Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial - ECOG-ACRIN EA6134.
Academic Article
Overview
abstract
PURPOSE: Combination PD-1/CTLA-4 blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600 mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. METHODS: In a phase III trial, patients with treatment-naïve BRAFV600-mutant metastatic melanoma were randomized to receive either combination nivolumab/ipilimumab (Arm A) or dabrafenib/trametinib (Arm B) in Step 1, and at disease progression were enrolled in Step 2 receiving the alternate therapy, dabrafenib/trametinib (Arm C) or nivolumab/ipilimumab (Arm D). The primary endpoint was 2-year overall survival. Secondary endpoints were 3-year overall survival, objective response rate, response duration, progression-free survival, crossover feasibility and safety. RESULTS: 265 patients were enrolled with 73 going onto Step 2 (27 Arm C, 46 Arm D). The study was stopped early by the independent DSMC due to a clinically significant endpoint being achieved. The 2-year overall survival for those starting on Arm A was 71.8% (62.5, 79.1%) and Arm B 51.5% (41.7, 60.4%) (log-rank p=0.010). Step 1 progression-free survival favored Arm A (p=0.054). Objective response rates were: Arm A:46.0%; Arm B:43.0%; Arm C:47.8%; Arm D:29.6%. Median duration of response was not reached for Arm A and 12.7 months for Arm B (p<0.001). Crossover occurred in 52% of patients with documented disease progression. Grade >3 toxicities occurred with similar frequency between arms and regimen toxicity profiles were as anticipated. CONCLUSION: Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.
