10205-CB-7 Preclinical and clinical assessment of salvage chemoradiation after mutant IDH inhibitor treatment in glioma

Abstract Background How mutant IDH inhibitors (mIDHi) impact salvage therapy efficacy in glioma is an increasingly clinically relevant question, though this has been difficult to address due to a lack of clinical data and mIDHi-responsive preclinical glioma models. Methods We identified patients treated with radiation (RT) following progression on mIDHi and report clinical outcomes. To experimentally address whether mIDHi treatment impacts salvage chemoradiotherapy, we developed and used a genetically engineered mouse model (GEMM) of IDH-mutant astrocytoma. We first assessed response of our GEMM to vorasidenib monotherapy. We then used our GEMM to test whether progression on vorasidenib affects salvage chemoradiotherapy efficacy. To do this, we treated mice with vorasidenib or vehicle until tumor progression on MRI. Vorasidenib/vehicle treatments were then stopped, and mice were randomized to concurrent RT and temozolomide (TMZ) or sham salvage treatments and assessed for survival. We also performed single-cell RNA sequencing, spatial transcriptomics, metabolomics, and whole exome sequencing on treated tumor samples. Results Nineteen patients across two institutions received RT+/-chemotherapy after mIDHi. At a median follow-up of 10.2 months, no progressions following RT were observed. In our GEMM, vorasidenib displayed monotherapy antitumor activity (survival: 6.1 vs. 7.2 months in vorasidenib and vehicle arms respectively, P = 0.0008) and reduced tumor growth by ∼3-fold. Mice that received vorasidenib followed by RT/TMZ displayed improved survival compared to mice that received vehicle prior to salvage RT/TMZ (P = 0.029). This effect was specific to the interaction between vorasidenib and RT/TMZ, as there was no survival difference between sham salvage arms (P = 0.978). Conclusions Vorasidenib improved response to salvage RT/TMZ in an mIDHi-responsive glioma GEMM. We complemented these findings by assessing outcomes of patients treated sequentially with mIDHi and salvage chemoradiation. Taken together, our results suggest that prior mIDHi therapy does not impair and may enhance efficacy of salvage chemoradiation.