Dabrafenib/Trametinib Combination Receives CHMP Recommendation for the Adjuvant Treatment of BRAF V600 Mutation–Positive Melanoma
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of dabrafenib (Tafinlar) in combination with trametinib (Mekinist) for the adjuvant treatment of adult patients with stage III melanoma with a BRAF V600 mutation, following complete resection. The CHMP recommendation is based on findings from the COMBI-AD study, which were published by Long et al in The New England Journal of Medicine.
Patients who have been diagnosed with stage III melanoma are at a higher risk of recurrence after surgical resection. The COMBI-AD study found a statistically significant 53% reduction in the risk of recurrence or death in patients treated with the BRAF and MEK inhibitor combination therapy after surgical resection vs placebo.
"These relapse-free survival results are unprecedented," said lead investigator Axel Hauschild, MD, PhD, Professor of Dermatology at University Hospital Schleswig-Holstein, in Kiel, Germany. "The overall survival improvements also demonstrated by dabrafenib in combination with trametinib, among other key secondary endpoints, are encouraging in the treatment of stage III BRAF V600E/K mutation–positive melanoma. Adjuvant treatment options are critical for this patient community at risk for recurrence.”
About the COMBI-AD Study
The COMBI-AD study evaluated dabrafenib plus trametinib among patients with stage III BRAF V600E/K–mutant melanoma without prior anticancer therapy, randomized within 12 weeks of complete surgical resection. Patients received the dabrafenib (150 mg twice a day) and trametinib (2 mg once a day) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint was met in that combination therapy significantly reduced the risk of disease recurrence or death by 53% vs. placebo (hazard ratio [HR] = 0.47; 95% confidence interval [CI] = 0.39–0.58; median not yet reached vs 16.6 months, respectively; P < .001). The relapse-free survival (RFS) benefit among the combination arm was observed across all patient subgroups, including stage IIIA, B and C. The estimated 1-year, 2-year, and 3-year RFS were consistently higher than placebo (1-year, 88% vs 56%; 2-year, 67% vs 44%; 3-year, 58% vs 39%). The combination treatment group also saw an improvement in a key secondary endpoint of OS (HR = 0.57; 95% CI = 0.42–0.79; P = .0006, which did not cross the predefined interim analysis boundary of P = .000019 to claim statistical significance). Other secondary endpoints where the combination demonstrated a clinically meaningful benefit include distant metastasis-free survival (HR = 0.51; 95% CI = 0.40–0.65), and freedom from relapse (HR = 0.47; 95% CI = 0.39–0.57).
Adverse events were consistent with other dabrafenib plus trametinib combination studies, and no new safety signals were reported. Of patients treated with the combination, the most frequently reported adverse events were pyrexia, fatigue, nausea, headache, chills, diarrhea, vomiting, arthralgia, and rash.
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