Dr. Timothy Cloughesy from UCLA and Dr. Ugur Sener from Mayo Clinic discuss the evolving treatment landscape for IDH-mutant gliomas, focusing on vorasidenib, the first FDA-approved targeted therapy for grade 2 IDH-mutant gliomas. The INDIGO trial demonstrated remarkable efficacy with vorasidenib versus placebo, showing a hazard ratio of 0.4 and extending median progression-free survival from 11.1 to 27.7 months at initial analysis. Updated data presented at ASCO 2026 reveals even more encouraging results with estimated progression-free survival reaching 44 months and only 28% of patients requiring subsequent radiation or chemotherapy. Key discussion points include patient selection criteria, optimal timing for treatment initiation, duration of therapy, and practical management considerations. The panelists emphasize that IDH-mutant gliomas represent a distinct disease entity affecting younger patients who typically present with seizures and face decades of disease management. The program addresses real-world clinical scenarios through case-based discussions, highlighting the paradigm shift from watchful waiting to early targeted intervention, particularly for astrocytomas which demonstrate more aggressive behavior than oligodendrogliomas.
Dr. Timothy Cloughesy introduces the program focusing on managing IDH-mutant gliomas after surgery, joined by Dr. Ugur Sener from Mayo Clinic. The discussion establishes IDH-mutant gliomas as a unique disease entity distinct from IDH-wild-type glioblastomas.
Dr. Cloughesy details the evolution from phase 1 studies observing gradual tumor shrinkage in non-enhancing tumors to the pivotal INDIGO phase 3 trial design. The study specifically enrolled patients with measurable tumors who experienced growth trajectories that subsequently changed during treatment, convincing investigators of meaningful drug activity.
Six months after initial data cleaning, the 20-month follow-up provided more robust PFS estimates. The updated analysis could not estimate median PFS for the vorasidenib arm, suggesting substantially longer disease control than initially projected.
The updated safety analysis demonstrates that liver function test abnormalities predominantly occur during the first year of treatment, with minimal additional cases emerging during extended follow-up. This temporal pattern provides reassurance about long-term hepatic safety with appropriate monitoring.
Dr. Sener raises practical questions about optimal treatment timing given the broad FDA approval spanning gross total resection to biopsy-only patients. The approval allows treatment initiation immediately post-surgery or at later timepoints based on clinical judgment.
Given the young patient population, reproductive considerations become paramount. Both male and female patients require contraception during treatment due to unknown teratogenic effects. Fertility preservation through egg or sperm harvesting represents standard counseling for patients considering vorasidenib therapy.
Dr. Cloughesy presents a 38-year-old woman with first generalized tonic-clonic seizure and non-enhancing left frontal lesion. Following gross total resection, pathology revealed WHO grade 2 IDH-mutant astrocytoma without 1p19q co-deletion. She maintains good performance status, works part-time, and experiences breakthrough focal seizures on levetiracetam. Six-month MRI shows stable but measurable T2-FLAIR signal change at the resection margin. Dr. Sener emphasizes that astrocytoma diagnosis driven by IDH mutation represents the key molecular change necessitating treatment consideration. Even with gross total resection, microscopic disease remains present and will continue growing. FDA-approved vorasidenib directly targets the tumor's underlying biology while potentially improving seizure control and delaying radiation/chemotherapy requirements.
Fourteen months into vorasidenib therapy, the patient remains clinically stable and seizure-free with continued work. Recent MRI shows stable T2-FLAIR signal without enhancement or measurable shrinkage. Transient liver function test elevations to 2.5 times upper limit of normal resolved after temporary dose hold.
Dr. Cloughesy discusses treatment sequencing considerations when patients progress on vorasidenib. The INDIGO trial showed discrepancies between independent review progression and investigator-assessed time to next intervention, with investigators often waiting beyond formal progression criteria before initiating alternative treatments.
The discussion addresses patients who had surgery years ago and have been followed with stable or slowly growing disease. These treatment-naïve patients present decision-making challenges about when to initiate vorasidenib therapy. Dr. Sener emphasizes individualized discussions about long-term treatment commitment, monitoring requirements, and expected outcomes.
