Adjuvant Dabrafenib plus Trametinib in Stage III<i>BRAF</i>-Mutated Melanoma

TLDR

Combination therapy with dabrafenib plus trametinib improves survival in patients with advanced melanoma harboring BRAF V600 mutations. This phase‑3 trial evaluated whether adjuvant dabrafenib plus trametinib improves outcomes in patients with completely resected stage III melanoma with BRAF V600E or V600K mutations. Patients were randomized to 12 months of oral dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or placebo, with relapse‑free survival as the primary endpoint and overall survival, distant‑metastasis‑free survival, freedom from relapse, and safety as secondary endpoints. At 2.8 years median follow‑up, 3‑year relapse‑free survival was 58 % versus 39 % (HR 0.47), overall survival 86 % versus 77 % (HR 0.57), and rates of distant‑metastasis‑free survival and freedom from relapse were higher in the combination group, with no new toxic effects. The study was funded by GlaxoSmithK.

Abstract

Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 . ).