Work

Vemurafenib and cobimetinib overcome resistance to vemurafenib in BRAF -mutant ganglioglioma

Year: 2018

Type: article

Abstract: V-raf murine sarcoma viral oncogene homolog B1 ( BRAF V600E) mutations are found in more than half of pleomorphic xanthoastrocytomas (PXA) and gangliogliomas, 2 rare primary brain tumors mainly affecting children and young adults.1 While patients with low-grade PXA and ganglioglioma typically carry a relatively favorable prognosis, clinicopathologic features such as older age, malignant histopathologic characteristics, as well as loss of p16/ CDKN2A are associated with aggressive behavior and unfavorable outcome.2 The BRAF inhibitor (BRAFi) vemurafenib showed activity in patients with BRAF V600E-mutant anaplastic PXA and ganglioglioma,3 representing one of the most significant successes of targeted therapy in gliomas over the past years. However, and as expected from experience in other cancers, acquired resistance to vemurafenib invariably develops. To date, there is no satisfactory therapeutic option for patients that have progressed on vemurafenib. Studies in BRAF V600E-mutant melanoma showed that a subset of tumors develop resistance to BRAFi through molecular events reactivating the mitogen-activated protein kinase (MAPK) pathway, such as NRAS , KRAS , or MEK mutations.4 This provided rationale for combined BRAF/MEK inhibition, which demonstrated superior outcomes in comparison to BRAFi monotherapy in BRAF V600E-mutant melanoma.5 We hypothesized that acquired resistance to vemurafenib may result from persistent MAPK activation in anaplastic ganglioglioma, and that combined BRAF/MEK inhibition could overcome resistance. In support of this, we report that combined treatment with vemurafenib and the MEK inhibitor cobimetinib resulted in major clinical benefit in a patient with refractory BRAF V600E-mutant anaplastic ganglioglioma who had progressed while receiving single-agent vemurafenib.

Source: Neurology

DOI: 10.1212/wnl.0000000000006171