As reported in The New England Journal of Medicine by Reinhard Dummer, MD, and colleagues, 5-year follow-up of the phase III COMBI-AD trial has shown continued relapse-free survival benefit with adjuvant dabrafenib/trametinib vs placebo in patients with stage III melanoma and BRAF V600E or V600K mutations.

The previously reported primary analysis showed significantly longer relapse-free survival with 12 months of treatment with the combination and supported the April 2018 U.S. Food and Drug Administration approval of dabrafenib/trametinib in this setting.

Reinhard Dummer, MD

Study Details

In the double-blind trial, 870 patients were randomly assigned to receive 12 months of oral dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily (n = 438) or two matched placebos (n = 432). The primary endpoint was relapse-free survival.

Five-Year Outcomes

The minimum duration of follow-up was 59 months, including median follow-up of 60 months in the dabrafenib/trametinib group and 58 months in the placebo group. Overall, 40% of patients in the combination therapy group and 54% of those in the placebo group received subsequent therapy, with the most common being immunotherapy in the combination group (26%) and small-molecule targeted therapy in the placebo group (35%).

At 5 years, relapse-free survival was 52% (95% confidence interval [CI] = 48%–58%) in the dabrafenib/trametinib group vs 36% (95% CI = 32%–41%) in the placebo group (hazard ratio [HR] = 0.51, 95% CI = 0.42–0.61). Hazard ratios favored dabrafenib/trametinib across all patient subgroups that were evaluated. Relapse-free survival at 5 years was 65% vs 58% (HR = 0.61, 95% CI= 0.35–1.07) among patients with stage IIIA disease, 55% vs 34% (HR = 0.50, 95% CI = 0.37–0.67) among those with stage IIIB disease, and 45% vs 29% (HR = 0.48, 95% CI = 0.36–0.64) among those with stage IIIC disease.

Among patients with relapse, first relapse at a distant site was more common than locoregional relapse in both groups. At 5 years, distant metastasis-free survival was 65% vs 54% (HR = 0.55, 95% CI = 0.44–0.70).

At current data cutoff, a total of 216 deaths had been reported in the two groups, with the number of events for final overall analysis (approximately 299) not being reached. Thus, no overall survival analysis was performed at the time of the current analysis. In a previously reported preplanned interim analysis (performed when 26% of planned events had occurred), 3-year overall survival was 86% in the combination group vs 77% in the placebo group; the hazard ratio was 0.57, with the P value of .0006 not reaching the prespecified significance threshold of P = .000019.

Adverse Events

The last study patient received the last dose of dabrafenib/trametinib or placebo in December 2015. During the follow-up period, there have been no clinically meaningful differences between groups in the incidence or severity of serious adverse events.

The investigators concluded, “In the 5-year follow-up of a phase III trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects.”

Disclosure: The study was funded by GlaxoSmithKline and Novartis. For full disclosures of the study authors, visit nejm.org.