Vorasidenib Elicits Early Metabolic Responses in IDH-Mutant Glioma

Serial amino acid PET detected metabolic responses earlier than structural MRI in patients with IDH-mutant glioma treated with vorasidenib (Voranigo), according to interim results from a retrospective, multicenter European study presented at the 2026 Society for Neuro-Oncology Annual Meeting.¹

Among the 50 patients included, response was assessed per Response Assessment in Neuro-Oncology 2.0 criteria in all patients (N = 50) and per PET Response Assessment in Neuro-Oncology (RANO) 1.0 criteria in those with a baseline PET scan (n = 34). A partial response was documented in 29% of patients assessed with PET RANO 1.0 criteria vs 6% of those assessed with RANO 2.0 criteria. The median time to response was 4 months (range, 1-14) with PET RANO 1.0 criteria vs 8 months (range, 1-11) with RANO 2.0 criteria.

Stable disease was recorded in 62% of patients assessed with PET RANO 1.0 criteria vs 74% of those assessed with RANO 2.0 criteria, and progressive disease was recorded in 6% vs 4% of patients, respectively. A minor response, a category that PET RANO 1.0 criteria does not define, occurred in 14% of patients assessed with RANO 2.0 criteria.

Change in metabolic tumor volume was the main parameter driving early PET-based response classification. Among 8 patients whose early classification was displayed, metabolic tumor volume (MTV) change ranged from −100% in a patient with a complete response to increases of 346% and 394% in 2 patients with progressive disease.

“We all face the clinical challenge that tumor volume on structural MRI changes slowly under treatment,” Sophie E.M. Veldhuijzen van Zanten, MD, PhD, stated in a presentation of the data. “The aim of our multicenter European study was to objectify whether serial [PET] scans could detect early metabolic changes in these patients.”

van Zanten is a researcher in radiology and nuclear medicine at Erasmus MC in Rotterdam, Netherlands.

How was the multicenter European study of PET in vorasidenib-treated IDH-mutant glioma designed?

The investigators conducted a retrospective cohort analysis of patients treated at hospitals in Germany and the Netherlands and applied RANO 2.0 and PET RANO 1.0 criteria to every scan they could obtain. Imaging reflected routine clinical practice rather than a predefined protocol. The cohort included patients with a median age of 47 years (range, 21-73); 56% had oligodendroglioma, and 44% had astrocytoma; additionally, 90% of tumors were grade 2 per central nervous system World Health Organization criteria. None of the patients had received prior radiotherapy or chemotherapy. Patients began treatment with vorasidenib at 40 mg once daily between May 2024 and March 2026, and the median imaging follow-up was 9 months (range, 1-20).

Vorasidenib is a brain-penetrant oral inhibitor that targets both mutant IDH1 and mutant IDH2. The agent was FDA approved in 2024 for the treatment of adult and pediatric patients at least 12 years of age who have grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery.²

The present study evaluated 2 amino acid tracers, [18F]FET and [18F]FDOPA.¹ In total, 236 imaging examinations were analyzed. Of the 50 patients, 31 underwent [18F]FET PET plus MRI, 3 underwent [18F]FDOPA PET plus MRI, and 16 underwent MRI only. PET scans comprised historical pretreatment scans (n = 45), baseline scans obtained from 4 months before treatment to the start of treatment (n = 34), early follow-up scans obtained up to 6 months after treatment initiation (n = 36), and late follow-up scans obtained afterward (n = 20).

Tumor segmentation on PET was automated, and MTV was calculated as the tumor volume in which uptake was at least 1.6-fold higher than the mean background uptake. Measurable disease required a maximum tumor-to-background ratio above 1.6 and an MTV above 0.5 mL, whereas scans with a ratio of 1.6 or lower, or those with a ratio above 1.6 with an MTV of 0.5 mL or lower, were classified as non-measurable. The investigators also assessed scans visually and cautioned about the limits of automation.

“Automatic segmentation is valuable, but not the holy grail yet,” van Zanten emphasized. “Always make sure you evaluate your scans.”

She shared an example of a positive uptake on a PET scan that, with MRI, was actually revealed to be a vascular structure and not a tumor. She added that reconstruction settings matter, explaining, “Each reconstruction changes the haziness of the scan, and this results in a different determination of tumor volume.”

What baseline imaging findings did the study report in patients with IDH-mutant glioma before vorasidenib?

Among patients with a baseline PET scan, 41% had measurable disease per PET RANO 1.0 criteria. Among all evaluable patients, RANO 2.0–measurable disease was present on fluid-attenuated inversion recovery MRI in 94% and on contrast-enhanced MRI in 4%. PET availability in patients declined over follow-up, from 68% at baseline to 48% at 3 months, 24% at 6 months, 14% at 9 months, 18% at 12 months, and 4% at both 15 and 18 months, whereas MRI was available for 94% of patients at baseline and at 3 months.

What happened on PET when vorasidenib was interrupted and restarted in a patient with IDH-mutant glioma?

The presentation included a case study of a patient who interrupted vorasidenib because of adverse effects. PET showed an increase in uptake volume at 3 months during the interruption and a decrease after the drug was restarted, with imaging again shown at 12 months.

What are the next steps for PET-guided monitoring of vorasidenib in IDH-mutant glioma?

van Zanten concluded that vorasidenib was linked with an early decline in metabolic activity on amino acid PET in a subset of patients, largely before structural MRI changes could be measured, and that PET remained useful in patients with no measurable baseline uptake, in whom new uptake may signal progression. She also advised the use of serial PET with standardized methods, using PET RANO 1.0 criteria alongside harmonized approaches to acquisition, reconstruction, and segmentation.

“Prospective validation is the next step towards [PET]-guided treatment and response monitoring,” van Zanten concluded.

References

1. Veldhuijzen van Zanten SEM, et al. Early metabolic changes on [18F]FET and [18F]FDOPA PET in IDH-mutant glioma treated with vorasidenib: interim results from a multicenter European study. Presented at: 2026 SNO Annual Meeting; November 12-15, 2026; Philadelphia, PA. Abstract IMG-89.
2. FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. FDA. August 6, 2024. Accessed November 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation