Js05.6.a Exploratory Analyses From Phase 3 Indigo Study Suggest Potential Mechanism of Seizure Control Through Tumor Volume Reduction Under Treatment With Vorasidenib

BACKGROUND Grade 2 isocitrate dehydrogenase 1 or 2 mutant (mIDH1/2) gliomas are slowly progressive, malignant, incurable brain tumors with poor long-term prognosis. Patients may experience tumor-related symptoms (eg 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 (NCT04164901). Herein, we investigate the potential relationship between vorasidenib and seizure rate and between tumor volume and seizure activity in patients with mIDH1/2 glioma. MATERIAL AND METHODS Patients aged ≥12 years with grade 2 mIDH1/2 oligodendroglioma or astrocytoma, with 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 ≥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. Due to the exploratory nature of these analyses, P-values were not prespecified and should be interpreted with caution. 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. Study sponsored by Servier.