Vorasidenib 40mg tablets

AbstractVorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDHglioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration ofd-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1–97.6) and 91.1% (95% CrI, 72.0–97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDHLGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

Abstract licence: CC BY 4.0

Gliomas account for approximately 25–29% of intracranial tumors and up to 80% of malignant brain tumors, with low-grade gliomas (LGGs) predominantly affecting younger individuals. Conventional treatments, including surgery, radiotherapy, and chemotherapy, provide disease control but are limited by neurotoxicity and long-term adverse effects, highlighting the need for targeted therapies. This systematic review evaluates the efficacy and safety of vorasidenib, a dual isocitrate dehydrogenase (IDH) 1/2 inhibitor, in patients with IDH-mutant gliomas, focusing on progression-free survival (PFS), overall survival (OS), and safety outcomes. Following PRISMA guidelines, six databases (PubMed, Cochrane, Wiley, Epistemonikos, EBSCO, and Google Scholar) were searched up to June 2025. Eligible studies included clinical trials involving patients with histologically confirmed IDH1- or IDH2-mutant gliomas. Data extracted included study design, patient characteristics, treatment regimens, efficacy endpoints, and safety profiles. Risk of bias was assessed using the Cochrane RoB 2 tool. Of 1,426 records identified, nine studies met the inclusion criteria. Vorasidenib significantly improved PFS compared with placebo in the Phase III INDIGO trial (median PFS 27.7 vs 11.1 months; HR 0.39, p  90% reduction in intratumoral 2-hydroxyglutarate. The most frequent adverse events were hepatic enzyme elevations, with grade ≥ 3 events occurring in approximately 20–25% of patients. Vorasidenib shows meaningful clinical benefit and a manageable safety profile, supporting its role as a promising targeted therapy for IDH-mutant LGGs.

Abstract licence: CC BY 4.0

Background: Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) enables the intraoperative visualization of glioma. However, its effectiveness varies based on tumor subtype and molecular profile, posing challenges for achieving complete resection. Our systematic review aims to explore the relationship between IDH mutation status and intraoperative fluorescence visualization. Importantly, this is the first study to propose that vorasidenib, an emerging IDH-targeting agent, could enhance 5-ALA-guided surgery, marking a novel direction for translational research. Methods: A systematic literature search was conducted using the PubMed, Cochrane Library, Scopus and Web of Science databases up to May 2025, following PRISMA guidelines. The primary outcomes included fluorescence detection rates across different glioma subtypes and their correlation with IDH mutation status. Secondary outcomes comprised surgical efficacy measures such as gross total resection (GTR), overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the metabolic consequences of IDH mutations and evaluated the potential role of vorasidenib in enhancing 5-ALA-induced fluorescence. Results: Seven studies including 621 patients included in the final analysis. Fluorescence detection was nearly universal in WHO grade 4 gliomas (94–100%), but lower in grade 3 (43–85%) and rare in grade 2 (7–26%). Several cohorts reported reduced fluorescence in IDH-mutant gliomas, although this was not consistent across all studies. In high-grade gliomas, visible fluorescence correlated with higher GTR rates and, in some series, longer OS. Conversely, in lower-grade IDH-mutant gliomas, fluorescence did not increase GTR and was associated with worse PFS and OS. Conclusions: The effectiveness of 5-ALA-guided fluorescence in glioma surgery is significantly influenced by both tumor grade and IDH mutation status. Vorasidenib may represent a potential avenue for modulating tumor metabolism and enhancing intraoperative fluorescence in IDH-mutant gliomas, a hypothesis that warrants further experimental validation.

Abstract licence: CC BY 4.0

Background/Objectives: Mutant isocitrate dehydrogenase (IDH) inhibitors represent a major advance in precision oncology. The recent Food and Drug Administration approval of vorasidenib for IDH-mutant glioma highlights its therapeutic potential in this setting. As this and other mutant IDH inhibitors enter the clinical setting, providers are tasked with staying informed of the evolving therapeutic landscape as more is learned about this unique class of medications. We aimed to summarize insights from preclinical studies and clinical trials exploring their use in IDH-mutant glioma. Methods: We reviewed notable preclinical studies establishing the rationale for targeting mutant IDH. We performed a systematic review of clincaltrials.gov to identify both completed and ongoing interventional IDH-directed trials in patients with IDH-mutant glioma. Results: We identified 8 published and 15 ongoing clinical trials evaluating IDH-directed therapies. IDH inhibitors have been shown to slow and, in some cases, reverse glioma tumor growth, with activity that may extend beyond their currently approved indications. The presence of contrast enhancement is consistently a negative predictor of response for ivosidenib and vorasidenib, although safusidenib and olutasidenib preliminarily may retain efficacy in these cases. Novel approaches such as IDH-directed vaccines and combination therapy using mutant IDH inhibitors with immunotherapy are currently under active investigation. Conclusions: Mutant IDH inhibition is a promising, well-tolerated, and evolving approach for many patients with IDH-mutant glioma. Ongoing research will clarify its optimal clinical utility and potentially expand its indication.

Abstract licence: CC BY

The abstract has been submitted for presentation to the AANS 2026 meeting being held in San Antonio, TX, USA. Introduction: Oligodendrogliomas are an uncommon subset of gliomas that are molecularly defined by 1p/19q codeletion in the setting of an isocitrate dehydrogenase (IDH) 1/2 mutation. Standard-of-care management involves maximal safe resection followed by adjuvant chemoradiation with procarbazine, lomustine, and vincristine (PCV). Although PCV confers a durable survival advantage, treatment-limiting toxicity is common and often necessitates discontinuation. IDH inhibitors such as vorasidenib have demonstrated promising efficacy and more favorable tolerability profiles, but a paucity of comparative data across therapeutic classes limits optimal treatment decision-making. Methods: A systematic search was conducted through to 7 March 2025 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Eligible studies included adult patients (≥18 years) with IDH-mutant, 1p/19q-codeleted oligodendrogliomas treated with PCV chemotherapy or IDH inhibitors and with a minimum follow-up of 12 months. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 adverse events (AEs) that led to treatment discontinuation. Results: Twenty-eight studies met the inclusion criteria, with a total of 406 patients. All 406 patients carried a confirmed diagnosis of oligodendroglioma. For mixed-histology cohorts, only oligodendroglioma-specific data were extracted and analyzed. Among PCV cohorts, median PFS ranged from 24.3 months to 8.4 years and median OS was reported up to 14.7 years in long-term follow-up from RTOG 9402 and EORTC 26951. Grade ≥ 3 AEs resulted in treatment discontinuation in 65-70% of patients, primarily due to hematologic or neurologic events. In comparison, vorasidenib achieved a median PFS of 27.7 months in the phase III INDIGO trial (HR 0.39; 95% CI 0.27-0.56; p Conclusions: While PCV chemotherapy remains the standard-of-care systemic therapy for oligodendroglioma supported by mature survival data, IDH inhibitors represent a mechanistically targeted alternative with encouraging early-phase outcomes and a significantly improved safety profile. Direct comparison across these regimens is constrained by differences in study design and limited long-term OS data for IDH inhibitors. Prospective head-to-head trials are essential for defining the optimal therapeutic sequence in this evolving treatment landscape. In the interim, we provide a recommend approach for current use.

Abstract licence: CC BY

Abstract Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Patients and Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2–40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8–6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.

Abstract licence: CC BY-NC-ND 4.0