IDH-mutant gliomas are a distinct subclass of gliomas defined by a cancer-associated mutation in the IDH1 or IDH2 enzyme. The IDH mutation arises early during gliomagenesis and, in most cases, persists throughout the lifespan of the tumor. Mutant IDH-mediated accumulation of the oncometabolite R-2-hydroxyglutarate is thought to drive glioma development, and, as such, inhibition of this oncogenic activity has been viewed as a potential therapeutic strategy. Several IDH inhibitors have been under clinical investigation in patients with glioma. Ivosidenib, an IDH1-specific inhibitor, and Vorasidenib, a dual IDH1 and IDH2 inhibitor, are the farthest along in development. In phase Ⅰ studies, both compounds demonstrated favorable safety profiles and preliminary evidence of anti-glioma activity in patients with recurrent, non-enhancing glioma on MRI. Vorasidenib is now being tested in a randomized phase Ⅲ trial in patients with low-risk IDH-mutant gliomas (NCT04164901).
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