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Adjuvant Dabrafenib Plus Trametinib Associated with Better RFS and DMFS than Placebo Among Patients with Resected Stage III Melanoma with BRAF V600 Mutations

Final results of the COMBI-AD study
09 Jul 2024
Targeted Therapy;  Molecular Oncology

After nearly 10 years of follow-up in the COMBI-AD study, 12 months of adjuvant treatment with dabrafenib plus trametinib was associated with better relapse-free survival (RFS) and distant metastasis–free survival (DMFS) than placebo among patients with resected stage III melanoma. The analysis of overall survival (OS) showed that the risk of death was 20% lower with combination treatment than with placebo, but the benefit was not significant.

Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination treatment. Findings from the final analysis of the COMBI-AD study are published by Dr. Georgina V. Long of the Melanoma Institute Australia, University of Sydney in Sydney, Australia and colleagues on 19 June 2024 in The New England Journal of Medicine.  

The authors wrote in the background that the combination of the BRAF-targeted agent dabrafenib and the MEK inhibitor trametinib is a current standard adjuvant treatment for patients with BRAF V600–mutated stage III melanoma. The COMBI-AD study evaluated 12 months of dabrafenib plus trametinib, as compared with placebo, as adjuvant treatment in patients with resected stage III melanoma with BRAF V600 mutations. Previously published interim analyses of the study showed that dabrafenib plus trametinib resulted in a significantly lower risk of recurrence than placebo. The results for RFS as a primary endpoint met the criterion for significance at the prespecified cut-off date of 30 June 2017.

In a prespecified interim analysis of the COMBI-AD trial, OS at 3 years was 86% with dabrafenib plus trametinib and 77% with placebo (hazard ratio [HR] for death 0.57; 95% confidence interval [CI] 0.42 to 0.79; p = 0.0006). However, the between-group difference did not cross the prespecified interim-analysis boundary of p = 0.000019.

In the latest article, the study team reports the final results of the COMBI-AD study, including results for OS, melanoma-specific survival, RFS, DMFS, and safety after a long-term follow-up of more than 8 years. The study investigators randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily or two matched placebos.

The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan–Meier estimates for OS favoured dabrafenib plus trametinib over placebo, although the benefit was not significant (HR for death 0.80; 95% CI 0.62 to 1.01; p = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (HR for death 0.75; 95% CI 0.58 to 0.96). RFS favoured dabrafenib plus trametinib over placebo (HR for relapse or death 0.52; 95% CI 0.43 to 0.63), as did DMFS (HR for distant metastasis or death 0.56; 95% CI 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous study reports.

The final analysis of this study had more than 8 years of follow-up for an approved adjuvant treatment in patients with resected stage III melanoma. One year of adjuvant treatment with dabrafenib plus trametinib was associated with better RFS and DMFS than placebo, no long-term safety concerns, and a 20% lower risk of death than placebo (although the benefit was not significant), as well as a 25% lower risk of death among patients with melanoma with a BRAF V600E mutation. The analysis of melanoma-specific survival suggested that the risk of death from melanoma was 22% lower with combination treatment than with placebo.

Whether or how therapies administered after relapse may have reduced the effect of adjuvant treatment on OS is unclear. Owing to a slow rate of death, the required number of events had been reduced from the originally 597 planned to the current 260, although the power of the study (80% for HR for death of 0.70) was not affected.

The authors commented that other studies of effective and available drugs in adjuvant treatment for stage III melanoma have shown no survival benefit, including the KEYNOTE-054 study, which has an identical design. In addition, in the CheckMate 238 study, the Kaplan–Meier curves for OS for adjuvant nivolumab and ipilimumab overlapped at 7 years. The EORTC phase III study of adjuvant ipilimumab as compared with placebo showed an OS benefit with an absolute difference in 7-year OS of 8.7%, but the study was conducted when no effective drugs at recurrence were available and this treatment was not approved because of side effects.

Key limitations of this placebo-controlled study include the smaller number of patients at risk after approximately 100 months, the reporting of distant metastasis as a first relapse only, and the inadequate power of the subgroup analyses to determine the effect of treatment on OS. For any patients who may have had a relapse after the first subsequent anticancer therapy or after extended loss to follow-up, data were censored for the analyses of RFS and DMFS.

The study was supported by GlaxoSmithKline and Novartis.


Long GV, Hauschild A, Santinami M, et al. Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. NEJM; Published online 19 June 2024. DOI: 10.1056/NEJMoa2404139

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