Overall survival results of a phase III COMBI-d trial reported in The Lancet by Long et al showed that the combination of the BRAF inhibitor dabrafenib (Tafinlar) with the MEK inhibitor trametinib (Mekinist) resulted in significantly prolonged overall survival vs dabrafenib alone in patients with BRAF V600–mutant melanoma. The primary analysis of the trial had shown that the combination significantly prolonged progression-free survival.
In this double-blind trial, 423 previously untreated patients from 14 countries with BRAF Val600Lys/Glu mutation–positive unresectable stage IIIC or stage IV melanoma were randomly assigned between May 2012 and November 2012 to receive oral dabrafenib at 150 mg twice daily and oral trametinib at 2 mg once daily (n = 211) or dabrafenib and placebo (n = 212). The primary endpoint was progression-free survival; overall survival was a secondary endpoint.
Improved Overall Survival
At the final data cutoff (January 2015), after 222 patients had died, median overall survival was 25.1 months (95% confidence interval [CI] = 19.2 months to not reached) in the combination group vs 18.7 months (95% CI = 15.2–23.7 months) in the dabrafenib group (hazard ratio [HR] = 0.71, P = .0107). Overall survival was 74% vs 68% at 1 year and 51% vs 42% at 2 years. Consistent benefit of the combination was observed across all subgroups.
At the current analysis, median progression-free survival was 11.0 months (95% CI = 8.0–13.9 months) in the combination group and 8.8 months (95% CI = 5.9–9.3 months) in the dabrafenib group (HR = 0.67, P = .0004, unadjusted for multiple testing).
Treatment-related adverse events of any grade occurred in 87% of the combination group and 90% of the dabrafenib group, with the most common in the combination group being pyrexia (52% vs 25%) and the most common in the dabrafenib group being hyperkeratosis (33% vs 6%). Treatment-related grade 3 or 4 adverse events occurred in 32% vs 31% of patients. Cutaneous squamous cell carcinoma occurred in 3% vs 9%.
The investigators concluded: “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.”
Georgina V. Long, MD, of The University of Sydney, is the corresponding author for The Lancet article.
The study was funded by GlaxoSmithKline. For full disclosures of the study authors, visit www.thelancet.com.
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