Targeting Mutant IDH to Treat Low-grade Glioma

Abstract

Adult-type diffuse low-grade gliomas (LGGs) develop in young adults and represent 5–10% of all primary brain tumours. While patients with LGG can survive longer than those with higher-grade tumours, progression, transformation and, ultimately, mortality occur. Median overall survival for patients with LGGs with multimodal treatment is roughly 13 years from time of diagnosis. Treatment regimens include surgery, radiation therapy and chemotherapy and are based not only on older clinical trials specific to LGG, but also on observations from larger trials in more prevalent high-grade gliomas, such as glioblastoma. LGGs are genetically distinct from glioblastoma, as they harbour mutations in isocitrate dehydrogenase, a key enzyme in the Krebs cycle, and this mutation leads to the production of 2-hydroxyglutarate, the critical driver of gliomagenesis. This article summarizes LGG treatment and how the recent results from the pivotal INDIGO (ClinicalTrials.gov identifier: NCT04164901) study involving vorasidenib, an oral brain-penetrant IDH mutant inhibitor, will change future treatment regimens and outcomes for patients with IDH-mutant LGG.