|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|CAS Registry Number|
|Synonyms||PLX4032, RG7204, RO5185426|
|Molecular mass||489.92 g/mol|
|(what is this?)|
|Mechanism of action||protein kinase inhibitor|
|PDB ligand id||032:,|
Vemurafenib (INN, marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma. The name "vemurafenib" comes from V600E mutated BRAF inhibition.
Approvals and indications
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.
Mechanism of action
Vemurafenib has been shown to cause programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.
(See BRAF_(gene)#Vemurafenib for details of drug structure interaction with B-Raf.)
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 early 2010 a Phase I trial for solid tumors (including colorectal cancer), and a phase II study (for Metastatic Melanoma) were ongoing, and a phase III trial (vs dacarbazine) in patients with previously untreated Metastatic Melanoma showed an improved rates of overall and progression-free survival.
Further trials are planned including a trial where vemurafenib will be co-administered with GDC-0973(Cobimetinib), a MEK-inhibitor. After good results in 2014 the combination has been submitted to EC and FDA for marketing approval.
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.
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- Notice of Decision for ZELBORAF
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