KS02.6.A INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE III STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH RESIDUAL OR RECURRENT GRADE 2 GLIOMA WITH AN IDH1/2 MUTATION
Authors: Mellinghoff I K , van den Bent M J , Blumenthal D T , Touat M , Peters K B , Clarke J , Mendez J , Welsh L , Mason W P , Hottinger A F , Sepulveda J M , Wick W , Soffietti R , Schoenfeld S , Zhao D , Pandya S , Steelman L , Hassan I , Wen P Y , Cloughesy T F 
Published: September 2023

Abstract

BACKGROUND
Grade 2 gliomas are slowly progressive, malignant brain tumours with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and chemotherapy) are not curative and can be associated with short- and long-term toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease-defining characteristic in the World Health Organization (WHO) 2021 definition. Vorasidenib (VOR) - an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes - has shown a tolerable safety profile and preliminary clinical activity in Phase I studies.

MATERIAL AND METHODS
In this randomized, double-blind, placebo (PBO)-controlled Phase III study (NCT04164901), patients (pts) were randomized 1:1 to receive VOR 40 mg daily or PBO daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumour size. Key eligibility criteria included: age ≥12; Karnofsky performance scale (KPS) &gt;80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI).

RESULTS
As of 6 Sep 2022 (2nd planned interim analysis data cutoff), 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Of the 331 pts: median age: 40.4 years (range, 16-71); KPS =100: 53.5%; histological subtype: oligodendroglioma (172) and astrocytoma (159); median time from last surgery until randomization: 2.4 years. Two hundred twenty-six (68.3%) pts remained on treatment (VOR: 131; PBO: 95). PFS by BIRC was statistically significant in favour of the VOR arm (HR 0.39, 95% CI 0.27-0.56; P=0.000000067). Median PFS: VOR: 27.7 months (mo); PBO: 11.1 mo. TTNI was statistically significant in favour of the VOR arm (HR 0.26, 95% CI 0.15-0.43; P=0.000000019). Median TTNI: PBO: 17.8 mo; VOR: not reached. All reported P values are one sided. All-grade adverse events (AEs) occurring in &gt;20% pts receiving VOR vs PBO were alanine aminotransferase (ALT) increased (38.9 vs 14.7%); COVID-19 (32.9 vs 28.8%); fatigue (32.3 vs 31.9%); aspartate aminotransferase increase (28.7 vs 8.0%); headache (26.9 vs 27.0%); diarrhoea (24.6 vs 16.6%); nausea (21.6 vs 22.7%). Common grade ≥3 AEs (&gt;5%): ALT increased (9.6% vs 0%).

CONCLUSION
This is the first prospective, randomized Phase III study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC, compared with PBO, with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed.