees for Advisory Board participation from Bristol-Meyers Squibb, Roche, Merck, GlaxoSmithKline, Novartis and Amgen; P. Rutkowski: receives personal fees Novartis, Pfizer, GSK, and Roche, in addition to travel grants and fees for participation in speakers bureau and Advisory Boards from GSK and Novartis; R. Dummer: received grants and personal fees from GSK, Roche, Novartis, MSD and BMS; L. Mortier: received personal fees from GSK; V. Chiarion-Sileni: receiving compensation for Advisory Board participation GlaxoSmithKline, Bristol-Meyers Squibb and Roche; A. Hauschild: Consult, Hon and Trial funding: mgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche; P. Sun, S. Rubin and J. Legos: is an employee of GlaxoSmithKline and owns stock in the company; W. Crist: is an employee of GlaxoSmithKline; S.M. Little: is an employee and owns stock in GSK; D. Schadendorf: received personal fees, other support, and non-financial support from GlaxoSmithKline, Roche, Novartis, Amgen, Bristol-Meyers Squibb and MSD/Merck, and grants from MSD/Merck. All other authors have declared no conflicts of interest.

LBA8509 Background: Dacarbazine (D) and paclitaxel (P) have been used to treat MM pts with limited effect. The MM treatment landscape has recently changed with the approval of vemurafenib and ipilimumab in 2011, but secondary malignancies or other toxicities are of concerns. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. In a PhII trial (NCT01037127), pts with BRAFV600E mutation MM had median PFS of 5.3 mos. This PhIII trial (NCT01245062) was conducted in pts with BRAFV600E/K mutant advanced or MM. Methods: Pts were randomized 2:1 to T (2mg QD) or C (D or P). Pts were stratified by baseline LDH level and prior C; pts in the C arm were allowed to crossover to receive T after confirmation of PD. Primary endpoint was PFS in pts with BRAFV600E mutation-positive MM and no prior brain mets; secondary endpoints were OS, ORR and safety in primary and ITT. PFS and OS were compared using a stratified log-rank test. The study was designed with ≥99% power and one-sided α = 0.025 to detect 57% reduction in the risk of PD or death in pts treated with T vs C. Results: Between Dec 2010 and Jul 2011, 322 pts were randomized to T (n=214) or C (n=108); 273 pts were BRAFV600E mutation-positive with no prior brain mets. HR for primary population for PFS by investigator was 0.44 (95% CI 0.31–0.64; pV600E/K mutant MM.

LBA8509 Background: Dacarbazine (D) and paclitaxel (P) have been used to treat MM pts with limited effect. The MM treatment landscape has recently changed with the approval of vemurafenib and ipilimumab in 2011, but secondary malignancies or other toxicities are of concerns. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. In a PhII trial (NCT01037127), pts with BRAFV600E mutation MM had median PFS of 5.3 mos. This PhIII trial (NCT01245062) was conducted in pts with BRAFV600E/K mutant advanced or MM. Methods: Pts were randomized 2:1 to T (2mg QD) or C (D or P). Pts were stratified by baseline LDH level and prior C; pts in the C arm were allowed to crossover to receive T after confirmation of PD. Primary endpoint was PFS in pts with BRAFV600E mutation-positive MM and no prior brain mets; secondary endpoints were OS, ORR and safety in primary and ITT. PFS and OS were compared using a stratified log-rank test. The study was designed with ≥99% power and one-si...