Dabrafenib plus trametinib combination therapy showed clinically meaningful and durable activity in patients with recurrent or progressive BRAF V600E mutation–positive high-grade and low-grade glioma, according to phase 2 study results published in Lancet Oncology.

BRAF mutations are seen in about 3% of glioblastoma cases — considered the most aggressive brain tumor — with 15% classified as low-grade gliomas. Currently, there is no specific treatment for adult patients with glioma with BRAF V600E mutations. In previous studies, dual blockage of the mitogen-activated protein kinase pathway with dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) has shown encouraging activity in multiple tumor types, and it’s also the standard of care in BRAF V600-mutant melanoma, non-small-cell lung cancer, and anaplastic thyroid cancer. Moreover, the researchers believe acquired resistance to BRAF inhibitor monotherapy developed in gliomas and other tumor types could be due to dual inhibition.

The current objective of the study was to evaluate activity and safety of dabrafenib plus trametinib in adult patients with recurrent or progressive BRAF V600E mutation–positive high-grade and low-grade glioma.

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Researchers reported interim analysis findings from the ongoing multicenter, open-label, single-arm, phase 2, basket Rare Oncology Agnostic Research (ROAR) study ClinicalTrials.gov Identifier: NCT02034110).

The trial enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients were recruited from 27 community and academic cancer centers in 13 countries.

Participants received oral dabrafenib (150 mg orally twice daily) and oral trametinib (2 mg orally once daily) until unacceptable toxicity, disease progression, or death. Investigator-assessed objective response rate using the Response Assessment in Neuro-Oncology criteria was the primary endpoint.

A total of 206 patients with BRAF V600E mutation–positive tumors were enrolled from 8 of the 9 cohorts from April 17, 2014, to July 25, 2018. On the data cutoff on September 14, 2020, 45 patients were included in the high-grade glioma cohort and 13 were included in the low-grade glioma cohort.

Patients with high-grade glioma (51% male) had a median age of 42 years (range, 18-72), with a median time since diagnosis of 1.4 years and median follow-up of 12.7 months (interquartile range [IQR], 5.4-32.3). Patients with low-grade glioma (69% female) had a median age of 33 years (range, 18-58), with a median time since diagnosis of 6.9 years and a median follow-up of 32.2 months (IQR, 25.1-47.8).

Among high-grade glioma participants, 15 (33%; 95% CI, 20-49) had an objective response by researcher assessment, including 3 complete responses and 12 partial responses. According to an independent radiology review, 14 patients (31%; 18-47) had an objective response (3 complete and 11 partial). In the low-grade glioma cohort, 9 patients (69%; 95% CI, 39-91) had an objective response by investigator assessment and by independent radiology review, including 1 complete response, 6 partial responses, and 2 minor responses.

An overall total of 54 (93%) patients had an adverse event — 21 (47%) in the high-grade glioma cohort and 8 (61%) in the low-grade glioma cohort. Serious adverse events occurred in 15 (33%) patients in the high-grade glioma cohort (7 related to treatment) and 3 (23%) patients in the low-grade glioma cohort (1 related to treatment).

The most frequently reported serious adverse events in the high-grade glioma cohort were seizure (4), vomiting (2), headache (2), and nausea (2). Those in the low-grade glioma cohort included pyrexia, urinary tract infection, and vomiting (1 each).

The researchers noted that the quality-of-life analysis did not include specific neurocognitive data for low-grade or high-grade glioma, and the nonrandomized, single-arm design did not support reliable interpretation of quality of life in the absence of a control group.

“Patients in these cohorts had a sufficiently long follow-up and the unmet medical need in this patient population outweighs any concern of reporting interim analysis data,” stated the researchers.

Disclosure: This trial was originally designed and sponsored by GlaxoSmithKline. Novartis Pharmaceuticals Corporation is the current sponsor of the trial. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Wen PY, Stein A, van den Bent M, et al. Dabrafenib plus trametinib in patients with BRAFV⁶⁰⁰E -mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. Published online November 24, 2021. doi: 10.1016/S1470-2045(21)00578-7

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