New data have brought clarity to therapy decision-making about targeted therapy for adult patients with glioma who test positive for BRAF oncogene mutations. A study reported at the 2022 34th EORTC-NCI-AACR Symposium suggests that some adults could potentially be treated with existing licensed BRAF-targeted drugs and that more subsets of patients could soon receive new agents when approved.
Researchers from Baltimore conducted a molecular and clinical analysis of BRAF-mutant glioma in adults. They concluded that next-generation sequencing (NGS) could benefit all patients with primary brain cancers-not just children-by helping clinicians choose an appropriate drug from among existing BRAF-targeted agents and others in the pipeline which could be approved soon.
"I think this gives us a potential treatment for a subset of patients with what is otherwise an incurable cancer," noted Karisa Schreck, MD, PhD, Assistant Professor of Neurology, Oncology and Neurosurgery, and Co-Director of the BRAF Brain Tumor Center at Johns Hopkins Medicine in Baltimore, after presenting her results at the symposium.
The study found a broad range of potentially targetable molecular alterations in gliomas from adults. So some tumors could potentially be treated off-label (or entered into clinical trials) with BRAF-targeted agents that had already been approved for use in other cancers, said Schreck. Adult patients with gliomas driven by other BRAF mutations could soon be entering trials with new agents.
Among the study's 206 adults with BRAF-mutated gliomas, those with the so-called class one mutation (BRAF V600E) could potentially be treated or entered into trials using approved anti-BRAF V600E drugs. Trials with other mutation-specific agents could then follow. This required next-generation sequence for all adults with glioma, according to the researchers.
The study compared the records of adult patients with BRAF-mutated gliomas with those from a cohort of nearly 100 pediatric patients. In the adult cohort, they found the most common mutation was V600. "This is the mutation for which there are FDA-approved targeted therapies," Schreck stated.
The researchers also found several other BRAF mutations currently without FDA-approved therapies-including class two and class three features (common in melanoma and other tumors driven by BRAF alteration). "What these results tell us is that there are many BRAF mutations," she noted. "Some could have direct therapeutic implications. But for others we don't know yet."
Schreck urged that clinicians should make it a priority to look for BRAF mutations in these patients. "I think the clearest signal [from our study] is that we should be looking for BRAF alterations in all patients with primary brain cancer-not just children. So, adults-even elderly adults-should have next-generation sequencing to look for targetable alterations."
Researching an Unmet Need
Schreck began her interest in BRAF mutations in adults with gliomas after taking care of several adult patients who turned out to have had this molecular marker. "And we really didn't know how best to treat them. [There was] very little data on how common their mutation was," she said. This led her team to investigate how many patients had this mutation.
Although children with gliomas more commonly had mutations in BRAF than adults, it had emerged that most low-grade gliomas in children had drivers in the extracellular signal-regulated kinase signaling pathway. BRAF was one of those drivers and-in children-could be targeted by approved drugs.
"In adults it's more complicated," said Schreck. "More commonly, the cancer that arises from the central nervous system is glioblastoma, a high-grade glioma, and more commonly the mutations that arise are in the PI3K signaling pathway or EGFR."
Schreck said that targeting BRAF mutations in adult glioma was tricky. "Not all BRAF alterations are the same. So, if there's a molecular tumor board available at [your] institution, [you] should access that." She said that her institution-The BRAF Brain Tumor Center at Johns Hopkins-could provide recommendations or a second opinion on the best targeted therapy. "Because it's different for each mutation."
When she was asked if the outlook for BRAF-mutant glioma had improved following her group's investigation, she said it was complicated. "If you take a patient with a glioblastoma who has a BRAF V600E mutation, do they live longer than patients who don't? And the answer is no. However, we looked at patients who received targeted therapy versus those who didn't. In those patients, the answer is yes. They do live longer."
Schreck said that this finding of an extension of life in patients treated with a targeted BRAF therapy had not been controlled for factors such as compliance or performance status. "But we definitely see a benefit," she said.
She warned, however, that BRAF-targeted therapies should be avoided in patients who do not have the specific mutation the drug is designed for. Such agents could even make the cancer grow faster.
"So, it's very important to make sure you pick the right ones. Recognizing that there is a BRAF alteration on NGS-but then knowing it's the right kind for the targeted therapy that you have-is critical."
When she was asked to spell out the procedure she recommended for clinicians, she said that NGS was needed on all patients with glioblastoma and other gliomas.
"[When identifying] BRAF alteration, if it is a V600 alteration, targeted therapy could be beneficial for this patient. If it is a different alteration, I definitely recommend a molecular tumor board to understand whether a clinical trial or other off-label targeted therapy could be useful."
Peter M. Goodwin is a contributing writer.