Combining two oral, targeted treatments in metastatic melanoma that has spread to the brain leads to a response in almost half of patients, according to research being presented at the American Society of Clinical Oncology conference.
Researchers examined 76 patients with melanoma carrying a BRAFV600 mutation in an open-label trial. Patients were given oral dabrafenib 150mg twice daily (a BRAF inhibitor) and oral trametinib 2mg once daily (a MEK inhibitor). These patients had asymptomatic brain metastases and had not previously received local brain therapy.
In the study, which is published in the Lancet Oncology (online, 4 June 2017),
the researchers found that, after a median follow up of 8.5 months, 44 (58%) of these patients showed a partial or complete intracranial response to the treatment.
In all, 78% achieved intracranial disease control, meaning that the disease remained stable or responded to the treatment.
The combination of dabrafenib and trametinib blocks a key pathway in melanoma development, called MAP kinase, at two different points. It is already used in non-metastatic melanoma, and is intended to enhance efficacy by overcoming resistance to single-agent BRAF inhibitor treatment.
In addition, the researchers tested the drug combination in three other cohorts involving a total of 49 patients with other disease characteristics including those with asymptomatic metastases who had undergone previous local therapy, and people with different types of BRAF mutation. In these patients, an intracranial response was also seen in 44–59% of patients.
However, the researchers note that the duration of response was short-lived, at a median of 6.5 months in the main cohort. By contrast, the median duration of response in patients without brain metastases was 12 months in one of the main clinical trials.
Lead author Michael Davies says that this is something that future research will need to address.
“The results of the trial demonstrate that the combination has very high initial activity,” says Davies. “In order to improve the durability of the responses, we need to understand what is different about brain metastases compared to tumours in other sites in the body, particularly in the context of BRAFi + MEKi treatment.”
He suggests duration of response might be improved by increasing doses of one or both of the drugs, or by adding another targeted therapy, immunotherapy or radiation therapy to the regimen.
Davies says it is also important that there were no unexpected safety issues in the trial, which supports future studies involving patients with brain metastases.
“The combination of BRAF and MEK inhibitors is generally tolerated better than either agent alone, which is very unusual for a combination therapy,” says Davies.
Kevin Harrington, professor of biological cancer therapies at The Institute of Cancer Research, London, and consultant clinical oncologist at The Royal Marsden NHS Foundation Trust, says that this approach to treating brain metastases could help overcome the limitations of existing local treatments, such as radiation and surgery.
“Local therapies are associated with a high risk of progression of disease in the brain (and outside the brain) so, ideally, we need active systemic agents that cross the blood–brain barrier, treat visible and occult disease in the brain and which also deliver systemic responses.”
He says the results provide “very encouraging evidence that patients with previously untreated and previously treated brain disease have a high chance of achieving a response to dabrafenib/trametinib,” but future research will need to confirm if the approach improves progression-free and overall survival.
 Davies MA, Saiag P, Robert C et al. Dabrafenib plus trametinib in patients with BRAFV600 -mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017. doi: 10.1016/S1470-2045(17)30429-1