Vemurafenib

BRAF inhibitors in melanoma and vemurafenib as a potential new treatment

This article describes how vemurafenib, (also known as Zelboraf) one of the new treatments currently in development, works on melanoma caused by a specific type of mutation.

BRAF

Cell growth is controlled by a complex set of communications between proteins that are collectively described as “cell signalling”.
These communications occur in a carefully controlled and ordered way, along “pathways”. There are literally hundreds of thousands of cell signalling pathways which control every function in every cell, of every tissue of our bodies.

BRAF is a protein that is part of the cell signalling pathway that controls cell growth in a number of different tissues in the body. In normal cells, BRAF is tightly controlled and only becomes active when the cell receives the right signals to grow. However, errors, or mutations, in the BRAF gene result in a protein that is inappropriately active all the time causing rapid, uncontrolled cell growth resulting in cancer. Researchers recently identified the V600E BRAF mutation as the most common BRAF mutation. This type of mutation is found in about 8 percent of all cancers, including approximately 40-60 percent of malignant melanomas. There are other BRAF mutations but they are less common. 

There is on-going research into V600E BRAF inhibitors.

Only patients with the V600E BRAF mutation appear to benefit from treatment with V600E BRAF inhibitors, so doctors need to be able to test whether patients have the mutation to determine if the therapy will benefit them. Testing kits for BRAF mutations are becoming commercially available. These are based on scientific methods that are highly sensitive, readily automated and suitable for diagnostic testing. Contact your treating physician or cancer centre to find out about testing for BRAF mutations.

Vemurafenib – a BRAF inhibitor

BRAF inhibitors are molecules designed to block the activity of the mutated form of the BRAF protein. Vemurafenib (formerly known as PLX4032) is an inhibitor of BRAF with the V600E mutation. Preclinical studies indicate that vemurafenib blocks the mutated BRAF protein, turning off the rapid cell growth and causing cell death in tumours with the BRAF mutation.

Phase I trials of vemurafenib
In the first (Phase I) clinical trial of Vemurafenib, 81 percent of 32 patients with previously treated BRAF V600E mutation-positive metastatic melanoma showed a positive response to the drug. The estimated median time in which patients’ disease does not progress (progression free survival) was seven months compared to historical progression-free survival of less than two months.

The most frequent adverse events reported to date from vemurafenib were predominantly mild and included rash, light sensitivity, joint pain and fatigue. Also reported was cutaneous squamous cell carcinoma (cSCC), a type of skin cancer. In these cases, the carcinomas were removed immediately and the patient continued with treatment.

Phase II trials of vemurafenib
A second trial (Phase II) in 132 patients also showed promising progression-free survival in patients with previously treated BRAF V600E mutation-positive metastatic melanoma. People who participated in the trial also lived a median of 6.2 months without their disease getting worse. The most common adverse events were rash, photosensitivity, hair loss and joint pain.

Phase III trials of vemurafenib
Vemurafenib is currently being evaluated in a global Phase III study called BRIM3 involving approximately 680 patients. Researchers are comparing it to the chemotherapy drug dacarbazine as a treatment for previously-treated patients who have melanoma with the V600E BRAF mutation. As well as international sites, the trial is being conducted in New Zealand at Auckland, Wellington, Dunedin, Palmerston North and Waikato hospitals.

In January 2011, Roche announced that interim analysis of the Phase III trial showed it had met its goal of showing a significant survival benefit in people with previously untreated BRAF V600 mutation-positive metastatic melanoma. Study participants who received vemurafenib lived longer (overall survival) and also lived longer without their disease getting worse compared to participants who received dacarbazine, the current standard of care. Full details of these results are expected to be presented at the American Society of Clinical Oncology (ASCO) international conference in June of this year.

Availability of vemurafenib in New Zealand

Vemurafenib is now known as Zelboraf and has now been registered for use in New Zealand. At this time (March 2012) Zelboraf is a privately funded medicine, meaning that patients need to pay for it. Patients with  private health insurance should consult their provider.  For more information on the steps involved in making a medicine available in New Zealand, refer to 'How medicines reach the market in New Zealand' .

Personalised healthcare

BRAF inhibitors do not work for everybody. Being able to select the patients most likely to benefit from BRAF inhibitors means those who don’t have the mutation won’t have to undergo unnecessary and expensive treatment, while those who do, will receive treatment targeted specifically at the type of melanoma they have.

Personalised healthcare means treatments that target specific groups of patients who will respond best to those medicines. Rather than treating all patients the same, it is healthcare that is tailored to the individual person and the individual type of disease affecting them. It has the potential to make healthcare better, safer and more effective for all.

If you have further questions about melanoma and its treatment, we encourage you to talk to your own clinical team.