Background
Phase III double-blind RCT of 423 patients with unresectable stage IIIC/IV BRAF V600E/K-mutant melanoma. 5-year follow-up of COMBI-d testing BRAF plus MEK inhibition versus BRAF inhibitor alone.
Interventions and follow up
Arm A: dabrafenib 150mg BID + trametinib 2mg daily
Arm B: dabrafenib 150mg BID + placebo
Primary endpoint: PFS
Median follow up: long-term (3- to 5-year landmark analysis)
Arm B: dabrafenib 150mg BID + placebo
Primary endpoint: PFS
Median follow up: long-term (3- to 5-year landmark analysis)
Results
3-yr PFS: 22% vs 12% (A vs B); HR 0.71, 95%CI 0.57-0.88
3-yr OS: 44% vs 32%; HR 0.75, 95%CI 0.58-0.96
ORR: higher with combination
Best outcomes: normal LDH and <3 organ sites of disease
3-yr OS: 44% vs 32%; HR 0.75, 95%CI 0.58-0.96
ORR: higher with combination
Best outcomes: normal LDH and <3 organ sites of disease
Adverse events
More with combination (A vs B): pyrexia (59% vs 33%), chills (32% vs 17%), diarrhea (31% vs 17%), vomiting (26% vs 15%), peripheral edema (22% vs 9%)
More with monotherapy (A vs B): hyperkeratosis (7% vs 35%), alopecia (9% vs 28%), skin papilloma (2% vs 22%)
More with monotherapy (A vs B): hyperkeratosis (7% vs 35%), alopecia (9% vs 28%), skin papilloma (2% vs 22%)
Conclusions
Dabrafenib plus trametinib improved long-term PFS and OS over dabrafenib alone, confirming that combined BRAF and MEK inhibition is superior to BRAF inhibitor monotherapy in BRAF V600-mutant melanoma.
Key Limitations
Restricted to BRAF V600E/K disease; no comparison against immunotherapy or BRAF/MEK plus checkpoint inhibitor combinations; eventual acquired resistance limits durability.
Clinical Context
Supports FDA- and EMA-approved dabrafenib plus trametinib for BRAF V600-mutant melanoma. ASCO and ESMO endorse combined BRAF/MEK inhibition as a standard targeted-therapy option.