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Modeling therapy sequencing in IDH-mutant glioma reveals that the mutant IDH inhibitor vorasidenib improves chemoradiation response

ABSTRACT: The mutant IDH1/2 inhibitor (mIDHi) vorasidenib was recently incorporated into clinical treatment guidelines for IDH-mutant gliomas, although its impact on chemoradiation is unclear. Specifically, it is unknown whether upfront mIDHi exposure alters subsequent chemoradiation efficacy. Addressing this critical question has been challenging due to limited clinical data and a paucity of mIDHi-responsive preclinical glioma models. We aggregated 29 patients across three institutions who were among the earliest to receive mIDHi prior to radiation+/-chemotherapy. We report outcomes of these patients compared to a similarly treated mIDHi-naïve cohort. To empirically address how mIDHi affects chemoradiotherapy efficacy, we used a mIDHi-responsive genetic mouse model of IDH-mutant astrocytoma. Mice that received vorasidenib before chemoradiation (vorasidenib-->chemoradiation) had improved survival compared to control mice (vehicle-->chemoradiation). In sum, we find no evidence from emerging real-world clinical data that upfront mIDHi therapy diminishes efficacy of subsequent chemoradiation. Moreover, preclinical modeling demonstrates that prior vorasidenib treatment enhances, rather than impairs, chemoradiation sensitivity of IDH-mutant glioma.

ORGANISM(S): Mus musculus

PROVIDER: GSE328196 | GEO | 2026/08/25

REPOSITORIES: GEO

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Modeling therapy sequencing in IDH-mutant glioma reveals that the mutant IDH inhibitor vorasidenib improves chemoradiation response

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