May 1, 2018—Yesterday, the U.S. Food and Drug Administration (FDA) granted regular approval of the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib for the adjuvant treatment of patients with melanoma harboring BRAF V600E or V600K mutations following complete surgical resection.
Dabrafenib plus trametinib was first approved for patients with BRAF-mutated metastatic melanoma in January 2014. The combination was later granted regular approval for the treatment of patients with BRAF-mutated non-small cell lung cancer (NSCLC) in June of last year.
This adjuvant approval was based on results from the international, multi-center, double-blind, placebo-controlled, phase III COMBI-AD trial (NCT01682083), in which 870 patients with stage III melanoma with BRAF V600E/K mutations were randomized (1:1) to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) [N=438], or two placebos (N=432) for up to 12 months.
Results published in The New England Journal of Medicine showed the adjuvant combination reduced the risk of relapse or death by 53% compared with placebo for patients with BRAF-mutated disease. Patients in the combination arm experienced fewer recurrences or deaths at the time of data-cutoff than patients receiving placebo. The relapse-free survival rate (RFS) was 38% (N=166) in the experimental arm, compared with 57% (N=248) in the placebo arm. Further, median RFS had not been reached for patients receiving the combination, compared with 16.6 months for those receiving placebo.
Early data for overall survival (OS) showed that, at 1 year the OS rates were 97% and 94% for the combination and placebo arms, respectively. At 2 years, the OS rates were 91% and 77%, respectively. At the interim analysis, the OS advantage was not yet deemed statistically significant, but 86% of patients in the combination arm were still alive at 3 years compared with 77% of patients receiving placebo.
The most common adverse events (AEs) associated with the combination included pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. Treatment-related AEs that resulted in the discontinuation, dose reduction, or dose interruption of dabrafenib occurred in 25%, 35%, and 66% of patients, respectively. For trametinib, AEs resulted in the discontinuation, reduction, or interruption of treatment in 24%, 23%, and 54% of patients, respectively.
Updated prescribing information for dabrafenib can be found here. Updated prescribing information for trametinib can be found here.
Jonathan A. Bell
Published Online: Tuesday, May 01, 2018