Vemurafenib (INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma.[2] It is an inhibitor of the B-Rafenzyme and was developed by Plexxikon.[2]
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).[4] 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.[5][6]
At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal.[2] 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, 91% of the MTD.[10]
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. The treated group had a median increased survival time of 6 months over the control group.[11][12][13][14]
A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. The regression lasted from 2 to 18 months.[15]
A phase III trial (vsdacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.[18]
In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[19] The BRIM3 trial reported good updated results in 2012.[20]
Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (cobimetinib), a MEK-inhibitor.[19] After good results in 2014, the combination was submitted to the European Medical Agency and the US Food and Drug Administration for marketing approval.[21]
In January 2015, trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma.[22]
Vemurafenib was approved in the United States for the treatment of late-stage melanoma in August 2011,[23] making it the first drug designed using fragment-based lead discovery to gain regulatory approval.[24]
Vemurafenib was approved for use in Canada in February 2012.[25]
In February 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adults with BRAF V600Emutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.[26]
In 2012, a grant from the Hairy cell leukemia Foundation supported the discovery of the BRAF mutation in classic HCL. This discovery charted a new path forward for many patients. It improved diagnosis and opened the door for additional therapies to be used in managing HCL.[30] In a phase II clinical trial, Memorial Sloan Kettering is testing Vemurafenib, plus Obinutuzumab, in patients with previously untreated classical hairy cell leukemia.[31] A separate clinical study treatment with only Vemurafenib (or monotherarpy) demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL), achieving an overall response rate of 86%, including 33% complete response (CR) and 53% partial response. However, after a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months).[32]
^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". Molecular Cancer Research. 6 (5): 751–759. doi:10.1158/1541-7786.MCR-07-2001. PMID18458053. S2CID16031942.
^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". Nature Reviews. Drug Discovery. 11 (11): 873–886. doi:10.1038/nrd3847. PMID23060265. S2CID9337155.
