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Vemurafenib (INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma.; It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon.
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 V600K BRAF (the normal valine is replaced by lysine) 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.
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.
In early 2010 a Phase I trial for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing.
A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.
In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study. The BRIM3 trial reported good updated results in 2012.
Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (cobimetinib), a MEK inhibitor. After good results in 2014, the combination was submitted to the European Medical Agency and the US Food and Drug Administration for marketing approval.
Vemurafenib was approved for use in Canada in February 2012.
In February 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adults with BRAF V600E mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.
In November 2017, the US Food and Drug Administration (FDA) approved vemurafenib for the treatment of people with Erdheim–Chester disease (ECD), a rare type of histiocytic neoplasm.
Society and culture
Legal status
Vemurafenib was approved in the United States for the treatment of late-stage melanoma in August 2011, making it the first drug designed using fragment-based lead discovery to gain regulatory approval.
Research
A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of Hepatotoxicity.
Treating Hairy Cell Leukemia (HCL)
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. In a phase II clinical trial, Memorial Sloan Kettering is testing Vemurafenib, plus Obinutuzumab, in patients with previously untreated classical hairy cell leukemia. 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 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).
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