Background
Note: this entry refers to the BREAK-3 trial (dabrafenib), Hauschild A et al, Lancet, 2012. Phase III open-label RCT of 250 treatment-naïve patients with unresectable stage III or IV BRAF V600E-mutant melanoma, randomised 3:1.
Interventions and follow up
Arm A: dabrafenib 150mg PO BID
Arm B: dacarbazine 1000mg/m2 IV q3wk (crossover to dabrafenib permitted at progression)
Primary endpoint: PFS by investigator assessment
Median follow up: ~5mo at primary analysis
Arm B: dacarbazine 1000mg/m2 IV q3wk (crossover to dabrafenib permitted at progression)
Primary endpoint: PFS by investigator assessment
Median follow up: ~5mo at primary analysis
Results
mPFS: 5.1mo vs 2.7mo (dabrafenib vs dacarbazine); HR 0.30, 95%CI 0.18-0.51, P<.0001
ORR: 50% vs 6%
OS: immature at primary report; crossover confounded long-term comparison
ORR: 50% vs 6%
OS: immature at primary report; crossover confounded long-term comparison
Adverse events
Cutaneous (dabrafenib): hyperkeratosis, cutaneous squamous cell carcinoma/keratoacanthoma (~6-10%), papillomas, palmar-plantar erythrodysesthesia
Systemic (dabrafenib): pyrexia, fatigue, arthralgia, headache
Grade 3 events: infrequent; discontinuation due to AEs uncommon
Systemic (dabrafenib): pyrexia, fatigue, arthralgia, headache
Grade 3 events: infrequent; discontinuation due to AEs uncommon
Conclusions
Dabrafenib significantly improved PFS over dacarbazine in BRAF V600E-mutant metastatic melanoma, establishing it as an effective BRAF-targeted monotherapy.
Key Limitations
Open-label design; crossover precluded mature OS comparison; restricted to V600E mutation; BRAF monotherapy now superseded by BRAF/MEK combinations.
Clinical Context
Supported FDA and EMA approval of dabrafenib for BRAF V600-mutant unresectable/metastatic melanoma. ASCO and ESMO now favour BRAF plus MEK inhibitor combinations over single-agent BRAF inhibition.