Vorasidenib Meets PFS End Point in IDH1/2-Mutant Low-Grade Glioma

Susan Pandya, MD

Vorasidenib(AG-881) monotherapy elicited a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with placebo in patients with residual or recurrent IDH1/2-mutant low-grade glioma, meeting the primary end point of the phase 3 INDIGO trial (NCT04164901).¹

Findings from a prespecified interim analysis also showed that the trial also met the key secondary end point of time to next intervention (TTNI). Investigators expect to present full presented at an upcoming medical meeting.

“Therapeutic progress in the low-grade glioma space has been stagnant for decades. The results of the phase 3 INDIGO trial, meeting both the primary end point of PFS and the key secondary end point TTNI, presents an opportunity to shift the treatment paradigm for patients with IDH-mutant low-grade glioma by potentially delivering the first targeted therapy,” Susan Pandya, MD, vice president of Clinical Development and head of Cancer Metabolism Global Development Oncology & Immuno-Oncology at Servier, stated in a news release.

Vorasidenib is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.²

The multicenter, randomized, double-blind, placebo-controlled INDIGO trial enrolled patients with residual or recurrent grade 2 glioma (oligodendroglioma or astrocytoma) harboring an IDH1/2 mutation who have undergone surgery as their only treatment.¹ Patients were required to be at least 12 years of age and weigh at least 40 kg. They were required to have received prior surgery at least 1 year but no more than 5 years prior to enrollment.3 Patients who were 16 years of age or older needed to have a Karnofsky performance status of at least 80%. Those younger than 16 years needed a Lansky Play Performance Scale score of at least 80%.

Patients were excluded from the trial if they had any prior anticancer therapy other than surgery for treatment of glioma, including systemic chemotherapy, radiotherapy, vaccines, small molecules, IDH inhibitors, investigational agents, or laser ablation. Patients with high-risk features, as assessed by the investigator, were not allowed.

Enrolled patients were randomly assigned 1:1 to receive 40 mg of vorasidenib per day or matching placebo. Patients in the placebo arm who experienced centrally confirmed radiographic disease progression were permitted to cross over to vorasidenib, provided certain criteria were met.

Along with the primary end point of PFS and the key secondary end point of TTNI, other secondary end points included safety, tumor growth rate, objective response rate, time to response, duration of response, overall survival, and health-related quality of life.

Findings from the prespecified interim analysis showed that the safety profile of vorasidenib monotherapy was consistent with previously published data.¹

“This potential therapeutic breakthrough is yet another concrete proof-point of the success of our oncology strategy, which aims to focus our science on difficult and hard-to-treat cancers such as those where an IDH mutation is present,” Patrick Therasse, MD, PhD, vice president andhead of Late Stage and Life Cycle Management Oncology & Immuno-oncology Therapeutic Area at Servier, stated in a news release. “The results from the phase 3 INDIGO trial offer patients with IDH-mutant low-grade glioma potential hope for a new treatment option for the first time in more than 20 years.”

References

1. Servier's pivotal phase 3 INDIGO rial investigating vorasidenib in IDH-mutant low-grade glioma meets primary endpoint of progression-free survival (PFS) and key secondary endpoint of time to next intervention (TTNI). News release. Servier. March 14, 2023. Accessed March 14, 2023. https://www.prnewswire.com/news-releases/
2. Mellinghoff IK, Penas-Prado M, Peters KB, et al. Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase I trial. Clin Cancer Res. 2021;27(16):4491-4499. doi:10.1158/1078-0432.CCR-21-0611
3. Study of vorasidenib (AG-881) in participants with residual or recurrent grade 2 glioma with an IDH1 or IDH2 mutation (INDIGO). ClinicalTrials.gov. Updated May 17, 2022. Accessed March 14, 202