A combination of two targeted cancer drugs showed an unprecedented, “clinically meaningful” activity in patients suffering from malignant brain tumors that had a rare genetic mutation according to a report of a clinical trial by researchers from Dana-Farber Cancer Institute.
The drug combination that blocks an overactive growth signaling pathway, reduced tumors by 50% in one-third to 45 patients with high-grade gliomas that are difficult to treat. This includes glioblastomas, which is the most serious brain tumor. Since their tumors carried an inherited mutation known as v600E in BRAF which causes BRAF to be inactive, they were chosen for the trial. This mutation is seen in only two to three percent of patients with high-grade gliomas but is found in as high as 60 percent of certain types of low-grade gliomas. The study included 13 patients suffering from low grade gliomas. Of these patients, nine had an objective response to treatment using the drug combination, which translates to an average response rate of 69 percent.
“This is the first clinical trial where a targeted drug has been shown to be effective in glioblastoma,” said Patrick Wen MD, first author of The Lancet Oncology and director of the Center for Neuro-Oncology, Dana-Farber. In all chemotherapy treatments currently available for glioblastomas rate is just five per cent according to Wen, which contrasts with the 33 percent response rate that was achieved through the combination. The rate of response was greater – approximately 40 percent in patients less than 40 years old age, according to Wen.
The study combined trametinib and dabrafenib. Both drugs target proteins in the MAPK pathway. This signaling pathway is a chain of signaling that regulates cell growth. It can become stuck in the “on” position, leading to uncontrolled growth that can cause tumors.
Three patients had complete responses, which means that their tumors could not be seen on an image scan. Twelve patients experienced a partial shrinkage. Patients were not completely cured, but those who responded to the medication were able to enjoy long-lasting benefits. according to one study, the median duration of response was 13.6 months, and according to another test, it was 36.9 months.
These findings are part of an ongoing phase 2 ROAR (Rare Oncology Adnostic Research) study that has been enrolling patients in 27 academic and community centers in 13 countries since 2014. It is an “basket” study which aims to enroll patients with a common tumor characteristic that is, in this case the BRAF v600E mutation. However, they could also be suffering from a variety of cancers. The ROAR study will include patients with thyroid and biliary tract cancers gastrointestinal stromal tumors, hairy cell leukemia, multiple myeloma, high- and low-grade glioma brain tumors, and many more.
The aim of the study is to determine the general response rate for dabrafenib and trametinib in patients with BRAF V600E mutation-mutated cancers. The BRAF protein is a growth signaling protein kinase, which plays a role in regulating the MAPK signaling pathway. BRAF V600E mutations trigger cancer by activating the MAPK pathway which is made up of several proteins, leading to uncontrolled growth of cells and the formation of a tumor.
Trametinib and dabrafenib were utilized in this study. They are oral drugs that block specific components of the MAPK signaling pathway. Dabrafenib inhibits B-Raf enzyme, while trametinib blocks molecules MEK1 and MEK2 both of which are part of the MAPK pathway. They have been used in combination to treat melanoma as well as non-small-cell lung cancer, and thyroid cancer.
Gliomas, brain tumors that develop in the glia (support cells of the brain) and not the brain neurons, are referred to as gliomas. Gliomas make up around 80 percent of malignant brain cancers. Some gliomas grow slowly and are low-grade, while others are aggressive and high-grade gliomas, such as glioblastomas. They are more difficult to treat and will almost always develop recurrence. The authors of the study stated that there have been no significant advances in the treatment of gliomas in the last decades. However there are isolated reports that show trametinib and dabrafenib activity in gliomas. Their report of the ROAR study “is the first time that a combination of BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) have shown significant activity in these difficult-to-treat gliomas including glioblastomas, which have been known to be resistant to therapies.”
Wen said that the drugs could only be efficient for patients who had tumors that carry the V600E mutation. However the results were encouraging because people were beginning believe that there would never be targeted therapies for glioblastoma. He said that there is emerging evidence that there could be other targets in gliomas that could be blocked by the use of designer drugs.
The ROAR trial was originally developed and was sponsored by GlaxoSmithKline and is currently sponsored by Novartis.
Wen reports research support from Agios, AstraZeneca/MedImmune, Bayer, Celgene, Eli Lilly, Genentech/Roche, Kazia Therapeutics, MediciNova, Merck, Novartis, Nuvation Bio, Oncoceutics, Vascular Biogenics, and VBI Vaccines; and has an advisory or board member role in Agios, AstraZeneca, Bayer, Black Diamond, Boston Pharmaceuticals, ElevateBio, Imvax, Karyopharm Therapeutics, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, QED Therapeutics, Sapience, Vascular Biogenics, VBI Vaccines, and Voyager.
Wen, P.Y., and. (2021). Dabrafenib plus trametinib for patients with BRAFV600E mutations high-grade or low-grade glioma. (ROAR) is a multicentre, open-label, single-arm trial in phase 2 of a basket. The Lancet Oncology. doi.org/10.1016/S1470-2045(21)00578-7.
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