On April 30, 2018, the U.S. Food and Drug Administration (FDA) approved dabrafenib (Tafinlar) in combination with trametinib (Mekinist) for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and lymph node involvement following complete resection. The combination received Breakthrough Therapy designation for this indication in October 2017 and Priority Review in December 2017.
Approval of the combination in the adjuvant setting was based on results from the randomized, double-blind phase III -COMBI-AD study of 870 patients with stage III BRAF V600E/600K mutation–positive melanoma treated with -dabrafenib/trametinib after complete surgical resection.1 Patients received dabrafenib at a dose of 150 mg twice daily plus trametinib, 2 mg, once a day (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival was met.
Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53% as compared to placebo (hazard ratio = 0.47, 95% confidence interval = 0.39–0.58, P < .0001; median not reached with combination therapy vs 16.6 months with placebo). The relapse-free survival benefit among the combination arm was observed across all patient subgroups, including disease substage. Improvements were also observed in key secondary endpoints including overall survival, distant metastasis–free survival, and freedom from relapse.
“Adjuvant therapy options are crucial today because more than half of patients [with BRAF-mutated melanoma] have a recurrence after surgery,” said John M. Kirkwood, MD, Usher Professor of Medicine, Director of Melanoma and Skin Cancer, University of Pittsburgh, and one of the study coauthors. “We now have the first effective oral targeted therapy combination that prevents relapse among patients with BRAF-mutated melanoma that has spread to lymph nodes.”
Adverse events were consistent with other studies of the combination, and no new safety signals were reported. Of patients treated with the combination, 97% experienced an adverse event, 41% had grade 3/4 adverse event, and 26% had adverse events leading to treatment discontinuation, vs 88%, 14%, and 3%, respectively, with placebo.
In the United States, dabrafenib in combination with trametinib is approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and for the adjuvant treatment of melanoma with BRAF V600E or V600K mutations and lymph node involvement following complete resection. The combination is also approved for BRAF V600E–mutant non–small cell lung cancer. ■
1. Long GV, Hauschild A, Santinami M, et al: Adjuvant dabrafenib plus trametinib for stage III BRAF V600E/K–mutant melanoma. N Engl J Med 377:1813-1823, 2017.