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Newly Approved BRAF-Targeted Therapy Can Benefit Adults With Glioma


NEW YORK – Patients with BRAF V600E-mutated glioblastoma have a new treatment option following last year's tissue-agnostic approval of Tafinlar (dabrafenib) with Mekinist (trametinib) by the US Food and Drug Administration, but as yet little is known about the benefits of BRAF-targeted therapies for adults with high-grade gliomas.

The FDA approval was based on data from the Phase II ROAR and NCI-MATCH trials, in which 80 percent of patients with BRAF V600E-mutated tumors, including high- and low-grade glioma, biliary tract cancer, and some gynecologic and gastrointestinal cancers, responded to treatment with Tafinlar-Mekinist.

In the course of her work as codirector of the BRAF Brain Tumor Center at Johns Hopkins School of Medicine, Karisa Schreck, a professor of neurology, noticed that some patients with high-grade, recurrent glioblastoma responded well to Tafinlar and Mekinist, and she became interested in exploring the significance of BRAF alterations in those patients as a prognostic indicator and predictor of response to therapy.

Schreck connected with Harvard neurosurgeon Wenya Bi at the Adult Brain Tumor Consortium annual meeting in 2020 and discovered the two had a shared interest. "Dr. Bi and I sat next to each other at the conference. I told her about my research area, and she told me she had this huge database of patients including some with the BRAF mutations," said Schreck, noting that because BRAF is a rare alteration in adult gliomas, found in only 3 to 5 percent of patients, it is difficult to find enough patients for a study.

The resulting study published in NPJ Precision Oncology in February had two goals. One was to understand the landscape of BRAF alterations in adult gliomas, and the second was to determine what the implications of BRAF alterations were for prognosis and response to therapy in those patients. In pediatric gliomas and some lower-grade adult brain tumors, BRAF alterations often signal a more favorable prognosis and predict that the patient will benefit from BRAF-targeted therapies. However, it wasn't clear whether the same was true in adults. By pulling together their collective institutional data and public databases, Schreck and Bi were able to better understand the spectrum of BRAF alterations in adult gliomas.

Schreck said that going into the study, they weren't sure what the range of effects of BRAF alterations would be. They knew that some of the BRAF alterations were cancer drivers and patients with those alterations were likely to see their tumors shrink in response to targeted therapy. But some patients received those treatments and did not respond. Those mutations, which Schreck describes as "passengers," may have been picked up along the way but did not seem to drive the cancer. Hopefully, by using a database of patients with BRAF-altered gliomas, they could learn more about these variations.

The study was carried out retrospectively using patient records from Johns Hopkins, Dana-Farber Cancer Institute, and two public databases, representing a total of over 200 adults with BRAF-mutant glioma. The data included clinical and molecular data and outcomes for most patients. Most samples were obtained at initial diagnosis, though some were collected at a follow-up resection or another time. These data were compared to samples from 90 children with glioma.

The most striking finding from the study, Schreck said, was that pediatric BRAF-altered glioma is different from adult glioma even when they have the same driver alteration. "When there is a BRAF V600E alteration, the pediatric patients had lower-grade tumors and different survival curves than in the adults," said Schreck.

Similarly, she noted that rearrangements are very common in children but less common in adults. And in children, those would be indolent tumors, whereas in adults, a third to half of them behaved more like glioblastoma. "You cannot just assume based on having an alteration that is thought to be low grade in pediatrics that it will be the same in adults," Schreck said.

Adults whose tumors carried a BRAF V600E mutation, on average, survived longer compared to those with other BRAF alterations. However, for those that specifically had high-grade glioma, or glioblastoma, those with the V600E mutation fared just as poorly as those without it. "When you have a patient with a glioblastoma, having that BRAF alteration is not going to change the natural history of that disease," said Schreck. She noted, however, that patients with BRAF V600E alterations benefited from targeted therapy and lived longer than matched cohorts and that further study is needed to define those benefits.

Several drug companies are evaluating BRAF-targeted therapies in glioma. Day One Biopharmaceuticals is investigating its pan-RAF kinase inhibitor tovorafenib in the FIREFLY-1 Phase II trial in relapsed pediatric patients with low-grade glioma (pLGG); in the FIRELIGHT-1 Phase I/II trial in patients with recurrent or progressive solid tumors with activating RAF alterations; and in the FIREFLY-2/LOGGIC Phase III study for newly diagnosed patients with pLGG. Pfizer conducted a small study of its BRAF-targeted drug Braftovi (encorafenib) with Mektovi (binimetinib) in adults with recurrent BRAF V600-mutated high-grade glioma, finding that the drug combo led to tumor responses in three out of five patients.

Bi said their study highlights differences in BRAF-mutated glioma that vary according to the type of alteration, the tumor context, and age and suggests that BRAF-targeted therapies could have a role in more complex tumors, such as glioblastoma, which have many driver mutations.

However, according to Bi, an equally important outcome of improved understanding of the role of BRAF alterations in glioma is patient empowerment. "Patients are increasingly educated and frequently read primary sources of literature," said Bi. "This can help empower both adults and parents of pediatric patients to think about available options [when they receive] molecular testing of a tumor."

"One of the wins in neuro-oncology is that patients' tumor tissues are being tested more frequently for genomic alterations that could be actionable, and so BRAF alterations are being identified even in nonacademic settings," said Schreck.

The researchers said that next steps in understanding the role of BRAF in glioma would be to investigate the interplay of genomic alterations with the tumor microenvironment and characterize mechanisms of resistance to BRAF-targeted therapies in order to develop next-line therapies.