The US Food and Drug Administration (FDA) granted approval to the combination of dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) for the adjuvant treatment of melanoma. Specifically, the combination is approved for patients with a BRAF V600E or V600K mutation and involvement in the lymph nodes, after complete resection of the tumor.
“Since the initial approval of Tafinlar and Mekinist in metastatic melanoma in 2013, the combination has become an important therapy for many patients carrying a BRAF mutation in both melanoma and lung cancers,” said Liz Barrett, the CEO of Novartis Oncology, in a press release. “Today’s FDA approval is an important milestone for patients who previously had limited treatment options in the adjuvant setting.”
The FDA previously granted both Breakthrough Therapy Designation and Priority Review to the combination of dabrafenib and trametinib. The approval is based on results of the COMBI-AD trial, a phase III study that included 870 patients with stage III melanoma and a BRAF mutation, as well as lymph node involvement.
In the study, patients were randomized to receive either dabrafenib plus trametinib for up to 1 year, or placebo. After a follow-up period of 2.8 years, the median relapse-free survival was not reached for those receiving the combination therapy, compared with 16.6 months in the placebo group. Thirty-eight percent of combination therapy patients experienced recurrence or death, compared with 57% of placebo patients, for a hazard ratio of 0.47 (95% CI, 0.39–0.58; P < .0001).
When results of the COMBI-AD trial were presented at the 2017 European Society for Medical Oncology (ESMO) Congress in Madrid in September, study author Axel Hauschild, MD, of the University of Kiel in Germany, called the results “practice-changing.”
There was also an improvement in overall survival, with a 3-year rate of 86% with dabrafenib/trametinib compared with 77% for placebo, but this did not meet a prespecified statistical boundary for significance.
The most common adverse events seen with the combination included pyrexia, fatigue, nausea, and others. Twenty-five percent of patients receiving the combination regimen had an adverse event resulting in discontinuation of dabrafenib; 35% required a dose reduction, and 66% required a dose interruption. For trametinib, those rates were 24%, 23%, and 54%, respectively.
The dabrafenib/trametinib combination is also being studied in the neoadjuvant setting, with positive results seen earlier this year in a phase II trial.