Gliomas are the most common malignant primary brain tumors in adults and are classified into different subtypes and grades based on histologic and molecular characteristics. Mutations in the genes IDH1 and IDH2, which encode metabolic enzymes, are present in nearly all grade 2 diffuse gliomas in adults. These mutations lead to the accumulation of 2-hydroxyglutarate, an altered metabolite that inhibits various enzymes and causes significant changes in DNA hydroxymethylation, gene expression, cellular differentiation, and the tumor microenvironment.
Due to their unique molecular pathogenesis, gliomas with IDH mutations are recognized as distinct disease entities according to the World Health Organization (WHO) classification. According to the New England Journal Of Medicine, a phase 3 clinical trial called the INDIGO trial has shown promising results for the molecularly targeted therapy vorasidenib in the treatment of IDH-mutant glioma, the most common malignant primary brain tumors in adults under 50 years of age. These gliomas, which continuously grow and infiltrate normal brain tissue, are incurable with existing therapies.
The trial demonstrated that treatment with vorasidenib significantly improved progression-free survival, as assessed by an independent imaging review, and extended the time to the subsequent intervention compared to placebo in patients who were potential candidates for a watch-and-wait approach. The positive results led to the unblinding of the trial, and patients in the placebo group were offered crossover to the vorasidenib group.
Vorasidenib exhibited a mainly low-grade safety profile, with grade 3 or higher adverse events being more common in the vorasidenib group than in the placebo group. However, serious adverse events and discontinuations of the drug were low. This analysis did not report other endpoints, such as the impact on seizures, health-related quality of life, and neurocognition. The trial is still ongoing to evaluate overall survival.
Molecularly targeted therapies, like vorasidenib, hold great potential for modifying the disease course of IDH-mutant glioma when used at an early stage. IDH mutations occur early in the disease, and the trial focused on patients within 1 to 5 years after surgery before any measurable contrast-enhancement of the tumor on MRI. This early stage of the disease allows for a clear signal of antitumor activity to be detected in placebo-controlled trials. Ivosidenib and enasidenib, inhibitors of mutant IDH1 and IDH2, have shown activity in other cancers, such as acute myeloid leukemia and cholangiocarcinoma.
While vorasidenib demonstrated single-agent activity in previously untreated grade 2 glioma, further trials are needed to determine its role, alone or in combination therapy, for glioma patients who have received prior treatment or have a higher-grade disease. The ongoing molecular examination of tumor samples and the evaluation of tumor-volume growth rates before and after trial enrollment may provide insights into potential combination therapies. However, data on these aspects from the current trial have yet to be available.
