Final Results from a Study of Adjuvant Therapy in Stage III Melanoma

For patients with stage III melanoma, the goal is cure, but the risk of relapse is high. Randomized, placebo-controlled studies such as COMBI-AD, initially reported in 2017 (N Engl J Med 2017; 377:1813), set the standard that has since been followed: complete surgical resection followed by adjuvant therapy to reduce the risk of recurrent disease by eliminating micrometastases. In the same decade, several studies clearly demonstrated a benefit for adjuvant treatment of resected stage III melanoma, which led to a bounty of FDA-approved options, including checkpoint-blocking antibodies (ipilimumab, nivolumab, pembrolizumab) and the targeted inhibitor combination of dabrafenib and trametinib.

Now, researchers report final results from the industry-sponsored COMBI-AD trail, in which 870 patients with resected stage III melanoma with BRAF mutations were randomized to adjuvant dabrafenib plus trametinib or placebo for 1 year. At approximately 8 years of follow-up, there was a nonsignificant trend towards better overall survival (OS) in the dabrafenib/trametinib group compared with the placebo group (71% vs. 65%; hazard ratio for death, 0.80; P=0.06). A predefined subset analysis of patients with the most common mutation (V600E) suggested a 25% OS benefit with dabrafenib/trametinib. In contrast, in patients with the less common V600K mutation, OS appeared to be inferior in those treated with dabrafenib/trametinib compared with placebo (HR, 1.95). Relapse-free survival and distant metastases–free survival favored dabrafenib/trametinib (HRs, 0.52 and 0.56, respectively).