10204-CS-21 Exploratory analyses from the INDIGO study on the mechanism of seizure control by vorasidenib through tumor volume reduction

Abstract Background Patients with grade 2 IDH1/2 mutant (mIDH1/2) gliomas may experience symptoms (e. g. seizures) that impact their daily lives. Vorasidenib, an oral, brain-penetrant, dual inhibitor of mIDH1/2, has shown significant clinical benefits, including gradual tumor shrinkage, and a manageable safety profile in the Phase 3 INDIGO study. Herein, we investigate the potential relationship between vorasidenib and seizure rate, and between tumor volume and seizure activity in patients with mIDH1/2 glioma. Methods Patients aged >12 years with grade 2 mIDH1/2 oligodendroglioma or astrocytoma, no prior treatment for glioma other than surgery, and no uncontrolled seizures were randomized 1:1 to receive vorasidenib 40 mg or placebo daily. Exploratory analyses for the number of on-treatment seizures were conducted in patients with more than 1 seizure in the baseline or on-treatment periods using a negative binomial regression model. The potential association between seizure activity and tumor volume was assessed using the mixed-effect model with repeated measurements. P-values were not prespecified. Results This analysis included 168 patients treated with vorasidenib (oligodendroglioma: n = 88; astrocytoma: n = 80) and 163 patients treated with placebo (oligodendroglioma: n = 84; astrocytoma: n = 79). Patients treated with vorasidenib had lower on-treatment rates of seizures than those treated with placebo (model-estimated rate of on-treatment seizures per person-year: 18.2 [95% confidence interval (CI) 8.4, 39.5] vs 51.2 [95% CI 22.9, 114.8]; ratio of rates: 0. 36 [95% CI 0.14, 0. 89]; P = 0.0263). There was a highly positive correlation between tumor volume and seizure number (log tumor size estimate of coefficient: 0.7; standard error: 0.26; P = 0.007). Conclusion Treatment with vorasidenib was associated with lower seizure activity than with placebo in patients with mIDH1/2 glioma. Smaller tumor volume was associated with a lower seizure rate. Since treatment with vorasidenib also leads to gradual tumor shrinkage, these results suggest a potential mechanism of seizure control by tumor size reduction with vorasidenib.