Prolonged Complete Response With Combined Dabrafenib and Trametinib After BRAF Inhibitor Failure in BRAF-Mutant Glioblastoma

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumor.1 Despite aggressive multimodality treatment, median overall survival (OS) is 14 to 18 months.2 One potential novel therapeutic target is V-raf murine sarcoma viral oncogene homolog B1 (BRAF), which is mutated in 1% to 2% of GBM,3-6 as well as other primary brain tumors including pleomorphic xanthoastrocytoma (PXA) and ganglioglioma. BRAF is among the most commonly mutated kinases in human cancer, particularly in melanoma.7 Typically regulated by extracellular factors, mutant BRAF results in uncontrolled cellular growth via the MEK-ERK extracellular signal-regulated kinase pathway.6 Although oral inhibitors of the oncogenic BRAFv600 kinase have demonstrated some efficacy in gliomas, several mechanisms mediating resistance to BRAF inhibitors (BRAFis) are described. Moreover, this therapy is associated with an increased risk of hyperproliferative skin lesions such as squamous cell carcinoma.8 Combining BRAF with MEK inhibitors mitigates these effects and improves progression-free survival and OS compared with BRAFi monotherapy in metastatic melanoma.9-12 Furthermore, studies demonstrate that the use of BRAFi in combination with MEK inhibitors prevents the development of resistance because of the reactivation of the MAPK pathway while simultaneously decreasing hyperproliferative skin lesions.8 Although there is strong evidence for the use of BRAF and MEK inhibitors in other malignancies, there are few cases in the literature of primary brain tumors treated with this combination, mainly in pediatric glioma.13-15 We present a case of a patient with a recurrent BRAF-mutant GBM, who had a clinical and radiographic response when treated with BRAFi dabrafenib in combination with MEK inhibitor trametinib (D+T), after failing treatment with BRAFi monotherapy.

Topics & Concepts