COMBI-AD trial

Background

Phase III RCT of 870 patients with resected stage IIIA (>1mm nodal deposit), IIIB, or IIIC melanoma harboring BRAF V600E or V600K mutations. Evaluated adjuvant targeted therapy vs placebo.

Interventions and follow up

Arm A: Dabrafenib (BRAFi) 150mg PO BID + trametinib (MEKi) 2mg PO daily x12mo
Arm B: Placebo
Primary endpoint: RFS
Original report: PMID:28891408, median follow-up 2.8yr
Median follow-up (this update): ~5yr

Results

RFS (overall): HR 0.47, 95%CI 0.39-0.58
5-yr RFS: 52% vs 36% (combination vs placebo); HR 0.51, 95%CI 0.42-0.61
5-yr DMFS: 65% vs 54%; HR 0.55, 95%CI 0.44-0.70
OS (earlier estimate): HR 0.57, 95%CI 0.42-0.79; formal OS analysis not performed due to insufficient events

Adverse events

Grade 3-4 AEs: 36% with dabrafenib-trametinib vs 10% with placebo
Most common (combination): pyrexia (8% grade 3+), fatigue, nausea, headache; treatment discontinuation due to AEs in 26%, mostly within the first 12mo

Conclusions

Twelve months of adjuvant dabrafenib plus trametinib produced durable, sustained improvements in RFS and DMFS over placebo in resected BRAF-mutant stage III melanoma.

Key Limitations

Restricted to BRAF V600E/K mutant disease; placebo comparator rather than adjuvant immunotherapy; mature OS not formally tested; no head-to-head comparison with adjuvant anti-PD-1.

Clinical Context

FDA and EMA approved adjuvant dabrafenib plus trametinib for resected stage III BRAF V600E/K melanoma (2018). Provides a targeted-therapy adjuvant option alongside anti-PD-1. ESMO endorses adjuvant dabrafenib-trametinib for BRAF-mutant resected stage III disease.

References