Gliomas are the most common primary tumours of the brain, diagnosed in approximately six per 100 000 people in the USA annually.1 The 2016 WHO criteria classify tumours into subtypes and grades based on histopathology and molecular and genetic markers, especially IDH (isocitrate dehydrogenase) mutational status and 1p/19q loss.2 The revised 2021 WHO criteria present changes that advance the role of molecular diagnostics in the classification of CNS tumours and different approaches to both nomenclature and grading of CNS tumours.3 Treatment options are dependent on histological classification and include maximal surgical resection where possible, with the potential addition of radiotherapy, with or without temozolomide-based or lomustine-based chemotherapy.4, 5 Treatment of recurrent glioblastoma with temozolomide is associated with poor response rates of 5–8%.6, 7, 8 The anti-VEGF monoclonal antibody bevacizumab is approved for recurrent glioblastoma; however, an improvement in overall survival has not been shown.9 Grade II and III IDH-mutated tumours, such as astrocytomas and oligodendrogliomas, have a better outcome and typically benefit more from the addition of chemotherapy to radiotherapy than glioblastomas.5 For IDH wild-type and circumscribed low-grade gliomas, such as gangliogliomas and pleomorphic xanthoastrocytomas, the effect of chemotherapy after incomplete resection or for inaccessible tumours is less clear.10, 11 Options are scarce for patients with low-grade glioma who progress after chemotherapy, and there is a risk of transformation to high-grade glioma and a much poorer prognosis over time.12 No substantial treatment advances have been made in recent years, with progress being hampered by the rarity of gliomas, difficulty in designing treatments capable of penetrating the blood–brain barrier, and molecular heterogeneity.4, 13
Research in context
Evidence before this study
We searched PubMed for reports of clinical trials published in English using the terms “BRAF-mutant”, “BRAF V600E”, “targeted therapy”, “immunotherapy”, “refractory clinical trial”, “glioma”, “low-grade glioma”, and “high-grade glioma”. We did not restrict our search by date. Our search results showed that no notable treatment advances have been made in the field of glioma in recent years, due to the rarity of these tumours, difficulty in designing treatments capable of penetrating the blood–brain barrier, and intertumoural and intratumoural heterogeneity. There has been progress in understanding the molecular pathogenesis and biology of these tumours, but it has not led to significantly improved outcomes for patients. Moreover, the prognostic significance of the BRAFV600E mutation in adult patients with glioma is unclear and could vary with histological subtype, with no specific treatment identified for this patient population. Dabrafenib has shown meaningful clinical activity in paediatric patients with BRAFV600E-mutant high-grade glioma and low-grade glioma. Vemurafenib has also shown durable antitumour activity in patients with BRAFV600-mutant gliomas. There is also emerging evidence that acquired resistance to BRAF inhibitor monotherapy develops in gliomas, which might be mitigated by dual inhibition. Dual blockade of the MAPK pathway using a combination of a BRAF inhibitor and a MEK inhibitor is now standard of care in BRAFV600-mutant melanoma, non-small-cell lung cancer, and anaplastic thyroid cancer and has shown activity in biliary tract cancer. Case reports of dabrafenib plus trametinib combination therapy in different types of gliomas were also found in our search.
Added value of this study
To our knowledge, this study is the first time that a combination of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) have shown notable activity in these difficult-to-treat gliomas, including glioblastomas, which have historically shown resistance to therapies. It is difficult to do clinical trials in this rare subset of patients who have scarce treatment options; however, the encouraging activity of the combination of dabrafenib and trametinib in this study suggests that targeting the MAPK pathway is a promising approach in these patients.
Implications of all the available evidence
The clinically meaningful and durable anti-tumour activity suggests that dabrafenib plus trametinib is a promising treatment option for patients with BRAFV600E-mutant recurrent high-grade glioma and low-grade glioma. Routine testing for BRAFV600E mutations should be considered in clinical practice for patients with glioma.
BRAF V600 mutations that constitutively activate the MAPK pathway have been identified in 5–15% of low-grade gliomas, including pleomorphic xanthoastrocytomas (60–80%), gangliogliomas (20–70%), pilocytic astrocytomas (10%), and less frequently in high-grade gliomas, including approximately 3% of glioblastomas.14 BRAFV600E mutations are typically mutually exclusive with IDH mutations.15 The prognostic significance of BRAFV600E mutations in adult patients with glioma is unclear and can vary with histological subtype.14, 15, 16, 17 No specific treatment has been identified for this subgroup of patients.
The BRAF inhibitor dabrafenib has shown meaningful clinical activity in paediatric patients with BRAF V600 mutation-positive low-grade glioma and high-grade glioma.18, 19 Dual blockade of the MAPK pathway using dabrafenib and the MEK inhibitor trametinib has shown activity in multiple tumour types and is a standard of care in BRAF V600-mutant melanoma, non-small-cell lung cancer, and anaplastic thyroid cancer.20, 21, 22, 23 Compared with BRAF inhibitor monotherapy, combined treatment showed superior outcomes with regard to progression-free survival and overall survival and reduced the incidence of skin-related toxicities in melanoma and non-small-cell lung cancer.20, 21, 22 Furthermore, there is emerging evidence that acquired resistance to BRAF inhibitor monotherapy develops in gliomas, as in other tumour types, which might be mitigated by dual inhibition.14, 24 Taken together, these data support the investigation of dabrafenib plus trametinib in adult patients with BRAFV600E mutation-positive glioma.
With no therapy showing a promising response, a high unmet medical need exists for low-grade glioma and high-grade glioma. We did a phase 2 basket study of dabrafenib plus trametinib in patients with BRAFV600E mutation-positive rare cancers (the Rare Oncology Agnostic Research [ROAR] trial). We report the activity and safety of this treatment combination in patients with relapsed or refractory BRAFV600E mutation-positive low-grade glioma and high-grade glioma from a preplanned interim analysis.