COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma

Abstract

Background: Surgery is curative for most patients (pts) with localized melanoma; however, those with regional nodal involvement (stage III disease) are at a higher risk for relapse and death after resection. In phase 3 trials of advanced or metastatic BRAF V600‐mutant melanoma, D+T combination therapy improved clinical outcomes and was well tolerated. Methods: In this randomized, double‐blind, placebo‐controlled, phase 3 study (COMBI‐AD [NCT01682083]), pts with high‐risk, stage III, BRAF V600E/K‐mutant melanoma without prior anticancer therapy were randomized 1:1 within 12 weeks of complete surgical resection to receive D 150 mg twice daily plus T 2 mg once daily or matching placebos. Pts were treated for 12 months and stratified based on BRAFmutation (V600E vs V600K) and stage (IIIA vs IIIB vs IIIC). The primary endpoint was relapse‐free survival (RFS). Secondary endpoints included overall survival (OS), distant metastasis‐free survival (DMFS), freedom from relapse (FFR), and safety. Results: A total of 870 pts (stage IIIA, 18%; IIIB, 41%; IIIC, 40%; unknown, 1%) were randomized (D+T, n=438; placebo, n=432). The primary endpoint was met. At the time of the data cutoff for the primary analysis (June 30, 2017; median follow‐up, 2.8 years), D+T significantly reduced the risk of disease recurrence or death by 53% vs placebo (HR, 0.47 [95% CI, 0.39‐0.58]; median not reached vs 16.6 months, respectively; P<0.001). RFS benefit with D+T was observed across all patient subgroups. D+T also improved secondary endpoints of OS (HR, 0.57 [95% CI, 0.42‐0.79]), DMFS (HR, 0.51 [95% CI, 0.40‐0.65]), and FFR (HR, 0.47 [95% CI, 0.39‐0.57]). With D+T, 97% of pts had an adverse event (AE), 41% had grade 3/4 AEs, and 26% had AEs leading to treatment discontinuation (vs 88%, 14%, and 3%, respectively, with placebo). Conclusions: Combination D+T adjuvant therapy was associated with improvements in RFS, OS, DMFS, and FFR, and manageable safety in pts with high‐risk, resected, stage III, BRAF V600E/K‐mutant melanoma. This regimen represents a new adjuvant treatment option in this setting.