AT ESMO 2017

MADRID (FRONTLINE MEDICAL NEWS) – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.

Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial , the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).

There was a numerical difference favoring the active combination in 3-year overall survival (OS) rates, but this difference did not cross the prespecified boundary for significance in the interim analysis, results of which were reported by Axel Hauschild, MD, PhD , of University Hospital Schleswig-Holstein in Kiel, Germany.

“The relapse-free survival benefits were observed across all 12 subgroups which have been evaluated, so there’s not a single subgroup that is an outlier,” he said in a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

Results of the study were published online concurrently in the New England Journal of Medicine.

In previous phase 3 trials in patients with BRAF V600 mutated metastatic or unresectable melanoma, the combination of dabrafenib and trametinib improved survival. Because treatment options for patients with resectable stage III melanomas are limited and less than optimal, the COMBI-AD investigators sought to explore whether the combination could improve outcomes when used in the adjuvant setting.

In the study reported by Dr. Hauschild, patients with completely resected, high-risk stage IIIA, IIIB, or IIIC cutaneous melanoma with the BRAF V600EK mutation who were surgically free of disease within 12 weeks of randomization were stratified by BRAF mutation status and disease stage, and then randomly assigned to receive either dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, or two matched placebos.

The RFS curves separated early in the study, and at 1 year the rate of RFS was 88% among patients treated with the combinations, compared with 56% for patients who got placebo. The respective rates at 2 and 3 years of follow-up were 67% vs. 44%, and, as noted before, 58% vs. 39%.

At this first interim analysis, the 1-year OS rate with dabrafenib/trametinib was 97% compared with 94% for placebo. Respective rates at 2 and 3 years of follow-up were 91% vs. 83%, and 86% vs. 77%, but as noted, the Kaplan-Meier survival curves appear to separate, but have yet to reach the prespecified boundary for significance.

As might be expected, the incidence of any grade 3 or 4 adverse events was higher in the combination group than in the placebo group, but there were no fatal adverse events related to assigned treatment. In all, 26% of patients assigned to dabrafenib/trametinib had to discontinue treatment due to adverse events, compared with 3% of patients assigned to placebo.

Dr. Hauschild said that the results of the COMBI-AD study and the Checkmate 238 study presented on the same day “will make a change in our textbooks and our current guidelines, because we have at least two new treatment options, and I think this is a new treatment option and a good day for our melanoma patients.”

His remarks were echoed by Olivier Michielin, MD, PhD, of the Swiss Institute of Bioinformatics in Lausanne. He said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new features for our patients.”

Dr. Michielin was invited by ESMO to comment on the study.

COMBI-AD was sponsored by GlaxoSmithKline. Dabrafenib and trametinib have been owned by Novartis AG since March, 2015. Dr. Hauschild disclosed trial support, honoraria, and/or consultancy fees from Novartis and others. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK.