Background
Note: this entry refers to the BRIM-3 trial (vemurafenib), Chapman PB et al, NEJM, 2011. Phase III RCT of 675 treatment-naïve patients with BRAF V600E-mutant metastatic melanoma.
Interventions and follow up
Arm A: vemurafenib 960mg PO BID
Arm B: dacarbazine 1000mg/m2 IV q3wk
Primary endpoints: OS and PFS
Median follow up: ~3mo at interim analysis
Arm B: dacarbazine 1000mg/m2 IV q3wk
Primary endpoints: OS and PFS
Median follow up: ~3mo at interim analysis
Results
Interim OS: HR for death 0.37, 95%CI 0.26-0.55, P<.001 (63% relative reduction in death with vemurafenib)
PFS: HR for progression 0.26, 95%CI 0.20-0.33, P<.001 (74% relative reduction in progression)
6-mo OS: 84% (vemurafenib) vs 64% (dacarbazine)
ORR: 48% vs 5%
Crossover: recommended from dacarbazine to vemurafenib at interim
PFS: HR for progression 0.26, 95%CI 0.20-0.33, P<.001 (74% relative reduction in progression)
6-mo OS: 84% (vemurafenib) vs 64% (dacarbazine)
ORR: 48% vs 5%
Crossover: recommended from dacarbazine to vemurafenib at interim
Adverse events
Cutaneous (vemurafenib): cutaneous squamous cell carcinoma/keratoacanthoma (~18-26%), rash, photosensitivity, keratoses
Systemic (vemurafenib): arthralgia, fatigue, alopecia, nausea
Discontinuation for AEs: uncommon; favourable versus dacarbazine
Systemic (vemurafenib): arthralgia, fatigue, alopecia, nausea
Discontinuation for AEs: uncommon; favourable versus dacarbazine
Conclusions
Vemurafenib significantly improved both OS and PFS over dacarbazine in BRAF V600E-mutant metastatic melanoma, validating BRAF inhibition as a transformative targeted therapy.
Key Limitations
Early crossover confounded long-term OS; restricted to V600E mutation; resistance and high rates of cutaneous SCC; BRAF monotherapy now superseded by BRAF/MEK combinations.
Clinical Context
Supported FDA and EMA approval of vemurafenib for BRAF V600-mutant unresectable/metastatic melanoma. ASCO and ESMO now recommend combined BRAF plus MEK inhibition over single-agent BRAF inhibitors.