Abstract
Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. 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. In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).
Overview
- The study aimed to investigate the efficacy of vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, in IDH-mutant grade 2 gliomas. The study was a double-blind, phase 3 trial that randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients).
- The study tested the hypothesis that vorasidenib would significantly improve progression-free survival and delay the time to the next intervention in patients with grade 2 IDH-mutant gliomas. The methodology used for the experiment included a double-blind, phase 3 trial design, with patients randomly assigned to receive either oral vorasidenib or matched placebo. The study used imaging-based progression-free survival as the primary end point and the time to the next intervention as the key secondary end point. The study also assessed safety and allowed for crossover to vorasidenib from placebo on confirmation of imaging-based disease progression. The study included a total of 331 patients, with 168 patients receiving vorasidenib and 163 patients receiving placebo. The study was funded by Servier and has an INDIGO ClinicalTrials.gov number of NCT04164901.
Comparative Analysis & Findings
- The study compared the outcomes observed under different experimental conditions, specifically the use of vorasidenib versus placebo in patients with residual or recurrent grade 2 IDH-mutant gliomas. The study found that 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 also 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). The study also found that 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. The study's findings support the hypothesis that vorasidenib significantly improved progression-free survival and delayed the time to the next intervention in patients with grade 2 IDH-mutant gliomas.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study provides preliminary evidence that vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, shows activity in IDH-mutant gliomas. The study's findings also support the hypothesis that vorasidenib significantly improved progression-free survival and delayed the time to the next intervention in patients with grade 2 IDH-mutant gliomas. The study's limitations include the small sample size and the need for further research to confirm the findings. Future research directions could include larger studies to confirm the efficacy of vorasidenib in IDH-mutant gliomas and to investigate the long-term safety and efficacy of vorasidenib in this population.