Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma

Adults with high-risk stage III cutaneous melanoma (IIIA with lymph node metastasis larger than 1 mm, IIIB or IIIC per AJCC 7th edition) with a BRAF V600E or V600K mutation (confirmed by the central laboratory), rendered disease-free by complete surgery (including complete lymph node dissection) no more than 12 weeks before randomisation; ECOG 0 or 1; no previous anticancer therapy (including radiotherapy). Mucosal or ocular melanoma, unresectable in-transit metastases and distant metastases were excluded (ClinicalTrials.gov NCT01682083).

Primary endpoint: relapse-free survival. In this report: 5-year relapse-free survival and distant metastasis-free survival. Overall survival was not analysed because the required number of events had not yet been reached.

During follow-up, no clinically meaningful difference in the incidence or severity of serious adverse events was reported between the two groups, and no apparent late toxic effects were seen. Common adverse events during treatment (fever, fatigue, nausea) are given in the primary report (Long et al., N Engl J Med 2017). According to the FDA label, the most common adverse events in COMBI-AD (20% or more) were pyrexia, fatigue, nausea, headache, rash, chills, diarrhoea, vomiting, arthralgia and myalgia; adverse events led to discontinuation of trametinib in 24%, interruption in 54% and dose reduction in 23% of patients (most common cause: pyrexia).

COMBI-AD made dabrafenib–trametinib a standard adjuvant option for BRAF V600-mutated stage III melanoma (FDA approval in 2018). In the final analysis with about 10 years of follow-up (2024), the 20% reduction in the risk of death was not statistically significant, but a survival benefit was seen with the V600E mutation; for this reason the ESMO 2025 guideline recommends adjuvant targeted therapy only for the V600E mutation [I, A] and does not recommend it for the V600K mutation because of a possible detrimental effect on overall survival [II, D]. The choice between it and adjuvant anti-PD-1 depends on patient preference and the toxicity profile; in macroscopic resectable disease, a neoadjuvant immunotherapy approach is preferred.

Overall survival data are not available in this report; there is no direct comparison with adjuvant anti-PD-1; staging was by AJCC 7th edition and all patients had undergone complete lymph node dissection.