BRAF Inhibitor Vemurafenib Plus MEK inhibitor Cobimetinib vs Vemurafenib Alone in Previously Untreated BRAF-Mutant Advanced Melanoma
In a phase III trial reported in The New England Journal of Medicine, Larkin and colleagues found that the combination of the BRAF inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib improved response rate and progression-free survival compared with vemurafenib 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 135 centers worldwide, 495 patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E or V600K mutation were randomly assigned between January 2013 and January 2014 to receive vemurafenib at 960 mg twice daily plus cobimetinib at 60 mg once daily for 21 of 28 days (n = 247) or vemurafenib plus placebo (n = 248). The primary endpoint was progression-free survival in the intent-to-treat population.
For the combination vs vemurafenib patients, median age was 56 vs 55 years, 59% vs 56% were male, 92% vs 95% were white, 76% vs 67% had Eastern Cooperative Oncology Group performance status of 0, 59% vs 62% had metastatic status of M1c, and 46% vs 43% had elevated lactate dehydrogenase. BRAF mutation status was V600E in 69% vs 70%, V600K in 10% vs 13%, and could not be evaluated in 21% vs 17%.
Improved Progression-Free Survival
Median follow-up was 7.3 months. Median progression-free survival was 9.9 months in the combination group vs 6.2 months in the vemurafenib group (hazard ratio [HR] = 0.51, P < .001). Subgroup analysis showed that hazard ratios favored combination treatment in all subgroups.
Response Rate and Overall Survival
The overall response rate was 68% in the combination group vs 45% in the vemurafenib group (P < .001). A preplanned interim analysis showed 9-month overall survival of 81% vs 73% (HR = 0.65, P = .046), with median overall survival not being reached in either group. However, the specified efficacy stopping boundary (HR = 0.65, boundary P < .0000037) was not crossed.
Toxicity
The most common adverse events of any grade in the combination group were diarrhea (46% vs 28%), nausea (40% vs 24%), rash (39% vs 35%), fatigue (32% vs 31%), and arthralgia (32% vs 40%). Grade 3 or 4 adverse events occurred in 65% vs 59%; the most common were increased creatine kinase (11%, including grade 4 in 4%, vs 0%), increased alanine transaminase (11% vs 6%), increased aspartate transaminase (8% vs 2%), diarrhea (6% vs 0%), and rash (6% vs 5%). Grade 3 incident cutaneous squamous cell carcinoma occurred in 2% vs 11% and grade 3 keratoacanthoma occurred in 1% vs 8%. Adverse events led to treatment discontinuation in 13% vs 12% of patients.
The investigators concluded: “The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity.”
The study was funded by F. Hoffmann–La Roche/Genentech.
James Larkin, MD, PhD, of Royal Marsden Hospital, and Paolo A. Ascierto, MD, of Istituto Nazionale Tumori Fondazione G. Pascale, contributed equally to the New England Journal of Medicine article.
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