Vemurafenib


Vemurafenib is an inhibitor of the B-Raf enzyme developed by Plexxikon and Genentech for the treatment of late-stage melanoma. The name "vemurafenib" comes from V600E mutated BRAF inhibition.

Approvals

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.
Vemurafenib later received Health Canada approval on February 15, 2012.
On February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600E mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.
On November 6, 2017, the FDA approved Vemurafenib for the treatment of some patients with Erdheim–Chester disease, a rare type of histiocytic neoplasm.

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.
Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation. 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.

Resistance

Three mechanisms of resistance to vemurafenib have been discovered:
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. 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. The regression lasted from 2 to 18 months.
In early 2010 a Phase I trial for solid tumors, and a phase II study were ongoing.
A phase III trial 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, a MEK-inhibitor. After good results in 2014 the combination was submitted to the EC and FDA for marketing approval.
In January 2015 trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma.

Side effects

At the maximum tolerated dose 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 MTD.
A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity.