Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011, making it the first drug designed using fragment-based lead discovery to gain regulatory approval. Vermurafenib later received Health Canada approval on February 15, 2012 and on February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.
Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.
Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:
The cancer cells begin to overexpress a cell surface protein PDGFRB creating an alternative survival pathway.
A second oncogene called NRAS mutates, reactivating the normal BRAF survival pathway.
Stromal cell secretion of hepatocyte growth factor (HGF).
In a phase I clinical study, vemurafenib (then known as PLX4032) was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma, and the treated group had a median increased survival time of 6 months over the control group. A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. However the regression only lasted from 2 to 18 months.
In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study. Further trials are planned including a trial where vemurafenib will be co-administered with GDC-0973, a MEK-inhibitor.
The BRIM3 trial reported good updated results in 2012.
At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal. The BRIM-2 trial investigated 132 patients; the most common adverse events were arthralgia in 58% of patients, skin rash in 52%, and photosensitivity in 52%. In order to better manage side effects some form of dose modification was necessary in 45% of patients. The median daily dose was 1750 mg, which is 91% of the MTD.
^Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P (November 2012). "Vemurafenib: the first drug approved for BRAF-mutant cancer". Nat Rev Drug Discov11 (11): 873–86. doi:10.1038/nrd3847. PMID23060265.
^Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C (May 2008). "BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells". Mol. Cancer Res.6 (5): 751–9. doi:10.1158/1541-7786.MCR-07-2001. PMID18458053.
^Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S (February 2010). "RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth". Nature464 (7287): 431–5. doi:10.1038/nature08833. PMID20130576.
^Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR (July 2012). "Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion". Nature487 (7408): 500–4. doi:10.1038/nature11183. PMID22763439.
^Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin DP, Koeppen H, Merchant M, Neve R, Settleman J. (July 2012). "Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors.". Nature487 (7408): 505–9. doi:10.1038/nature11249. PMID22763448.
^Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (August 2010). "Inhibition of mutated, activated BRAF in metastatic melanoma". N. Engl. J. Med.363 (9): 809–19. doi:10.1056/NEJMoa1002011. PMID20818844. Lay summary – Corante: In the Pipeline.