In a study reported in the Journal of Clinical Oncology, Menzer et al found that combined BRAF/MEK inhibitor therapy appeared to be more active than single-inhibitor therapy in advanced melanoma with rare BRAF mutations.
Study Details
The study involved data from 103 patients with advanced melanoma with rare, activating non–V600E/K BRAF mutations treated with a BRAF inhibitor, MEK inhibitor, or both. Overall, 58 patients (56%) had non-E/K V600 mutations, 38 (37%) had non-V600 mutations, and 7 (7%) both V600E and a rare BRAF mutation.
The most common mutations were V600R (43%), L597P/Q/R/S (15%), and K601E (11%). In total, 58% of patients received combined BRAF/MEK inhibitor therapy, 37% received BRAF inhibitor monotherapy, and 5% received MEK inhibitor monotherapy.
Treatment Outcomes
Among the 58 patients with V600 mutations, overall response was observed in 6 (27%) of 22 patients treated with BRAF inhibitor monotherapy and in 20 (56%) of 36 patients treated with BRAF/MEK inhibitor combination therapy. On multivariate analysis, median progression-free survival was 3.7 months and 8.0 months (P = .002) and median overall survival was 7.3 months and 17.3 months (P < .001), respectively.
KEY POINTS
- BRAF and MEK inhibition produced responses in patients with rare BRAF mutations.
- Combined BRAF/MEK inhibitor therapy appeared to be the most effective treatment.
Among 38 patients with non-V600 mutations, overall response was observed in 0 (0%) of 15 patients treated with BRAF inhibitor monotherapy, 2 (40%) of 5 patients treated with MEK inhibitor monotherapy, and 5 (28%) of 18 patients treated with BRAF/MEK inhibitor combination therapy. On multivariate analysis, median progression-free survival was 1.8 months, 3.7 months, and 3.3 months (P = .02 for combination vs BRAF inhibitor; P = .047 for combination vs MEK inhibitor), respectively, and median overall survival was 7.6 months, 5.9 months, and 11.3 months (P = .014 for combination vs BRAF inhibitor; P = .07 for combination vs MEK inhibitor), respectively.
Among the seven patients with both V600E and a rare BRAF mutation, objective response was not observed in the one patient treated with BRAF inhibitor monotherapy, but was observed in three of the six patients treated with BRAF/MEK inhibitor combination therapy.
The investigators concluded: “Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E-mutated melanoma. Combination BRAF [inhibitor]/MEK [inhibitor] seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care, because of the heterogeneity of patients with small sample sizes for some of the reported mutations.”
Jessica C. Hassel, MD, of the Department of Dermatology and National Center for Tumor Diseases, Heidelberg University Hospital, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.
