A combination of two targeted cancer drugs demonstrated significant anti-cancer activity in patients with glioblastoma that carry a specific genetic mutation, according to a clinical trial report by investigators from Dana-Farber Cancer Institute and published in Lancet Oncology.
Gliomas are cancer that originate in the glia – the supporting cells of the brain – not the brain neurons themselves. Gliomas comprise about 80 percent of all malignant brain tumors. Some are slow-growing low-grade gliomas, while others are aggressive high-grade gliomas including glioblastomas that are difficult to remove and almost always recur. Until recently it was not known that BRAF gene mutations occurred in Glioblastoma. The BRAFV600 mutation is found in only 3% of patients with high-grade gliomas but is found in up to 60% of certain types of low-grade gliomas.
Not all cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing is performed to test for certain genetic mutations or the proteins they produce because the results can help select treatment including newer precision cancer medicines designed to attack specific cancer cells with specific genetic mutations.
Two precision cancer medicines, dabrafenib and trametinib are widely used to treat BRAFV600 mutations in melanoma and other cancer types. Both drugs target proteins in the MAPK pathway, a signaling chain of proteins that acts as a switch for cell growth and can become stuck in the “on” position, causing uncontrolled growth leading to tumors. Dabrafenib inhibits an enzyme, B-Raf, and trametinib inhibits molecules called MEK1 and MEK2, which are part of the MAPK pathway.
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The drug combination shrank tumors by 50% or more in one-third of 45 patients with hard-to-treat high-grade gliomas, including glioblastomas. The study included 13 patients with low-grade gliomas. Of those patients, nine had an objective response to treatment with the drug combination, for a response rate of 69%. The patients were not cured, but those who responded to the drugs experienced remarkably durable benefits – by one assessment, the median duration of response was 13.6 months, and by another assessment, it was 36.9 months.
The findings are from an ongoing phase 2 study called ROAR (Rare Oncology Agnostic Research) that has been enrolling patients since 2014 in 27 community and academic cancer centers in 13 countries. The study is a so-called “basket” trial, which seeks to enroll patients who share a common tumor characteristic – in this case the BRAF v600E mutation – although they may have an array of different cancers. The ROAR study includes patients with thyroid and biliary tract cancers, gastrointestinal stromal tumors, hairy cell leukemia, multiple myeloma, low- and high-grade glioma brain tumors, and others. The study is designed to determine the overall response rate of dabrafenib combined with trametinib in patients with BRAF V600E-mutated cancers. The BRAF protein is a growth signaling protein kinase that plays a role in regulating the MAPK signaling pathway. BRAF V600E mutations drive cancer by activating the MAPK pathway, which is made up of many proteins, resulting in uncontrolled cell growth and the development of a tumor.
In most other cancer types routine NGS testing is performed to look for cancer growth driving mutations that can be targeted with precision cancer medicines. Until recently researchers did not believe this approach was viable for brain tumors but now there is emerging evidence that there may be other targets in gliomas that could be blocked by precision medicines. According to the lead study author Dr Patrick Wen of Dana Farber director of the Center for Neuro-Oncology at Dana-Farber “This is the first time that any targeted drug has been shown to work in glioblastoma in a clinical trial.