Vemurafenib: B-raf kinase inhibitor, oncolytic

Vemurafenib (RG-7204, PLX-4032) is a potent inhibitor of the V600E mutation-positive B-raf kinase. Mutations in this protein have been implicated in approximately 50% of melanomas, 30-70% of thyroid tumors, 30% of serous low-grade ovarian tumors and 10% of colorectal cancers. Vemurafenib has shown promising preclinical and clinical efficacy against mutant BRAF cell lines and tumors. Vemurafenib exhibits selectivity over a broad range of kinases, which has translated into cellular selectivity for cancer cell lines expressing BRAF^V600E, BRAF^V600D and BRAF^V600R, with no activity against cells lacking oncogenic B-raf. Pharmacokinetic analyses have shown that exposure increases with dose from 160 mg to 1,120 mg twice daily, and a dose of 960 mg twice daily was selected for phase II and III evaluation. Phase I and II clinical data have demonstrated promising activity, with the recently reported BRIM-2 study in patients with metastatic melanoma having met its primary endpoint, demonstrating a best overall response rate of > 50% in the context of manageable side effects.