A global, randomized, double-blinded, phase 3 trial of vorasidenib vs placebo in patients with grade 2 glioma with an IDH1/2 mutation (INDIGO): Updated efficacy and safety.

2010 Background: Grade 2 gliomas with isocitrate dehydrogenase 1/2 mutations (mIDH1/2) are diffuse, slowly progressive, malignant brain tumors with a poor long-term prognosis. In the Phase 3 INDIGO trial (NCT04164901) of patients (pts) with grade 2 mIDH1/2 glioma, vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mIDH1/2, demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint, progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint, time to next intervention (TTNI), vs placebo (PBO) at the preplanned interim analysis (data cut-off [DCO]: September 6, 2022). An additional 6 months of data up to study unblinding, March 7, 2023, showed that median PFS was not reached (95% confidence interval [CI]: 22.1 mos, not estimable [NE]) with VOR vs 11.4 mos (95% CI: 11.1, 13.9) with PBO, and median TTNI was NE (95% CI: NE, NE) with VOR vs 20.1 mos (95% CI: 17.5, 27.1) with PBO. Here, we present updated efficacy and safety results as of January 17, 2025, from pts randomized to VOR. Methods: Key eligibility criteria included residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma after surgery only; aged ≥12 years; Karnofsky performance score ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy (CT/RT). Pts were randomized 1:1 to VOR 40 mg daily in 28-day cycles or PBO. After study unblinding, pts receiving PBO were permitted to cross over to VOR. Primary endpoint: radiographic PFS per BIRC. Key secondary endpoint: TTNI. Results: 331 pts were randomized: 168 to VOR and 163 to PBO (median age: 40.0 years [range: 16–71]; oligodendroglioma: 172; astrocytoma: 159). As of January 17, 2025, 98/168 (58.3%) pts remained on VOR, and median follow-up was 41.6 mos (95% CI: 40.5, 42.7). Median PFS per investigator (INV) in pts randomized to VOR was 49.9 mos (95% CI: 39.6, NE), and median TTNI was NE (95% CI: 52.0 mos, NE). At 42 mos, 59.2% (95% CI: 49.9, 67.4) of pts were progression-free and 75.1% (95% CI: 67.4, 81.2) were not in need of CT/RT or surgery. Objective response rate per INV was 31.5% (95% CI: 24.6, 39.2). Median overall survival was not reached. PFS and overall response per BIRC will be presented. The safety profile of VOR was consistent with previous reports. No new safety signals were observed. Conclusions: In the randomized, Phase 3 trial of a targeted therapy in grade 2 mIDH1/2 glioma, over 3 years of follow-up in pts randomized to VOR support the robustness of PFS and TTNI results and confirm a durable and sustained treatment benefit with VOR. VOR is now approved in over 40 countries as a monotherapy for pts with grade 2 mIDH1/2 glioma following surgery. Clinical trial information: NCT04164901 .