Timothy F. Cloughesy, MD, is a professor and director in the Department of Neurology, Neurological Services, and the Neuro-Oncology Program; a physician in the Department of Neurology; a member of the Brain Research Institute; a member of Cancer Molecular Imaging, Nanotechnology, and Theranostics; and a member of Signal Transduction and Therapeutics at the UCLA Health Jonsson Comprehensive Cancer Center
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.
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.
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 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.
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. 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.
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.
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.
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.
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.
Timothy Cloughesy, MD, presents updated INDIGO data showing that vorasidenib provides durable progression-free survival benefit and delays subsequent intervention in patients with IDH-mutant grade 2 glioma.
Timothy F. Cloughesy, MD, discusses the FDA approval of dordaviprone for the treatment of patients with H3K27M-mutated diffuse midline glioma.
Timothy Cloughesy, MD, reviews data from the phase 3 INDIGO trial investigating vorasidenib in patients with residual or recurrent grade 2 glioma with an IDH1 or IDH2 mutation.
