Adjuvant Dabrafenib and Trametinib in Resected Stage III BRAF-Mutated Melanoma


Key Points

  • In patients with resected stage III melanoma with BRAF V600E or V600K mutations, adjuvant dabrafenib plus trametinib improved relapse-free survival vs placebo.
  • Grade 3 or 4 adverse events were more common with active treatment.

The phase III COMBI-AD trial has shown a significant improvement in relapse-free survival with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) vs placebo as adjuvant therapy in patients with resected stage III melanoma with BRAF V600E or V600K mutations. The findings were reported by Long et al in The New England Journal of Medicine.

Study Details

In the double-blind trial, 870 patients from 169 sites in 26 countries were randomized between January 2013 and December 2014 to receive dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily (n = 438 patients) or matched placebo tablets (n = 432 patients) for 12 months. The primary endpoint was relapse-free survival.

Relapse-Free Survival

Median follow-up was 2.8 years. The 3-year rate of relapse-free survival was 58% in the combination group vs 39% in the placebo group (hazard ratio [HR] = 0.47, P < .001). Three-year overall survival was 86% vs 77% (HR = 0.57, P = 0.0006), but the difference did not cross the prespecified interim analysis boundary (P = .000019). Distant metastasis or death occurred in 25% vs 35% of patients (HR = 0.51, P < .001).

Adverse Events

The safety profile of dabrafenib plus trametinib was consistent with that observed in the setting of metastatic melanoma. Grade 3 or 4 adverse events occurred in 41% of the combination group vs 14% of the placebo group; the most common adverse events in the combination group were hypertension (6%) and pyrexia (5%). Serious adverse events occurred in 36% vs 10%. Adverse events led to discontinuation of the study drug in 26% vs 3%.

The investigators concluded: “Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects.”

The study was funded by GlaxoSmithKline and Novartis.

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