New Analyses from Pivotal Phase 3 INDIGO Study Reinforce Vorasidenib's Potential to Change the Treatment Paradigm for IDH-Mutant Diffuse Glioma

Late-breaking analysis from pivotal INDIGO Phase 3 trial demonstrates vorasidenib led to tumor shrinkage in IDH1/2-mutant diffuse glioma

First data from Phase 1 trial show the safety and tolerability of vorasidenib plus KEYTRUDA® (pembrolizumab) in recurrent or progressive enhancing IDH1-mutant diffuse astrocytomas

BOSTON, Nov. 18, 2023 /PRNewswire/ -- New data from Servier's clinical development program for vorasidenib in IDH-mutant diffuse glioma, presented at the 28^th Annual Meeting of the Society for Neuro-Oncology (SNO) in Vancouver, Canada, showed that vorasidenib reduced tumor growth as measured by a blinded independent radiology committee. Additional data from the INDIGO study being presented at SNO include health-related quality of life data, indicating patients receiving vorasidenib experience preservation of quality of life, stable neurocognitive function, and seizure control, as well as translational data demonstrating vorasidenib's efficacy across IDH-mutant diffuse gliomas with various additional mutations.

"These data further add to the growing body of evidence in vorasidenib as a potential first-in-class treatment option in IDH-mutant diffuse glioma, and we look forward to the opportunity to deliver vorasidenib as the first targeted treatment option in this disease space to patients across the globe," said Susan Pandya, M.D., Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "With these analyses now complete, we are moving forward with the submission of a new drug application for vorasidenib in IDH-mutant diffuse glioma to the U.S. Food and Drug Administration by the end of 2023. We are honored and excited at the prospect of ushering in a new era of targeted treatment options for patients living with this devastating disease."

Vorasidenib has been granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA). Servier plans to submit a new drug application (NDA) for vorasidenib to the FDA by the end of 2023 and the European Medicines Agency (EMA) in early 2024, with commercial availability for the drug to be available at launch.

Impact of vorasidenib treatment on mutant IDH1 or IDH2 diffuse glioma tumor growth rate (Abstract # LTBK-06; late-breaker)

In the pivotal randomized, double-blind Phase 3 INDIGO^[1],[2] clinical trial, vorasidenib demonstrated a remarkable improvement in progression-free survival (PFS) with a median of 27.7 months for vorasidenib vs. 11.1 months for placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. In a late-breaking new analysis, treatment with vorasidenib reduced tumor growth rate (TGR) and shrunk tumor volume, whereas continued growth in tumor volume was observed in patients randomized to the placebo arm.

"Tumor growth rate is an innovative and advanced analysis that requires significant rigor to capture the impact of vorasidenib on these tumors beyond delaying disease progression," said Patrick Wen, Chief, Division of Neuro-Oncology, Dana Farber Cancer Institute. "These data from the INDIGO study offer the first prospective volumetric dataset in IDH-mutant gliomas and provide robust evidence that treatment with vorasidenib not only delays or prevents tumor growth, but also lead to tumor shrinkage."

In patients randomized to the vorasidenib arm, tumor volume decreased by a mean of 2.5% (TGR of -2.5%; 95% CI: -4.7 to -0.2) every 6 months, while tumor volume increased by a mean of 13.9% (TGR of 13.9%; 95% CI: 11.1 to 16.8) every 6 months for patients randomized to the placebo arm, as measured by a blinded independent radiology committee.

Phase 1 safety lead-in and randomized open-label perioperative study of vorasidenib combined with pembrolizumab in recurrent or progressive enhancing IDH1-mutant astrocytomas(Abstract # CTIM-14; oral)

In the first results from the safety lead-in of a new Phase 1 study, vorasidenib 40 mg orally once daily plus KEYTRUDA® (pembrolizumab), Merck & Co., Inc., Rahway, NJ., USA's anti-PD-1 therapy, 200 mg intravenously once every three weeks was safe and tolerable among seven patients with recurrent or progressive enhancing IDH1-mutant grade 2/3 astrocytoma.

As of April 2023, patients received a median of two (range, 2–5) cycles of combination treatment, with six ongoing and one discontinuation due to disease progression. No dose-limiting toxicities, adverse events (AE) leading to study drug discontinuation, or AEs of special interest were reported. Six patients (86%) experienced a treatment-related AE, none of which were higher than grade 2.

The safety lead-in was conducted to determine the recommended combination dose for the recently initiated perioperative phase of the study. In this phase, approximately 60 patients will be randomized to the combination treatment, vorasidenib 40 mg once-daily alone, or no treatment prior to surgery.

KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About Glioma³
Gliomas are tumors that arise from glial or precursor cells within the central nervous system (CNS). The 2021 WHO classification recognizes four general groups of gliomas, one of which is adult-type diffuse gliomas. These diffuse gliomas are the most common primary malignant brain tumors in adults. The pathogenesis and prognosis of these tumors are tightly linked to mutations (or lack thereof) in the metabolic enzyme isocitrate dehydrogenase (IDH), and molecular testing is required for proper diagnosis. As of 2021, adult-type diffuse gliomas are sub-divided into only three categories:

• Astrocytoma, IDH-mutant (CNS WHO grades 2-4)
• Oligodendroglioma, IDH-mutant and1p19q-codeleted (CNS WHO grades 2-3)
• Glioblastoma, IDH-wildtype (CNS WHO grade 4)

About Servier in Oncology
Servier is a global leader in oncology focused on delivering meaningful therapeutic progress for the patients it serves. Governed by a non-profit foundation, Servier approaches innovation with a long-term vision, free of influence from investors and outside pressure to chase short-term monetary targets.

As a leader in oncology, Servier has significantly accelerated its investment in difficult and hard-to-treat cancers, with more than 50% of its research and development dedicated to delivering significant advances in areas of high unmet need throughout oncology with the potential to change the lives of the patients it serves. Within these areas, Servier is the leader in mutant IDH inhibition, with the first ever mutant IDH1 inhibitor approved in the U.S. and the European Union, and the company continues to drive the science behind targeted mutant IDH inhibition.

Servier's commitment to therapeutic progress guides its collaboration strategy. While many companies across the industry are scaling back investments, Servier is actively building alliances, completing acquisitions, conducting licensing deals and entering new partnerships that can help to accelerate access to therapies for patients in need. With the company's commercial expertise, global reach, scientific expertise and commitment to clinical excellence, Servier is dedicated to bringing the promise of tomorrow to the patients it serves.

Press Contact
Servier Pharmaceuticals
Nathan Mellor
nathan.mellor@servier.com 

Disclosures

This release contains general information about the Servier Group and its entities (hereinafter "Servier and its Affiliates") and is intended for informational purposes only. The information is thought to be reliable; however, Servier and its Affiliates make no representation as to the accuracy or completeness of the information contained herein or otherwise provided and accept no responsibility or liability, in contract, in tort, in negligence, or otherwise, should the information be found to be inaccurate or incomplete in any respect.

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[1] Mellinghoff, I., et al. (2023). INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. Journal of Clinical Oncology, 41(17_suppl), LBA1–LBA1. https://doi.org/10.1200/jco.2023.41.17_suppl.lba1.

[2] Mellinghoff, I., et al. (2023). Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. The New England Journal of Medicine, 389:589-601. https://doi.org/10.1056/nejmoa2304194.

[3] Louis, D., et. al. (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncology, 23(8). https://doi.org/10.1093/neuonc/noab106.

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