Gliomas are the most common type of primary brain tumors in adults. Despite important advances in understanding the molecular pathogenesis and biology of these tumors, these advances have not translated into significant improvements in treatments or outcomes for patients. Possible reasons for this lack of clinical progress include the relative rarity of gliomas, the challenges of designing therapeutics that cross the blood-brain barrier, and tumor heterogeneity. The identification of therapeutic targets in glioma and precision cancer medicine is a high unmet need.BRAF V600 mutations are involved in activating the MAPK pathway in multiple tumor types, including up to 15% of low-grade gliomas and 3% of glioblastomas. Dual blockade of the MAPK pathway with the BRAF inhibitor dabrafenib, and the MEK inhibitor trametinib has demonstrated clinically meaningful efficacy in BRAF V600E-mutated melanoma, anaplastic thyroid cancer, and non-small cell lung cancer, and is standard of care for patients harboring this mutation. The activity and safety of this combination in patients with rare tumors harboring BRAF V600E mutations were evaluated in a multicohort multicenter, single-arm, phase II basket trial, the Rare Oncology Agnostic-Research (ROAR) trial.

The results from the preplanned interim analysis of patients with relapsed/refractory BRAF V600E mutant low- and high-grade glioma in the ROAR trial were recently reported.  During a 4-year period, the investigators enrolled 45 patients in the high-grade cohort, including 31 patients with glioblastoma, and 13 patients in the low-grade glioma cohort. The study’s primary endpoint was investigator-assessed objective response rate (ORR) according to Response Assessment in Neuro-Oncology (RANO) criteria. The median follow-up was 12.7 months in the high-grade group, and 32.2 months in the low-grade cohort. Fifteen patients (33%) in the high-grade cohort had an objective response, including 3 complete responses (CR). In the low-grade cohort, 9 patients (69%) had an objective response, including 1 CR. Independent radiology review corroborated these results, identifying 31% of the high-grade cohort and 69% of the low-grade cohort as having achieved an objective response. The duration of response per independent review was 13.6 months and 27.5 months for high-grade and low- grade glioma, respectively. Of note, overall survival (OS) for patients with high-grade glioma treated with dabrafenib/trametinib was 17.6 months (13.6 months for glioblastoma), which is more than double the OS reported with chemotherapy for patients with pretreated recurrent/refractory disease. Half of the patients experienced grade 3 or higher adverse events; the most common were fatigue (9%), decreased neutrophil count (9%), headache (5%), and neutropenia (5%). There were no treatment-related deaths in either cohort. In general, the combined safety profile was consistent with that observed in other tumor types.

In concluding that dabrafenib plus trametinib showed significant response rates and durable clinical benefit in patients with recurrent gliomas with BRAF V600E mutations, the authors noted that this study is the first to show clinically meaningful activity in glioblastoma from any targeted therapies. They believe these results warrant further study of this drug regimen in the same study population, as well as in treatment-naïve patients who harbor BRAF V600E mutations. Additionally, they recommend that clinicians who care for patients with glioma incorporate molecular screening strategies that include BRAFV600E mutations to identify patients who might benefit from this treatment combination. Katherine B. Peters, MD, PhD, of Duke Cancer Center, who commented on the study, agreed and noted that this study “represents a paradigm shift in thoughtfully integrating targeted therapies into care of patients with glioma.”

Reference:
Wen PY et al. Lancet Oncol. 2021 Nov 24. [Online ahead of print].