Vorasidenib helps prevent seizures in grade 2 mIDH1/2 gliomas

Patients with grade 2 isocitrate dehydrogenase 1 or 2 mutant (mIDH1/2) gliomas receiving vorasidenib experience fewer seizure activities than those on placebo, as shown by the results of the INDIGO study.

“Grade 2 mIDH1/2 gliomas are slowly progressive, malignant, incurable brain tumours with poor long-term prognosis,” said lead author Dr Mehdi Touat, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France. “Patients may experience tumour-related symptoms (eg, seizures) that impact their daily lives.”

INDIGO met its primary endpoint of progression-free survival (PFS) compared with placebo at 12 months (77.3 percent vs 47.3 percent) and at 24 months (58.8 percent vs 26.2 percent), with a gradual decrease in tumour volume. [Mellinghoff IK, et al, SNO 2024]

In subgroup analysis, the vorasidenib arm demonstrated lower on-treatment rates of seizures than the placebo arm (18.2 percent, 95 percent confidence interval [CI], 8.4‒39.5 vs 51.2 percent, 95 percent CI, 22.9‒114.8). This was more pronounced among patients with oligodendroglioma than those with astrocytoma (86 percent vs 9 percent). [EAN 2025, abstract EPR-285]

Notably, tumour volume showed a highly positive association with seizure number (log tumour size estimate of coefficient, 0.7; standard error: 0.26; p=0.007).

“Smaller tumour volume was associated with a lower seizure rate in the overall population,” Touat said. “Patients treated with vorasidenib showed a lower seizure activity than the placebo group.”

Seizure control

The findings of the INDIGO study point to a potential mechanism of seizure control by tumour volume and 2-hydroxyglutarate dehydrogenase (2HG) reduction with the use of vorasidenib, according to Touat and colleagues.

“In mIDH1/2 glioma, lower seizure rates are a high patient value outcome,” Touat said. “As such, seizures could be considered a clinical marker of efficacy for treatments.”

The INDIGO study randomized a total of 331 patients aged ≥12 years with grade 2 mIDH1/2 oligodendroglioma or astrocytoma, with no prior treatment for glioma other than surgery, and no uncontrolled seizures to receive either vorasidenib 40 mg (n=168) or placebo (n=163) daily.

Touat at colleagues used a negative binomial regression model to perform exploratory analyses for the number of on-treatment seizures in patients with one or more seizures during the study. Additionally, they assessed the potential relationship between seizure activity and tumour volume using the mixed effect model with repeated measurements.

Vorasidenib, an oral, brain-penetrant, dual inhibitor of mIDH1/2 enzymes, has been approved for the treatment of adult grade 2 mIDH1/2 diffuse glioma in Australia, Canada, Israel, Switzerland, the UAE, and the US following the positive outcomes of the INDIGO clinical trial. [J Neurosurg 2024;3:712-721; N Engl Med J 2009;360:756-773]

“Seizures are the most frequent symptom experienced by patients with mIDH1/2 glioma,” Touat said. “They heavily impact the quality of life and working capacity of these patients and can occur at any point along the disease trajectory.” [Brain 2014;137:449-462; N Engl J Med 2023;389:589-601]

IDH mutations and the production of the oncometabolite 2HG may result in an increased risk of seizures. [J Neurosurg 2024;3:712-721; Neuro Oncol 2024;26:7-24]