Combined dabrafenib plus trametinib as an adjuvant treatment for patients with high-risk BRAF V600-mutated melanoma after surgical resection significantly decreased the risk of death or recurrent disease, according to findings from the phase III COMBI-AD study presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Axel Hauschild, University Hospital Schleswig-Holstein, Kiel, Germany and colleagues conducted this trial to develop an adjuvant regimen for patients with melanoma and regional nodal involvement (stage III disease), who are still at a high risk for relapse and death after a complete lymphadenectomy.
The randomised double-blind, placebo-controlled, phase III COMBI-AD trial (NCT01682083) investigated dabrafenib plus trametinib as an adjuvant treatment for patients with high-risk stage III BRAF V600E/K-mutated melanoma following complete surgical resection. The trial stratified 870 patients according to BRAF mutation (V600E versus V600K) and stage (IIIA versus IIIB versus IIIC); 18% of patients were stage IIIA, 41% IIIB, 40% were IIIC, and 1% of patients had unknown stage disease.
In this study, 438 patients were randomised to receive dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily, and 432 patients to receive matching placebo for 12 months. The primary endpoint was relapse-free survival (RFS), with secondary endpoints of overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety.
The primary endpoint of relapse-free survival was met
After a median follow up of 2.8 years, the risk of disease recurrence or death was reduced by adjuvant dabrafenib plus trametinib by 53% compared to placebo, hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.39, 0.58.
The median RFS was not reached versus 16.6 months, respectively, with dabrafenib plus trametinib versus placebo (p < 0.001). This RFS benefit was consistent across all patient subgroups.
Secondary endpoint also showed a benefit; the hazard ratio for OS was 0.57 in favour of the combination (95% CI, 0.42, 0.79), for DMFS the HR was 0.51 (95% CI 0.40, 0.65), and FFR was HR 0.47 (95% CI 0.39, 0.57).
Forty-one percent of patients had grade 3/4 adverse events (AEs) in the combination arm compared to 14% of patients on placebo. Additionally, 26% of patients in the dabrafenib plus trametinib arm discontinued the trial due to an AE compared to 3% of patients in the placebo arm. The type and severity of treatment-related AEs did not differ from already known toxicities observed in randomised trials for advanced unresectable metastatic melanoma leading to the approval for this stage of melanoma in 2015.
In COMBI-AD, adjuvant therapy with dabrafenib and trametinib was associated with improvements in RFS, OS, DMFS, and FFR, and demonstrated manageable safety in patients with high-risk, resected, stage III, BRAF V600E/K–mutated melanoma.
The authors concluded that a combined dabrafenib and trametinib regimen represents a new adjuvant treatment option in this setting.
Alexander Eggermont of the Gustave Roussy Cancer Campus, Villejuif, France who discussed the study results said that dabrafenib/trametinib is convenient oral adjuvant treatment for resected BRAF-mutant melanoma.
This trial was sponsored by Novartis.
LBA6_PR – Hauschild A, et al. COMBI-AD: Adjuvant Dabrafenib (D) Plus Trametinib (T) for Resected Stage III BRAF V600E/K–Mutant Melanoma.