Use of vorasidenib to treat IDH1- and IDH2-mutant low-grade glioma
Gliomas, the most common malignant primary brain tumors in adults, are characterized and classified by their histologic and molecular features, one of the most important of which is mutational status in IDH1 or IDH2 genes. These genes encode the enzymes isocitrate dehydrogenase 1 and 2, which are used in the citric acid cycle to catalyze the decarboxylation of isocitrate into 2-oxoglutarate. However, somatic alterations in these genes, most frequently at the arginine codon 172 of IDH1, can result in a mutant enzyme that instead produces 2-hydroxyglutarate, an oncometabolite that accumulates in tumor cells and causes aberrant downstream effects that alter the epigenetic regulation of gene expression. For patients with IDH1– or IDH2-mutant gliomas that have a higher risk of progression (World Health Organization [WHO] grade 3 or high-risk WHO grade 2), the standard-of-care postoperative treatment is a combination of chemotherapy and radiation. However, these adjuvant treatments are not curative, and they carry many long-term risks, such as neurocognitive dysfunction and DNA hypermutation. Therefore, patients with low-risk WHO grade 2 tumors are usually monitored with serial imaging. The authors evaluated the investigational drug vorasidenib, a potent oral inhibitor of the mutant IDH1 and IDH2 enzymes that can cross the blood-brain barrier. During the period of active surveillance in the postoperative setting, patients with WHO grade 2 IDH-mutant gliomas were randomized to receive vorasidenib or a placebo. A total of 331 patients from 77 sites across 10 countries were enrolled in the trial. Baseline characteristics, such as median age and performance status, were similar between the vorasidenib and control groups. Patients receiving vorasidenib had significantly longer progression-free survival compared with those in the control group (median, 27.7 versus 11.1 months, P<.001). Patients receiving vorasidenib also had significant improvement in time to the next intervention compared with those in the control group (hazard ratio, 0.26, P<.001) as 85.6 percent of patients receiving vorasidenib received no other treatments after 18 months compared with only 47.4 percent of patients in the control group. Adverse events were primarily low grade. The most common serious side effect was an elevation in alanine aminotransferase or other liver enzymes. Overall, patients with IDH-mutant low-grade glioma who were receiving vorasidenib demonstrated a significant improvement in progression-free survival and time to the next intervention. Given that the standard of care in the postoperative setting is active surveillance, this therapy represents a significant treatment opportunity for patients during this critical period.
Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. 2023. doi:10.1056/NEJMoa2304194
Correspondence: Dr. Ingo K. Mellinghoff at mellingi@mskcc.org