The European Commission has approved vemurafenib (ZelborafTM, Roche) as a monotherapy for the treatment of adult patients with BRAF V600 mutationpositive unresectable or metastatic melanoma. This form of melanoma is the most aggressive form of skin cancer. Vemurafenib is designed to target and inhibit mutated forms of the BRAF protein found in about half of all cases of melanoma.

When melanoma is diagnosed early, it is generally a curable disease. However, when it spreads to other parts of the body, it is the deadliest and most aggressive form of skin cancer. A person with metastatic melanoma typically has on average a short life expectancy that is measured in months. Only around one in four people with metastatic melanoma are expected to be alive one year after their diagnosis.[1]

The BRAF protein is a key component of the RAS-RAF pathway involved in normal cell growth and survival. Mutations that keep the BRAF protein in an active state may cause excessive signalling in the pathway, leading to uncontrolled cell growth and survival. These mutations of the BRAF protein are thought to occur in an estimated half of all melanomas and eight percent of solid tumours.

New treatment option
Vemurafenib is an oral, small molecule, kinase inhibitor indicated for the monotherapy treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma. The drug is not recommended for use in melanoma patients with wild-type BRAF.

?Today?s approval is important news for people with BRAF mutation-positive metastatic melanoma as vemurafenib significantly improves patient survival and exemplifies the benefits that Roche?s personalized approach to medicine can provide for patients, physicians and society,? said Hal Barron, M.D., Chief Medical Officer and Head, Global Product Development at Roche.

Advertisement #3

Clinical trials
In pivotal clinical trials, vemurafenib is the only treatment to benefit patient survival in both previously untreated and previously treated people with advanced melanoma who tested positive for BRAF V600 mutations using the cobas 4800 BRAF V600 Mutation Test, a polymerase chain reaction-based diagnostic test developed by Roche. In the pre-specified interim analysis of the phase III BRIM3 trial,a global, randomised, open-label, controlled, multicentre, phase III study that compared vemurafenib to dacarbazine chemotherapy (a standard of care), in 675 patients with previously untreated BRAF V600E mutation-positive, unresectable or metastatic melanoma, the risk of death was reduced by 63% for people who received vemurafenib compared to those who received standard first-line treatment (hazard ratio [HR]=0.37, p<0.0001).

In another, post-hoc analysis of BRIM3 data with a longer follow up compared to previous analyses, including cross-over of patients from the placebo to the active treatment arm, vemurafenib significantly improved survival over standard first-line treatment by providing a median overall survival (OS) of 13.2 months compared to 9.6 months for chemotherapy (hazard ratio [HR]=0.62). A survival benefit was also shown in pre-treated patients in the phase II BRIM2 study, a global, single-arm, multicentre, openlabel phase II trial that enrolled 132 patients with previously treated BRAF V600E mutation-positive, metastatic melanoma. The data from this study will be published later in 2012.

In theconducted trials, the safety profile of vemurafenib was generally consistent. The most common grade 3 or higher adverse events seen more often in people receiving vemurafenib compared to those receiving chemotherapy were a common type of skin cancer, cutaneous squamous cell carcinoma (cSCC) including keratoacanthomas, rash, liver function abnormalities, joint pain and sensitivity to the sun. In cases of cSCC, the lesions were generally removed and the patients continued with treatment.

Regulatory Status
In 2011, vemurafenib became the first and only US FDA approved personalised medicine that is shown to improve survival for people with BRAF V600 mutation-positive unresectable or metastatic melanoma. Vemurafenib has also been approved in Switzerland, Brazil, Israel, Canada and New Zealand and marketing authorization submissions are currently under review by health authorities in Australia, India and other countries worldwide.

[1] Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and
overall survival benchmarks for future phase II trials. J Clin Oncol. 2008 Feb 1;26(4):527-34.

For more information:
– Companies Announce Clinical Collaboration Agreement for Studies with Ipilimumab and Vemurafenib – Onco’Zine, June 2, 2012
Vemurafenib Improves Overall Survival in Advanced Melanoma – Onco’Zine, June 8, 2011
– Overall Survival Improves in Metastatic Melanoma after First-Line Ipilimumab Plus Chemotherapy – Onco’Zine, June 8, 2011.

Picture credit: Vemurafenib, also known as PLX4032, RG7204 or RO5185426, marketed as ZelborafTM) 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.

Advertisement #5