498O - INDIGO: A randomized, double-blinded, phase III study of vorasidenib versus placebo in IDH1 or IDH2 low-grade glioma

Background

Grade 2 gliomas are slowly progressive brain tumours with poor long-term prognosis. Current treatments are not curative and can be associated with toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in nearly all grade 2 gliomas and are a disease-defining characteristic in the World Health Organization 2021 definition. Vorasidenib (VOR) is an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes.

Methods

In this double-blind phase 3 study, patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles, stratified by 1p19q status and baseline tumour size. Key eligibility criteria: age ≥12 y; Karnofsky performance scale (KPS) >80; residual or recurrent grade 2 mIDH1/2 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 review committee (BIRC). Key secondary endpoint: time to next intervention (TTNI).

Results

As of 6 Sep 2022 (2nd planned interim analysis data cut-off date), 168 pts were randomized to VOR and 163 to PBO (median age, 40.4 y; KPS=100, 53.5%; oligodendroglioma, 172; astrocytoma, 159; median time from last surgery to randomization, 2.4 y). Median follow-up was 14.2 mo. PFS by BIRC was significantly improved with VOR vs PBO (hazard ratio [HR] 0.39, 95% CI 0.27–0.56; 1-sided P=0.000000067). Median PFS: VOR, 27.7 mo; PBO, 11.1 mo. TTNI was significantly improved with VOR vs PBO (HR 0.26, 95% CI 0.15–0.43; 1-sided P=0.000000019). Median TTNI: VOR, not reached; PBO, 17.8 mo. In pts with IDH1-R132H variant (n=284, 85.8%) the HR for PFS by BIRC was 0.33 (95% CI 0.22–0.50). Adverse event of grade ≥3 elevated alanine aminotransferase was seen in 9.6% of pts with VOR (and 0% with PBO).

Conclusions

In the first randomized phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, VOR significantly improved PFS by BIRC compared with PBO, with a manageable safety profile. Findings show the clinical benefit of VOR in pts for whom chemotherapy and radiotherapy are being delayed. (NCT04164901 funded by Servier Pharmaceuticals LLC).

Clinical trial identification

NCT04164901.

Editorial acknowledgement

Medical writing assistance was provided by Debbi Gorman, PhD, at Cogent (an AMICULUM agency), funded by Servier Pharmaceuticals LLC..

Legal entity responsible for the study

Servier Pharmaceuticals LLC.

Funding

Servier Pharmaceuticals LLC.

Disclosure

D. Blumenthal: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Novocure, and Takeda; Financial Interests, Personal, Research Grant: Merck Sharp & Dome, Novocure; Financial Interests, Personal, Advisory Role: Servier Pharmaceuticals LLC. I.K. Mellinghoff: Financial Interests, Personal, Speaker, Consultant, Advisor: 501c3 Global Coalition for Adaptive Research; Financial Interests, Personal, Other, Honoraria: Doris Duke Charitable Foundation; Financial Interests, Personal, Advisory Board: Black Diamond Therapeutics, Roche Therapeutics, Prelude Therapeutics Incorporated, Voyager Therapeutics; Financial Interests, Personal, Research Funding: Erasca Therapeutics, Servier Pharmaceuticals LLC, Kazia Therapeutics, Vigeo Therapeutics, and Samus Therapeutics, Inc. M.J. van den Bent: Financial Interests, Personal, Speaker, Consultant, Advisor: Agios, Servier, AstraZeneca, Boehringer Ingelheim, Geneta, Incyte, Nerviano, Chimerix, Roche, Fore Biotherapeutics and Stemline Therapeutics. M. Touat: Financial Interests, Personal, Research Funding: Sanofi; Financial Interests, Personal, Speaker, Consultant, Advisor: Agios Pharmaceuticals, Servier Pharmaceuticals LLC and Novocure. K. Peters: Financial Interests, Personal, Advisory Board: Sapience, Servier Pharmaceuticals LLC, NuVox Therapeutics,Cordance Medical, and Vivicitas Oncology; Financial Interests, Personal, Research Funding: Varian, Biomimetix, Sapience, and Servier Pharmaceuticals LLC. J. Clarke: Financial Interests, Personal, Speaker, Consultant, Advisor: Agios Pharmaceuticals Inc. and Servier Pharmaceuticals LLC; Financial Interests, Personal, Research Funding: Merck, Agios Pharmaceuticals Inc. and Servier Pharmaceuticals LLC. W. Mason: Financial Interests, Personal, Advisory Board: Novocure, Merck; Financial Interests, Personal, Speaker, Consultant, Advisor: Boehringer Ingelheim, Century Therapeutics; Financial Interests, Personal, Research Funding: Hoffman La Roche, Servier Pharmaceuticals LLC, Orbus Therapeutics; Financial Interests, Personal, Other, Data monitoring committee: Ono Therapeutics. A.F. Hottinger: Financial Interests, Personal, Research Funding: Novocure; Financial Interests, Personal, Advisory Board: Novocure and Bayer. J.M. Sepulveda Sanchez: Financial Interests, Personal, Research Grant: Pfizer, IDP Pharma and Cantex; Financial Interests, Personal, Speaker, Consultant, Advisor: Cantex Pharma; Financial Interests, Personal, Advisory Board: MSD, Servier Pharmaceuticals, Novocure and CeCaVa. W. Wick: Financial Interests, Personal, Other, Honoraria: Apogenix, Bayer, Merck Sharp & Dome, AstraZeneca, Merck Serono, Novartis, Roche and Mundipharma; Non-Financial Interests, Personal, Other, Non-financial clinical trial support: Apogenix, Bayer, Merck Sharp & Dome, AstraZeneca, Merck Serono, Novartis, Roche and Mundipharma. R. Soffietti: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck Sharp & Dome, AstraZeneca, Merck Serono, Celldex Therapeutics, Novartis, Puma Technology, AbbVie, and Mundipharma. A. Tron: Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc; Financial Interests, Personal, Full or part-time Employment: Agios Pharmaceuticals Inc, Servier Pharmaceuticals LLC. D. Zhao: Financial Interests, Personal, Full or part-time Employment: Agios Pharmaceuticals Inc, Servier Pharmaceuticals LLC; Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc. S. Pandya: Financial Interests, Personal, Full or part-time Employment: Agios Pharmaceuticals Inc, Servier Pharmaceuticals LLC; Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc. L. Steelman: Financial Interests, Personal, Full or part-time Employment: Servier Pharmaceuticals LLC, Agios Pharmaceuticals Inc; Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc. I. Hassan: Financial Interests, Personal, Stocks/Shares: Agios Pharmaceuticals Inc; Financial Interests, Personal, Full or part-time Employment: Agios Pharmaceuticals Inc, Servier Pharmaceuticals LLC.. P. Wen: Financial Interests, Personal, Research Funding: AstraZeneca/MedImmune, BeiGene, Celgene, Chimerix, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier Pharmaceuticals LLC, Vascular Biogenics, and VBI Vaccines; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Boston Pharmaceuticals, Celularity, Chimerix, Day One Bio, Genenta, GSK, Karyopharm, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier Pharmac. T. Cloughesy: Financial Interests, Personal, Member of Board of Directors, Cofounder, major stock holder, consultant and board member: Katmai Pharmaceuticals; Financial Interests, Personal, Speaker, Consultant, Advisor: 501c3 Global Coalition for Adaptive Research, Sagimet, Clinical Care Options, Ideology Health, Servier Pharmaceuticals LLC, Jubilant, Immvira, Gan & Lee, BrainStorm, Katmai, Sapience, Inovio, Vigeo Therapeutics, DNATrix, Tyme, SDP, Novartis, Roche, Kintara, Bayer, Merck, Boehringer Ingelheim, VBL, Am; Financial Interests, Personal, Stocks or ownership, And receiving milestone payments and possible future royalties: Chimerix; Financial Interests, Personal, Stocks or ownership: Erasca; Non-Financial Interests, Personal, Membership or affiliation, Membership of the scientific advisory boards: Break Through Cancer and Cure Brain Cancer Foundation; Financial Interests, Personal, Other, Contracts with UCLA for the Brain Tumor Program: Oncovir, Merck, Oncoceutics, Novartis, Amgen, AbbVie, DNAtrix, BeiGene, Bristol Myers Squibb, AstraZeneca, Kazia, Agios, Boston Biomedical, Deciphera, Tocagen, Orbus, AstraZeneca, and Karyopharm; Financial Interests, Institutional, Licencing Fees, Regents of the University of California (T.F.C.’s employer) have licensed intellectual property co-invented by T.F.C. to Katmai Pharmaceuticals: Regents of the University of California. All other authors have declared no conflicts of interest.