Adjuvant Vemurafenib in Resected BRAF V600–Mutant Melanoma
In the international phase III BRIM8 trial reported in The Lancet Oncology, Maio et al found inconclusive evidence of benefit of adjuvant vemurafenib treatment in patients with BRAF V600–mutant melanoma.
Study Details
In the double-blind trial, 498 patients with fully resected stage IIC, IIIA, or IIIB (cohort 1, n = 314) or stage IIIC disease (cohort 2, n = 184) from 124 sites in North and South America, Australia, Europe, and South Africa were randomized to receive twice-daily adjuvant oral vemurafenib (Zelboraf) at 960 mg (n = 157 in cohort 1, n = 93 in cohort 2) or placebo (n = 157 in cohort 1, n = 91 in cohort 2) for 52 weeks. Randomization was stratified by pathologic stage and region in cohort 1 and by region in cohort 2.
The primary endpoint was disease-free survival in the intention-to-treat population evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified.
Disease-Free Survival
At data cutoff in April 2017, median follow-up was 33.5 months in cohort 2 and 30.8 months in cohort 1. In cohort 2 (stage IIIC disease), median disease-free survival was 23.1 months in the vemurafenib group vs 15.4 months in the placebo group (hazard ratio [HR] = 0.80, P = .26). In cohort 1 (stage IIC, IIIA, and IIIB disease), median disease-free survival was not reached vs 36.9 months (HR = 0.54, P = .0010); the result could not be considered statistically significant due to the prespecified hierarchical analysis.
Adverse Events
Grade 3 or 4 adverse events occurred in 57% of patients receiving vemurafenib and 15% of those receiving placebo, with the most common in vemurafenib patients being keratoacanthoma (10%), arthralgia (7%), squamous cell carcinoma (7%), rash (6%), and elevated alanine transaminase (6%). Serious adverse events occurred in 16% vs 10%; basal cell carcinoma was reported in 3% of patients in each group.
The investigators concluded, “The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC/IIIA/IIIB BRAF V600 mutation–positive melanoma must be considered exploratory only. One year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population.”
The study was funded by F. Hoffman-La Roche Ltd.
Michele Maio, MD, of the Division of Medical Oncology and Immunotherapy, University Hospital of Siena, is the corresponding author for The Lancet Oncology article.
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