Zelboraf (vemurafenib) Tablets – Treatment for Metastatic Melanoma

Zelboraf is a drug indicated for the treatment of Metastatic Melanoma. The drug was developed by Plexxikon in collaboration with Roche. Plexxikon was acquired by Daiichi Sankyo in April 2011.

Genentech, a member of the Roche Group, submitted a new drug application for Zelboraf to the US Food and Drug Administration (FDA) in May 2011.

The drug was reviewed under fast track designation and approved for use in patients with metastatic melanoma in August 2011.

The FDA approval was based on the results of Phase II and Phase III clinical trials, named BRIM2 and BRIM3 respectively.

A marketing authorisation application was submitted to the European Medicines Agency (EMA) in May 2011. The EMA is currently reviewing the application and a decision is expected by the end of 2011.

The drug is also under review in Australia, Switzerland, New Zealand, Brazil, India, Mexico and Canada.

Zelboraf will be marketed by Genentech in the US. The drug is expected to generate annual sales of $732m by the end of 2015.

Metastatic melanoma, an advanced skin cancer

Melanoma is a type of skin cancer that forms in the skin cells called melanocytes, which are responsible for the colour of the skin. Melanoma can be observed in any part of the body containing melanocytes.

Melanoma at the earlier stages can be treated. If untreated it spreads to other parts of the body, causing metastatic melanoma, the most aggressive and advanced stage, or stage IV, of skin cancer.

Metastatic melanoma patients have low life expectancy, usually months. Symptoms include loss of appetite, nausea, vomiting and fatigue. Spread of cancer to the brain (brain metastases) is common in these patients.

Around 160,000 patients worldwide are diagnosed with Melanoma every year.

Zelboraf mechanism of action

Normal cell growth and survival are caused by a protein called BRAF protein. Mutations in these proteins (V600E mutations mostly observed in the melanomas) may lead to locking of the protein, resulting in constant growth signals. These signals lead to the cancer development and growth.

Zelboraf is designed using a diagnostic test called cobas 4800 BRAF V600 mutation test. It has the ability to inhibit the mutant forms of BRAF protein, including V600E.

It targets and suppresses the mutant BRAF protein and hence prevents the cell growth and cancer development.

Phase I and II clinical trials of Zelboraf

Plexxikon jointly conducted Phase I, Phase II and Phase III trials with Roche part of a deal that was signed in 2006.

Phase I trial data was released in June 2009. Around 55 melanoma patients were enrolled, of which 24 were positive to BRAF mutant protein. Trial data from 16 BRAF positive melanoma patients showed the drug was tolerable.

Tumor regression of 30% was achieved in nine of the patients. The median progression free survival was seven months. Around 20% of the treated patients developed squamous cell carcinoma.

A Phase II trial, named BRIM2, was conducted on 132 patients who received prior treatment for BRAF V600 mutation positive metastatic melanoma. The trial was initiated in September 2009. The trial data was released in November 2010.

The primary endpoint was to achieve overall response rate. Tumor shrinkage was observed in around 53% of the patients at a median time of 6.7 months. Median overall survival was not yet achieved after a follow-up of ten months. The side effects observed were joint pains, rashes, sensitivity to sun and fatigue.

In January 2011, a Phase I trial was initiated to evaluate the effect of food on the pharmacokinetics of a single dose of the drug. Patients will be administered a single dose of vemurafenib with or without food.

They will later be administered twice daily doses until disease progression or until toxicity is observed. The trial is expected to be completed by February 2013.

Around 132 patients were enrolled in a Phase II trial to evaluate the safety and efficacy of the drug in melanoma patients with brain metastases. The trial was initiated in July 2011 and is scheduled to be completed by September 2012. Patients will be administered 960mg of vemurafenib twice daily until disease progression, toxicity or consent withdrawal.

In September 2011, Phase I/II trial was initiated in 50 patients with BRAF V600 positive metastatic melanoma. The trial is being conducted to evaluate safety and efficacy and determine the anti-cancer effects and survival rate of patients treated with Vemurafenib in combination with ipilimumab. The trial is scheduled to be completed by September 2015.

Phase III clinical trials of the drug

A Phase III trial named BRIM3 was initiated in January 2010. Around 675 patients with previously untreated BRAF V600 mutation-positive melanoma were enrolled. The primary endpoint was overall survival rates and progression free survival.

Trial data released in June 2011 showed around 63% of the patients had lower risk of worsening the disease compared to that of patients given chemotherapy.

The response rate in patients treated with vemurafenib was nine times higher than in those treated with chemotherapy. Around 84% of the patients survived after six months of treatment, compared to 64% in case of chemotherapy.