Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

Abstract

Background Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. Methods We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. Results At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

“…In phase 2, the primary end‐point was confirmed ORR (based on the investigator's assessment). In phase 2, with a threshold ORR of 10% and an expected ORR of 70% (based on phase 3 studies with dacarbazine, vemurafenib and dabrafenib therapies),13, 22 the sample size of six was estimated to provide 90% or more of power, given a one‐sided alpha error of less than 0.05. Patients who were not evaluable were treated as non‐responders, that is, they were included in the denominator when calculating the percentage.…”

Emerging findings into molecular mechanism of brain metastasis

“…On account of the V600E‐mutated of BRAF, vemurafenib and dabrafenib, as two BRAF V600E inhibitors are currently approved for clinical use. Vemurafenib is a specific inhibitor of BRAF V600E mutated protein, which get 70% response rate with improved PFS and OS in BRAF V600E mutated metastatic melanoma patients 101. Similar to some other anticancer agents, treatment of BRAF V600E positive metastatic melanoma with vemurafenib showed good clinical responses at initial stage.…”

Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

“…This pathway has thus been a key focus in cancer drug development. A recent breakthrough came with the BRAF inhibitor vemurafenib, which achieved high response rates in BRAF‐mutated metastatic melanoma 2. Interestingly, BRAF inhibition in RAS‐mutated tumors induces paradoxical ERK activation and tumor progression owing to the formation of RAF dimers 3.…”