Dabrafenib plus Trametinib Achieves Overall and Intracranial Responses

Treatment with the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib has clinical activity in patients with BRAF-mutant metastatic melanoma, but has not yet been evaluated in patients with brain metastases. In an open-label phase II trial, Davies, Saiag, and colleagues evaluated the safety and efficacy of dabrafenib plus trametinib in four cohorts of patients with BRAF^V600-mutant melanoma brain metastases. Cohort A was comprised of 76 patients with BRAF^V600E-positive, asymptomatic melanoma brain metastases with no prior local brain therapy. Additional exploratory cohorts included patients with BRAF^V600E-positive, asymptomatic melanoma brain metastases with previous local brain therapy (Cohort B, 16 patients); BRAF^V600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy (cohort C, 16 patients); and BRAF^V600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy (Cohort D, 17 patients). The primary endpoint was intracranial response in cohort A. Secondary endpoints included intracranial responses in cohorts B, C, and D, overall responses, and progression-free survival. Intracranial responses were achieved in 44 of 76 (58%) patients in cohort A, including 3 complete and 41 partial responses, 9 of 16 (56%) patients in cohort B, 7 of 16 (44%) patients in cohort C, and 10 of 17 (59%) patients in cohort D. Overall responses were observed in 58% of patients in cohort A, 56% of patients in cohort B, 44% of patients in cohort C, and 65% of patients in cohort D. Median progression-free survival was 5.6 months in cohort A, 7.2 months in cohort B, 4.2 months in cohort C, and 5.5 months in cohort D. Dabrafenib plus trametinib had a manageable safety profile and no unexpected toxicities. Collectively, these findings demonstrate that dabrafenib plus trametinib is safe and tolerable and achieves intracranial and overall responses in patients with BRAF-mutant melanoma with brain metastases, supporting further clinical and translational investigation.

Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAF^V600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017 Jun 2 [Epub ahead of print].