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Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients., Patients and Methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics., Results: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use., Conclusions: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article., Methods: We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648., Findings: Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group., Interpretation: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing., Funding: GlaxoSmithKline., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations., Methods: In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted., Results: The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group., Conclusions: A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.).