Impact of vorasidenib vs placebo on seizure rates and quality of life: Exploratory analysis from the phase 3 INDIGO study.

2043 Background: Grade 2 diffuse gliomas with isocitrate dehydrogenase 1/2 mutations (mIDH1/2) are incurable brain tumors with poor long-term prognosis and tumor-related symptoms, eg seizures, that negatively impact patients’ (pts) quality of life (QoL). Vorasidenib (VOR) is an oral, brain-penetrant, dual inhibitor of mIDH1/2 approved in >40 countries for treating grade 2 mIDH1/2 gliomas following the positive clinical outcomes, including tumor volume reduction, shown in the Phase 3 INDIGO study (NCT04164901). We investigated the effect of long-term VOR treatment on seizure activity and QoL in pts with mIDH1/2 glioma in INDIGO. Methods: Pts aged ≥12 years with grade 2 mIDH1/2 glioma, no prior glioma treatment other than surgery and with controlled seizures were randomized 1:1 to receive VOR 40 mg or placebo (PBO) daily. Data from the pre- and post-unblinding periods were used; PBO pts after crossover were excluded from the analyses. Exploratory analyses for the number of on-treatment seizures were conducted in pts with ≥1 seizure in the baseline or on-treatment periods using a negative binomial regression model. Seizure severity was self-reported (1 [not bad] to 10 [as bad as imaginable]). QoL was measured using the Functional Assessment of Cancer Therapy – Brain (FACT-Br) scale and FACT-Br brain cancer subscale (BrCS), and changes were estimated with time-to-event analysis. Results: During the study, 110/331 pts (33.2%) reported ≥1 seizure (VOR n=55; PBO n=55). VOR treatment showed a constant and sustained effect on seizure control, reflected by significantly lower seizure rates per person per year than in the PBO group (Table), and lower number and severity of seizures over time. In addition, in pts with a seizure burden (≥1 seizure), VOR significantly delayed time to first worsening of FACT-Br and FACT-Br BrCS scores (hazard ratio [95% confidence interval]: FACT-Br, 0.38 [0.15, 1.00], P =0.0435; FACT-Br BrCS, 0.32 [0.11, 0.91], P =0.0263). Conclusions: In pts with mIDH glioma and ≥1 on-study seizure, long-term VOR treatment generally led to a sustained decrease in seizure activity and severity and delayed worsening of QoL. These results suggest that VOR may have an additional benefit on QoL in pts who experience seizures. Clinical trial information: NCT04164901 . Exploratory analyses of VOR treatment and seizure rate in pts who reported ≥1 seizure in the baseline or on-treatment periods in INDIGO. VOR(n = 56) PBO(n = 56) Patients with ≥1 on-treatment seizure, n (%) 55 (98.2) 55 (98.2) Rate of on-treatment seizures per person-year* (95% CI) 13.2 (5.8, 29.8) 64.9 (26.5, 159.1) Ratio of rates: VOR vs PBO (95% CI) 0.20 (0.08, 0.52) Two-sided P value † 0.0008 *Estimated using negative binomial regression model adjusted by number of seizures and tumor size at baseline. † Not prespecified and not adjusted for multiplicity; should be interpreted with caution. Data cut-off: January 17, 2025. CI, confidence interval; PBO, placebo; VOR, vorasidenib.