Vemurafenib

Overview

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.[1] WP

Risks and side effects

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, 91% of the total daily MTD.[1][2] WP

Pharmacology

Mechanism of action

Vemurafenib causes 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.[3] WP

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.[4][5][6] WP

Resistance

Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered: WP⚠ Wikipedia itself has flagged this text: citation needed.

• Cancer cells begin to overexpress cell surface protein PDGFRB, creating an alternative survival pathway. WP
• A second oncogene called NRAS mutates, reactivating the normal BRAF survival pathway.[7][8] WP
• Stromal cell secretion of hepatocyte growth factor (HGF).[9][10] WP

Research

Research

A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity.[11] WP

History

History

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.[12–15] WP

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.[16][17] WP

In early 2010 a Phase I trial for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing.[18][19] WP

A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.[20] WP

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.[21][22] WP

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.[21][23] WP

Legal status

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.[24][25] WP

Vemurafenib was approved for use in Canada in February 2012.[26] WP

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.[27] WP

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.[28][29] WP

Chemistry

Formula

C23H18ClF2N3O3S PC

CAS number

918504-65-1 PC

Molar mass (g/mol)

489.9 PC

IUPAC name (computed by PubChem)

N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]propane-1-sulfonamide PC

SMILES

CCCS(=O)(=O)NC1=C(C(=C(C=C1)F)C(=O)C2=CNC3=C2C=C(C=N3)C4=CC=C(C=C4)Cl)F PC

InChIKey

GPXBXXGIAQBQNI-UHFFFAOYSA-N PC

PubChem CID

42611257

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

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11. Other Getting close and personal. January 4, 2014
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23. Other Cobimetinib at exelixis.com
24. Other FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer
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26. Other Notice of Decision for ZELBORAF. 11 March 2012
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