Vemurafenib

Vemurafenib

File:PLX4032 BRAF inhibitor.png
Clinical data
Trade names	Zelboraf
Synonyms	PLX4032, RG7204, RO5185426
AHFS/Drugs.com	FDA Professional Drug Information
MedlinePlus	a612009
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: by INN US FDA: Vemurafenib
Pregnancy category	US: D (Evidence of risk)
Routes of administration	Oral
ATC code	L01XE15 (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	1029872-54-5
PubChem CID	42611257
ChemSpider	24747352 Y
UNII	207SMY3FQT
ChEMBL	ChEMBL1229517
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C23H18ClF2N3O3S
Molar mass	489.92 g/mol
3D model (JSmol)	Interactive image
SMILES CCCS(=O)(=O)Nc1ccc(c(c1F)C(=O)c2c[nH]c3c2cc(cn3)c4ccc
InChI InChI=1S/C23H18ClF2N3O3S/c1-2-9-33(31,32)29-19-8-7-18(25)20(21(19)26)22(30)17-12-28-23-16(17)10-14(11-27-23)13-3-5-15(24)6-4-13/h3-8,10-12,29H,2,9H2,1H3,(H,27,28) Y Key:GPXBXXGIAQBQNI-UHFFFAOYSA-N Y
(verify)

Crystallographic structure of B-Raf (rainbow colored, N-terminus = blue, C-terminus = red) complexed with vemurafenib (spheres, carbon = white, oxygen = red, nitrogen = blue, chlorine = green, fluorine = cyan, sulfur = yellow).

WikiDoc Resources for Vemurafenib
Articles
Most recent articles on Vemurafenib Most cited articles on Vemurafenib Review articles on Vemurafenib Articles on Vemurafenib in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Vemurafenib Images of Vemurafenib Photos of Vemurafenib Podcasts & MP3s on Vemurafenib Videos on Vemurafenib
Evidence Based Medicine
Cochrane Collaboration on Vemurafenib Bandolier on Vemurafenib TRIP on Vemurafenib
Clinical Trials
Ongoing Trials on Vemurafenib at Clinical Trials.gov Trial results on Vemurafenib Clinical Trials on Vemurafenib at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Vemurafenib NICE Guidance on Vemurafenib NHS PRODIGY Guidance FDA on Vemurafenib CDC on Vemurafenib
Books
Books on Vemurafenib
News
Vemurafenib in the news Be alerted to news on Vemurafenib News trends on Vemurafenib
Commentary
Blogs on Vemurafenib
Definitions
Definitions of Vemurafenib
Patient Resources / Community
Patient resources on Vemurafenib Discussion groups on Vemurafenib Patient Handouts on Vemurafenib Directions to Hospitals Treating Vemurafenib Risk calculators and risk factors for Vemurafenib
Healthcare Provider Resources
Symptoms of Vemurafenib Causes & Risk Factors for Vemurafenib Diagnostic studies for Vemurafenib Treatment of Vemurafenib
Continuing Medical Education (CME)
CME Programs on Vemurafenib
International
Vemurafenib en Espanol Vemurafenib en Francais
Business
Vemurafenib in the Marketplace Patents on Vemurafenib
Experimental / Informatics
List of terms related to Vemurafenib

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Vemurafenib (INN, marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma. The name "vemurafenib" comes from V600E mutated BRAF inhibition.

Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011, 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.

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. Melanoma cells without this mutation are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.

In vitro, a melanoma cell line A375 is inhibited by silencing the BRAF gene by short hairpin RNA.

Resistance

Two 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 alternate survival pathway.
• A second oncogene called NRAS mutates, reactivating the normal BRAF survival pathway.

Clinical trials

In a phase I clinical study, vemurafenib 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.

Phase I and phase II studies are ongoing, and a phase III trial has been started.

In 2010, it was also in phase I trials for colorectal cancer.

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.

Side effects

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.