Extended Follow-up in BRIM-3 Shows Prolonged Survival With Vemurafenib in BRAF V600E/K Mutation–Positive Melanoma

Key Points

  • Vemurafenib was associated with significantly prolonged overall and progression-free survival compared with dacarbazine.
  • Survival benefit with vemurafenib occurred in both the BRAF V600E and BRAF V600K mutation subgroups.

In the BRIM-3 trial, vemurafenib (Zelboraf) was associated with improved progression-free and overall survival vs dacarbazine in patients with advanced BRAF V600 mutation–positive melanoma. In an extended follow-up reported in The Lancet Oncology, McArthur et al found that superior survival outcomes were maintained and were present in both the BRAF V600E and BRAF V600K mutation subgroups.

Study Details

In this open-label trial, 675 patients with treatment-naive BRAF V600 mutation–positive metastatic melanoma from 104 centers in 12 countries were randomly assigned between January and December 2010 to receive vemurafenib at 960 mg orally twice daily (n = 337) or intravenous dacarbazine at 1,000 mg/m² every 3 weeks (n = 338). Patients had to have a life expectancy of ≥ 3 months and Eastern Cooperative Oncology Group performance status of 0 or 1. The coprimary endpoints were overall survival and progression-free survival in the intention-to-treat population, with data censored at crossover.  

Median follow-up was 12.5 months on vemurafenib and 9.5 months on dacarbazine. Overall, 44% of the dacarbazine group received subsequent anticancer treatment, including 25% who crossed over to vemurafenib treatment, 22% who received ipilimumab (Yervoy), and 1% who received dabrafenib (Tafinlar). Approximately 36% of vemurafenib-treated patients received subsequent therapy, including ipilimumab in 18%.

Improved Survival Overall and in Subgroups

Both median overall survival (13.6 vs 9.7 months, hazard ratio [HR] = 0.70, P = .0008) and progression-free survival (6.9 vs 1.6 months, HR = 0.38, P < .0001) were significantly longer in the vemurafenib group. Both overall survival (13.3 vs 10.0 months, HR = 0.75, P = .0085) and progression-free survival (6.9 vs 1.6 months, HR = 0.39, P < .0001) were significantly prolonged with vemurafenib among the 598 patients (91% of total population) with BRAF V600E mutations. Both overall survival (14.5 vs 7.6 months, HR = 0.43, P = .024) and progression-free survival (5.9 vs 1.7 months, HR = 0.30, P < .0001) were also significantly prolonged with vemurafenib among the 57 patients with BRAF V600K mutations.

The most frequent grade 3 or 4 events were cutaneous squamous cell carcinoma (19%), abnormal liver function tests (11%), keratoacanthomas (10%), and rash (9%) in the vemurafenib group and neutropenia (9%) in the dacarbazine group. Grade 4 or worse adverse events occurred in 8% of patients in the vemurafenib group and 11% of patients in the dacarbazine group, and grade 5 adverse events occurred in 2% of patients in each group. New primary melanomas occurred in eight patients in the vemurafenib group (2%). Treatment was discontinued due to adverse events in 7% of the vemurafenib group and 2% of the dacarbazine group.

The investigators concluded, “Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF V600E mutation and in patients with the less common BRAF V600K mutation.”

Grant A. McArthur, MBBS, of the Peter MacCallum Cancer Centre, East Melbourne, Australia, is the corresponding author for The Lancet Oncology article.

The study was funded by F Hoffmann-La Roche-Genentech. For full disclosures of the study authors, visit www.thelancet.com.

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®.