BRAF Inhibitor Dabrafenib Plus MEK Inhibitor Trametinib Improves Outcomes vs Dabrafenib Alone in Previously Untreated BRAF-Mutant Advanced Melanoma
In a phase III trial reported in The New England Journal of Medicine, Long and colleagues found that the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) improved response rate and progression-free survival compared with dabrafenib alone in treatment-naive patients with BRAF V600–mutant advanced melanoma. An interim analysis of overall survival favored combination treatment.
Study Details
In the double-blind trial, performed in 113 centers worldwide, 423 patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E or V600K mutation were randomly assigned between May 2012 and January 2013 to receive dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily (n = 211) or dabrafenib and placebo (n = 212). The primary endpoint was progression-free survival in the intent-to-treat population.
Overall, patients had a median age of 56 years, 53% were male, 28% had received previous immunotherapy, 72% had Eastern Cooperative Oncology Group performance status of 0, 85% had the V600E mutation, 66% had stage IV M1c disease, 35% had lactate dehydrogenase (LDH) above the upper limit of normal, 73% had visceral disease (78% in combination group vs 68% in dabrafenib group), and 46% had ≥ 3 disease sites.
Improved Progression-Free Survival
Median follow-up was 9 months. Median progression-free survival was 9.3 months in the dabrafenib/trametinib group and 8.8 months in the dabrafenib group (hazard ratio [HR] = 0.75, P = .03). Subgroup analysis showed that hazard ratios favored combination treatment in all subgroups except for ≤ 2 disease sites and age ≥ 65 years. In patients with elevated LDH, median progression-free survival was 7.1 vs 3.8 months (HR = 0.64, 95% confidence interval [CI] = 0.42–0.95).
Response Rate and Overall Survival
The overall response rate was 67% in the dabrafenib/trametinib group vs 51% in the dabrafenib/placebo group (P = .002). A preplanned interim analysis showed 6-month overall survival of 93% vs 85% (HR = 0.63, P = 0.02), with median overall survival not reached in either group. However, the specified efficacy stopping boundary (P = .00028) was not crossed. In patients with elevated LDH, median overall survival was 13.7 vs 8.9 months (HR = 0.48, 95% CI = 0.29–0.80). Subsequent anticancer therapy was received by 20% vs 31% of patients, and study treatment was continued beyond progression in 19% vs 16% of patients.
Toxicity
The most common adverse events of any grade in the combination and dabrafenib groups were pyrexia (51% vs 28%), fatigue (35% vs 35%), nausea (30% vs 26%), headache (30% vs 29%), chills (30% vs 16%), diarrhea (24% vs 14%), arthralgia (24% vs 27%), rash (23% vs 22%), and hypertension (22% vs 14%). Grade 3 adverse events occurred in 32% vs 34% of patients, with the most common being pyrexia (6% vs 2%) and hypertension (4% vs 5%). Incident cutaneous squamous cell carcinoma occurred in 2% vs 9% and cutaneous hyperkeratoses occurred in 3% vs 32%.
Adverse events led to dose reduction in 25% vs 13%, interruption in 49% vs 33%, and discontinuation in 9% vs 5% of patients. Pyrexia was the most common reason for dose reduction (13% vs 3%) and interruption (32% vs 13%). The most common reason for discontinuation was pyrexia in the combination group (2%) and decreased ejection fraction in the dabrafenib group (1%).
The investigators concluded: “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.”
The study was funded by GlaxoSmithKline.
The corresponding author for the New England Journal of Medicine article is Georgina V. Long, BSc, PhD, MBBS, FRACP, of Melanoma Institute Australia, University of Sydney.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
