Vemurafenib had a significant survival benefit compared with dacarbazine in adults with treatment-naive, BRAFV600E and BRAFV600K mutation–positive metastatic melanoma, investigators reported in the March issue of Lancet Oncology.
In the phase III trial, 675 patients with BRAFV600 mutations were randomized to receive BRAF inhibitor vemurafenib (960 mg orally b.i.d.) or dacarbazine (1,000 mg/m2 IV every 3 weeks). The median overall survival was 13.6 months among 337 patients randomized to receive vemurafenib, compared with 9.7 months for the 338 patients randomized to receive dacarbazine (hazard ratio, 0.70; 95% confidence interval, 0.57-0.87, P = .0008), reported Dr. Grant McArthur of Peter MacCallum Cancer Centre, East Melbourne, Australia, and his associates.
Researchers followed vemurafenib and dacarbazine patients for a median of 12.5 and 9.5 months, respectively. One-quarter of dacarbazine patients later crossed over to vemurafenib (Lancet Oncol. 2014;15:323-32).
Median progression-free survival times also favored vemurafenib (6.9 months vs. 1.6 months for dacarbazine; HR for vemurafenib, 0.38; 95% CI, 0.32-0.46, P less than .0001). Among those patients available for follow-up at 18 months, after crossover had occurred, the difference in overall survival was insignificant (39% for vemurafenib vs. 34% for dacarbazine), the investigators reported.
Although BRAFV600E is the most common mutation in patients with metastatic melanoma, a substantial proportion of patients carry the BRAFV600K mutation (8.6% in the current study), and data suggest that these patients might be at increased risk for brain and lung metastases and might have a shorter time from diagnosis to metastasis and death than patients with a BRAFVV600E mutation, the investigators said.
Benefit from vemurafenib was found for both types of BRAF mutations. For the 598 patients with BRAFV600E disease (91%), the median overall survival in the vemurafenib group was 13.3 months compared with 10.0 months in the dacarbazine group (HR, 0.75; 95% CI, 0.60-0.93, P = .0085). For the 57 patients with BRAFV600K disease (9%), the median overall survival in the vemurafenib group was 14.5 months (95% CI, 11.2 to not estimable) compared with 7.6 months in the dacarbazine group (HR, 0.43; 95% CI, 0.21-0.90, P = .024), the investigators reported.
Grade 3-4 events included cutaneous squamous cell carcinoma (19%), keratoacanthomas (10%), rash (9%), and abnormal liver function tests (11%) in the vemurafenib group, and neutropenia (9%) in the dacarbazine group. Eight patients (2%) in the vemurafenib group developed new primary melanomas. The death rate due to adverse events was 2% in each group.
F Hoffman/La Roche/Genentech funded the trial. Dr. McArthur reported providing uncompensated services to Roche/Genentech. Sixteen of his associates reported receiving support from or serving as consultants or advisers to Roche, Roche/Genentech, or Genentech. Three other associates are employees of Roche/Genentech, Roche Molecular Systems, or F Hoffman/La Roche.