In the phase 3 Vorasidenib in Glioma (INDIGO) trial, patients with isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas had significantly better progression-free survival and time to the next intervention when treated with vorasidenib. Nearly all grade 2 diffuse gliomas in adults have mutations in the genes for IDH1 and IDH2.
A total of 331 patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery were randomized to oral vorasidenib 40 mg once daily or matched placebo in 28-day cycles. Imaging-based progression-free survival was the primary endpoint, and time to the next anticancer intervention was the key secondary endpoint.
“At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo,” report the authors. “Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P <0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P <0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo.”
Editorial 1: “Molecularly targeted agents have the greatest potential when used early,” writes an editorialist. “This observation is consistent with the lack of activity of agents targeting the IDH mutation in pretreated contrast-enhancing tumors that are likely to have accrued additional molecular alterations, including homozygous deletion of CDKN2A and other cell-cycle gene alterations or alkylator-induced hypermutation. The combination of radiation therapy and alkylating chemotherapy in patients with IDH-mutant gliomas leads to longer overall survival than sequential use. Whether the combined use of vorasidenib with postradiation chemotherapy will improve survival is a critical question, as is whether the results of this trial will translate to patients with biologically related, newly diagnosed grade 3 IDH-mutant gliomas.”
Editorial 2: “Vorasidenib is the first treatment method in many years to show improved progression-free survival and a relatively low side-effect profile in persons with IDH-mutant grade 2 glioma, independent of 1p/19q codeletion status,” editorialists write. “Gaining an understanding whether vorasidenib enhances overall survival, when added to currently used chemoradiation treatments, will be an important next step. Identifying biomarkers that predict response to treatment and the development of resistance to treatment will help to further improve the use of this new treatment method. It is possible that treatment with IDH inhibitors will mitigate seizure risk among persons with IDH-mutant glioma; follow-up of the patients in the INDIGO trial may shed light on this question. Because current adjuvant treatments for grade 2 glioma can lead to considerable physical and cognitive impairments, the ability to delay tumor progression and the time to the next intervention, as well as to maintain or improve quality of life, is a step forward. The results with respect to overall survival will be eagerly awaited.”