P12.22.a a Genetic Mouse Model of Idh-Mutant Glioma Responds to Mutant Idh Inhibition and Reveals Enhanced Efficacy of Salvage Chemoradiation After Vorasidenib

BACKGROUND The mutant isocitrate dehydrogenase (IDH) inhibitor vorasidenib is increasingly being incorporated as first-line treatment for diffuse IDH-mutant gliomas, though how vorasidenib affects efficacy of salvage chemoradiation is unknown. MATERIAL AND METHODS We developed a genetically engineered mouse model (GEMM) of IDH-mutant astrocytoma (harboring Idh1, Atrx, Trp53, and Pik3ca mutations) and used this model to study the response to vorasidenib monotherapy. We then employed this GEMM in a 4-arm study testing a clinically relevant sequence of therapies. Mice were first treated with vorasidenib or vehicle. At time of tumor progression on MRI, vorasidenib and vehicle treatments were stopped, and mice were randomized to concurrent radiation (RT) and temozolomide (TMZ) or sham salvage treatments and assessed for survival. We also obtained molecular correlates to these studies, including single-cell RNA sequencing (scRNAseq), spatial transcriptomics, metabolomics, and whole exome sequencing data. RESULTS Vorasidenib displayed monotherapy antitumor activity in our IDH-mutant glioma GEMM, extending median survival by 17% (n = 21 and 22 in vorasidenib and vehicle arms respectively, 6.1 vs. 7.2 months, P = 0.0008) and reducing tumor growth by ~3-fold. scRNAseq revealed that vorasidenib treatment caused astrocytic differentiation of tumor cells, consistent with observations in human gliomas. Mice that received vorasidenib followed by RT/TMZ displayed improved overall survival compared to mice that received vehicle prior to salvage RT/TMZ (n = 17 and 14 respectively, P = 0.029). A survival benefit was not observed between vorasidenib- and vehicle-treated mice randomized to sham salvage (n = 10 and 11 respectively, P = 0.978), suggesting that this effect was specific to the interaction between vorasidenib and RT/TMZ. CONCLUSION Our data introduce a preclinical model of IDH-mutant glioma that is responsive to vorasidenib and can be used to study treatments involving vorasidenib in diffuse gliomas. Data from our GEMM suggest that vorasidenib does not impair but rather enhances efficacy of salvage chemoradiation in IDH-mutant gliomas. Salvage chemoradiation may therefore be effective in IDH-mutant glioma patients who have progressed on a mutant IDH inhibitor. Ongoing studies aim to further elucidate mechanisms underlying interactions between mutant IDH inhibitors, radiation, and chemotherapy.