by Simon Rodwell | 15 January 2014 11:30
Study gives hope of delaying resistance to the melanoma drug dabrafenib
See also Technical Summary of this paper
The discovery of an abnormality (mutation) in a key cancer-causing gene known as BRAF, which controls melanoma in about 50% of patients, has led to the development of new drugs that have revolutionised the treatment of this disease. The normal BRAF gene controls a vital signalling pathway (the ‘MAPK pathway’) in the melanoma cell, while mutations in the BRAF gene switch the pathway on, causing the melanoma cells to grow and spread. See the Figure below, showing the pathway and where dabrafenib and trametinib work.
Inside a typical melanoma cell, showing the MAPK pathway from external signal to the nucleus of the cell containing the DNA (genes). The points at which dabrafenib and trametinib act are shown. Cell membrane in yellow, nuclear membrane in blue and a cell surface receptor in green.
Two drugs – dabrafenib and vemurafenib – are very effective in blocking the faulty BRAF gene in most patients with the mutation. But this effect lasts for only about six months, after which the melanoma cells become resistant. In addition, both drugs may cause side effects. Another melanoma drug, trametinib, works to counter the effects of the faulty BRAF gene by blocking MEK, another component of the pathway (see Figure).
A recent study investigated whether dabrafenib and trametinib could be given together safely and if they would have a greater effect than either drug on its own. The results were published in 2012 in The New England Journal of Medicine. 247 melanoma patients took part in the trial, all of whom had the BRAF mutation. The study looked at how much of the combined drugs could be given (the dose), the side effects (toxicity) and how effective the combined drugs were (efficacy). Patients were split into three groups and given either dabrafenib, or a reduced dose of dabrafenib plus trametinib, or both drugs at full dose.
There were three major findings: 1. the two drugs could be safely combined at the maximum dose normally used for each drug administered on its own; 2. some of the side effects usually found when the drugs are given individually (such as skin lesions, acne-like conditions and other forms of skin cancer) were reduced with the combination of both drugs. Other side effects, including fever and gastrointestinal complaints, were more frequent, although these were relatively mild and could be managed with other medication; and 3. the combination was more effective than a single agent.
Patients receiving the combined treatment at full dose had a significantly higher rate of tumour shrinkage (response rate). This was seen in approximately 50% more patients than for the dabrafenib-only group. The length of time during which the disease did not get any worse increased from just under six months – with dabrafenib on its own – to over nine months for the two-drug combination. After one year of treatment more than 40% of patients receiving the combination of drugs had experienced no progression in their disease, compared with 9% of patients receiving dabrafenib only. This was a highly significant outcome: indeed, many patients were switched over to the combined drugs during the course of the study.
These very encouraging results suggest that combining dabrafenib with trametinib can help to delay, or possibly stop, the cancer becoming resistant to treatment, while this drug combination can increase the response rate and reduce some of the side effects. Although they have generated much excitement, these findings are still considered preliminary. A larger, definitive trial has now been completed. The results, which will be published soon, could accelerate the pace of this new drug combination receiving approval for patient use.
See also Technical Summary of this paper
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