The median follow-up duration was 8.33 years for targeted therapy and 6.87 years for placebo. The estimated overall survival was 71% versus 65%, favoring dabrafenib plus trametinib over placebo.
A survival benefit was seen in several prespecified subgroups, including 792 patients with melanoma with the BRAF V600E mutation (hazard ratio for death, 0.75), but not for patients with the BRAF V600K mutation who did not benefit. Disease-free survival was longer with dabrafenib plus trametinib compared with placebo (hazard ratio for relapse or death, 0.52), as was distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56). No new safety signals were reported, which is consistent with previous test reports.
Conclusions
After nearly 10 years of follow-up, adjuvant dabrafenib plus trametinib was associated with better disease-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. An analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant.
Commentary on the research results of Prof. Dr. Alexander S. J. van Accooey
The final results of the COMBI-AD trial by Long et al are a key piece of the puzzle in the field of adjuvant melanoma therapy. This study analysis was performed after a median follow-up of 8.33 years. Analysis of overall survival showed a trend toward benefit from adjuvant therapy with dabrafenib and trametinib, but this did not reach statistical significance, and patients with the BRAF V600K mutation did not benefit from this therapy.
In practice, adjuvant anti-PD-1 therapies with nivolumab or pembrolizumab are alternative options. There have been no direct comparisons of targeted therapy with immunotherapy in the adjuvant setting, but cross-sectional comparisons (with caveats) indicate similar efficacy among the different treatments. Importantly, none of the adjuvant immunotherapy trials have demonstrated an overall survival benefit (yet), but final analyzes from these trials are still awaited.
In conclusion, adjuvant targeted therapy with dabrafenib and trametinib for patients with stage III melanoma with the BRAF V600E mutation should continue to be considered as a possible option when considering adjuvant therapy.
Long-term results of adjuvant therapy with dabrafenib and trametinib in stage III melanoma. COMBI-AD study
This study presents the final analysis of a phase III trial that evaluated the use of 12 months of adjuvant dabrafenib plus trametinib in patients with stage III BRAF V600-mutated melanoma after more than 8 years of follow-up.
At baseline, the authors randomized 870 patients with resected stage III melanoma with BRAF V600E/K mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or placebo.
This publication reports the final results of this study, including results for overall survival, melanoma-related survival, recurrence-free survival, and distant metastasis-free survival.