Astrocytoma, IDH-Mutant

Pictured: Brain scans from an MRI/iStock, Nur Cere Servier on Saturday unveiled new data from the pivotal Phase III INDIGO trial, demonstrating that its investigational drug vorasidenib induced the shrinking of tumors in patients with IDH1/2-mutant diffuse glioma. Armed with these additional data, Servier is readying a New Drug Application for vorasidenib by the end of 2023, according to its news release. The company will make a similar regulatory application to the European Medicines Agency in early 2024. Vorasidenib is an orally available and brain-penetrant inhibitor of mutant IDH1 and IDH2 proteins. Under healthy circumstances, these proteins function as enzymes that catalyze the production of alpha-ketoglutarate. When mutated, IDH1 and IDH2 produce 2-hydroxyglutarate, a known oncometabolite. Vorasidenib is being developed specifically for glioma patients harboring these mutations and has previously won the FDA’s breakthrough therapy designation for this indication. In the company’s statement, Susan Pandya, head of Cancer Metabolism Global Development Oncology & Immuno-Oncology at Servier, called vorasidenib a “potentially first-in-class treatment option” for IDH-mutant glioma, adding that the company is aiming to “deliver vorasidenib as the first targeted treatment option in this disease space.” New data from INDIGO, presented over the weekend at the 28th Annual Meeting of the Society for Neuro-Oncology (SNO), showed that vorasidenib treatment shrank tumor volume by a mean of 2.5% every six months. In placebo groups, tumor volume increased by 13.9% on average over the same length of time. Previously, at the American Society for Clinical Oncology annual meeting in June 2023, Servier also posted promising data from INDIGO, showing that vorasidenib more than doubled progression-free survival versus placebo and reduced tumor growth by 61%. Servier simultaneously published those data in The New England Journal of Medicine. Patients treated with Servier’s candidate had a median PFS of 27.7 months, as opposed to only 11.1 months for placebo. At the time, the company called this effect an “unprecedented improvement” in PFS. Vorasidenib likewise led to a substantial delay in the initiation of a subsequent intervention. As for safety, vorasidenib induced elevation in the liver enzyme alanine aminotransferase in 9.6% of treated patients. Though this was classified as a grade 3 toxicity, Servier noted at the time that these episodes were resolved following medical attention. Servier is also testing vorasidenib with Merck’s blockbuster PD-1 inhibitor Keytruda (pembrolizumab) in the same indication. The combination regimen is currently in Phase I, data from which were also presented at SNO and demonstrated a favorable safety and tolerability pro patients with recurrent or progressive enhancing IDH1-mutant astrocytoma. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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 28th 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 Glioma 3 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 [email protected] 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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The information contained in this document is neither an offer to sell nor the solicitation of an offer to enter into a transaction. The content of this document is a summary only, is not complete, and does not include all material information about Servier and its Affiliates, including potential conflicts of interest. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates disclaim all representations, warranties, conditions and guarantees, whether express, implied, statutory or of other kind, nor does it accept any duty to any person, in connection with this document. Without prejudice to the generality of the foregoing, Servier and its Affiliates do not warrant or represent that the information or opinions contained in this document is accurate or complete. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates shall not be liable for any loss, damage or expense whatsoever, whether direct or indirect, howsoever arising, whether in contract, tort (including negligence), strict liability or otherwise, for direct, indirect, incidental, consequential, punitive or special damages arising out of or in connection with this document, including (without limitation) any course of action taken on the basis of the same. The estimates, strategies, and views expressed in this document are based upon past or current data and information and are subject to change without notice. [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. . [2] Mellinghoff, I., et al. (2023). Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. The New England Journal of Medicine, 389:589-601. . [3] Louis, D., et. al. (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncology, 23(8). . SOURCE Servier Pharmaceuticals