Gliomas are tumors that originate in the glia, a brain support material that surrounds neurons. They account for about 80% of all malignant brain tumors and although some are slow growing, others are aggressive, such as glioblastoma: the most aggressive of all brain tumors, difficult to remove and almost always recurrent. In recent years, major advances have been made in the treatment of these cancers, and some research has indicated that targeted therapy with dabrafenib and trametinib in combination may be hopeful for patients. Now, the results of a study published in Lancet Oncology confirm those hypotheses: the two drugs combined reduced tumors by 50% in at least one third of the 45 patients enrolled with difficult-to-treat high-grade gliomas, including glioblastomas.
The two drugs
“This is the first time that a combination of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) has been shown to show such remarkable activity in these gliomas, including historically resistant glioblastomas,” said the authors of the publication. But how do the two drugs work? Dabrafenib inhibits BRAF, a gene that codes for a protein that regulates the growth of cancer cells. When the BRAF gene is mutated, the protein is altered: it works continuously, that is, it constantly stimulates the proliferation of tumor cells. Dabrafenib binds to this protein and blocks it. Trametinib, on the other hand, is a MEK-inhibitor and is able to block an enzyme that works downstream of BRAF in the process that leads to cell proliferation. In practice, simplifying, with the two drugs used together it is possible to strengthen the blocking of the signaling pathway of uncontrolled tumor growth.
The results
All patients enrolled in the study are carriers of the V600E gene mutation of the BRAF gene (or BRAF-v600E). This is a rare mutation, found in only 2-3% of patients with high-grade gliomas, but it can be present in up to 60% in some types of low-grade gliomas. Well, of the low-grade glioma patients, 13 in all in the Lancet study, nine had a combined treatment response rate of 69%.
How did things go with the glioblastomas? The response rate in this case was 33%, and in patients under the age of 40 it was about 40%. Patrick Wen, first author of the publication and director of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, said, “This is the first time a targeted treatment has been shown to work in glioblastoma in a clinical trial.” With current chemotherapies, the oncologist recalled, the response rate for this aggressive form of cancer does not exceed 5%. A big leap, in short.
Three patients had a complete response, meaning their tumors were no longer visible on imaging, and 12 had partial reduction in mass. The patients did not recover, but those who responded to the drugs experienced lasting benefits: in fact, the median duration of response was 13.6 months according to one evaluation, and 36.9 months based on another evaluation.
New targets
Although the drugs have only helped patients with tumors carrying the rare V600E mutation, according to Wen the results are still encouraging “because it was beginning to think that we would never have targeted therapies for glioblastoma.” Additionally, he added, evidence is emerging of other targets in gliomas that could be blocked by targeted drugs.
ROAR a basketball studio
The glioma study is part of the ROAR project, which stands for Rare Oncology Agnostic Research. ROAR is a Phase 2 clinical trial launched in 2014 and still ongoing involving 27 cancer centers in 13 countries. And it is a so-called basketball study, that is, carried out on patients suffering from different types of cancer, all however sharing the same mutational profile. The ROAR study includes patients with thyroid and biliary tract cancers, gastrointestinal stromal tumors, hairy cell leukemias, multiple myeloma, low and high grade brain gliomas and more and is designed to measure the overall response rate to dabrafenib combined with trametinib in patients with tumors with the BRAF V600E mutation.
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