Vemurafenib

The BRIM-3 (BRAF Inhibitor in Melanoma-3) trial results represent the most dramatic advance ever in the treatment of metastatic melanoma. For the first time, a personalised therapy called vemurafenib, which targets the faulty BRAF protein, was seen to prolong both the period of disease control and increase life expectancy.

The Royal Marsden’s Dr James Larkin also led a further ‘expanded access’ international study of vemurafenib which aimed to make this drug available to patients all over the UK.

Vemurafenib showed an immediate and dramatic effect: patients began feeling better within days of starting treatment and CT scans showed remarkable tumour shrinkage. There are now a number of patients who have been on treatment for over a year, suggesting the possibility of prolonged disease control.

Vemurafenib was approved for use as a treatment option for metastatic melanoma by the National Institute for Health and Clinical Excellence (NICE) in 2012.

Melanoma: a serious type of skin cancer

Melanoma can be cured with surgery in 80–90% of cases. Unfortunately, in the remaining 10–20% of cases it becomes metastatic and involves the internal organs. Curative treatment is generally not possible when this happens. Drug treatment is given in this situation to try to shrink the melanoma and reduce related symptoms in an effort to improve quality of life for the patient.

Until very recently, there has never been any significant progress in developing improved treatments for metastatic melanoma. Dacarbazine, a drug that was used in the 1970s, was still used to treat melanoma in 2010. The response rate to dacarbazine is generally low – significant tumour shrinkage occurs in only about 5–10% of cases and the average period of disease control is about six weeks. There is clearly a need for better treatment options for patients with metastatic melanoma.

Dr Larkin talks about breakthroughs in melanoma

BRAF: a faulty protein switch found in 50% of melanomas

BRAF is a protein found inside the cell which acts as a switch that controls cell growth. Importantly, the BRAF gene is mutated in about 50% of patients with melanoma. This means effectively that the switch is stuck in the ‘on’ position and causes cells to survive, divide and spread when they should not. As a consequence, the BRAF mutation drives the growth of melanomas that have spread around the body from the primary site in the skin.

The BRIM-3 trial

The most recent trial examining the effectiveness of vemurafenib (BRIM-3: BRAF Inhibitor in Melanoma-3) was an international trial carried out in 12 countries. It was designed to test vemurafenib in comparison with dacarbazine in patients with metastatic melanoma with BRAF mutations.

Vemurafenib showed an immediate and dramatic effect: patients began feeling better within days of starting treatment. Moreover, computerised tomography (CT) scans showed remarkable tumour shrinkage in approximately 50% of patients taking vemurafenib in comparison with only 5% for those on dacarbazine. Prolongation of disease control was on average from about six weeks on dacarbazine to approximately six months on vemurafenib. This is without question a major breakthrough in the treatment of this disease. There are now a number of patients who have been on treatment for over a year, suggesting the possibility of prolonged disease control.

Future directions

The success of vemurafenib is a result of the work of Professor Richard Marais from the ICR and other scientists who have increased our understanding of the biology of melanoma, as well as clinicians including Dr James Larkin who have led clinical trials showing the impact of this drug.

The success of vemurafenib is just the beginning of a long road in which we hope first to transform metastatic melanoma into a treatable disease and then to aim for cure. In the short term, we are working hard to understand how and why some patients respond less well to vemurafenib than others and why resistance to treatment emerges. We are also working on other ways to target melanomas with BRAF mutations and developing ways to treat the 50% of melanomas that do not have this mutation. There is still a lot of work to do, but the development of vemurafenib is a solid foundation on which to build and it shows the power of scientists and clinicians working closely together to tackle this disease.

Vemurafenib has been licensed for use in the UK as Zelboraf by Roche Pharmaceuticals. Applications for funding on the NHS in England need to be made to the Cancer Drugs Fund. Please speak to your GP in the first instance to check whether a referral to a specialist to discuss this is appropriate.

It is currently awaiting NICE review.


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www.royalmarsden.nhs.uk/research/highlights/vemurafenib

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