Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).

Figure 1.. Enrollment and Randomization of Patients

*One patient withdrew consent from study treatment and later withdrew consent from the study overall.

Figure 2.. Progression-free Survival and Time to Next Intervention in the Full Analysis Set.

Panel A shows the Kaplan–Meier plot of the probability of imaging-based progression-free survival per blinded independent review among patients assigned to the vorasidenib group as compared with those assigned to the placebo group. Panel B shows the Kaplan–Meier plot of the probability of time to next anticancer treatment intervention among patients assigned to the vorasidenib group as compared with those assigned to the placebo group. ⁺Censored CI confidence interval; HR hazard ratio.

Figure 2.. Progression-free Survival and Time to Next Intervention in the Full Analysis Set.

Panel A shows the Kaplan–Meier plot of the probability of imaging-based progression-free survival per blinded independent review among patients assigned to the vorasidenib group as compared with those assigned to the placebo group. Panel B shows the Kaplan–Meier plot of the probability of time to next anticancer treatment intervention among patients assigned to the vorasidenib group as compared with those assigned to the placebo group. ⁺Censored CI confidence interval; HR hazard ratio.

Figure 3.. Subgroup Analyses of Progression-free Survival and Time to Next Intervention in the Full Analysis Set.

Panel A shows a forest plot of HRs for imaging-based progression-free survival per blinded independent review in key subgroups. Panel B shows a forest plot of HRs for time to next intervention in key subgroups. Subgroup analyses are based on stratification factor data as entered in the interactive web response system. For data shown in both panels, the widths of the CIs have not been adjusted for multiplicity. Thus, the CIs should not be used to reject (or not reject) the trial agent effects. CI confidence interval; HR hazard ratio; NE not estimable.

Figure 3.. Subgroup Analyses of Progression-free Survival and Time to Next Intervention in the Full Analysis Set.

Panel A shows a forest plot of HRs for imaging-based progression-free survival per blinded independent review in key subgroups. Panel B shows a forest plot of HRs for time to next intervention in key subgroups. Subgroup analyses are based on stratification factor data as entered in the interactive web response system. For data shown in both panels, the widths of the CIs have not been adjusted for multiplicity. Thus, the CIs should not be used to reject (or not reject) the trial agent effects. CI confidence interval; HR hazard ratio; NE not estimable.