Background
Phase III open-label RCT of 704 treatment-naïve patients with BRAF V600E/K-mutant metastatic melanoma, comparing combined BRAF/MEK inhibition with BRAF inhibitor monotherapy.
Interventions and follow up
Arm A: dabrafenib 150mg BID + trametinib 2mg daily
Arm B: vemurafenib 960mg BID
Primary endpoint: OS
Median follow up: ~11mo at primary analysis
Arm B: vemurafenib 960mg BID
Primary endpoint: OS
Median follow up: ~11mo at primary analysis
Results
OS: HR for death 0.69, 95%CI 0.53-0.89, P=.005 (A vs B)
1-yr OS: 72% vs 65%
mPFS: 11.4mo vs 7.3mo; HR 0.56, 95%CI 0.46-0.69, P<.001
ORR: 64% vs 51%, P<.001
1-yr OS: 72% vs 65%
mPFS: 11.4mo vs 7.3mo; HR 0.56, 95%CI 0.46-0.69, P<.001
ORR: 64% vs 51%, P<.001
Adverse events
Grade 3-4 AEs: 52% (dabrafenib-trametinib) vs 63% (vemurafenib)
More with combination: pyrexia (53%), commonly grade 3 in a subset
More with vemurafenib: cutaneous squamous cell carcinoma (18% vs 1%), photosensitivity, hyperkeratosis
More with combination: pyrexia (53%), commonly grade 3 in a subset
More with vemurafenib: cutaneous squamous cell carcinoma (18% vs 1%), photosensitivity, hyperkeratosis
Conclusions
Dabrafenib plus trametinib significantly improved OS, PFS, and ORR over vemurafenib monotherapy, establishing combined BRAF/MEK inhibition as superior to single-agent BRAF inhibition.
Key Limitations
Open-label design; restricted to BRAF V600E/K disease; no comparison against immunotherapy; eventual acquired resistance limits durability of benefit.
Clinical Context
Supports FDA- and EMA-approved dabrafenib plus trametinib for BRAF V600-mutant metastatic melanoma. ASCO and ESMO recommend combined BRAF/MEK inhibition over BRAF monotherapy.