Vorasidenib may break a 20-year gap in treatment advances for IDH-mutant low-grade glioma, according to phase 3 findings from the INDIGO study.
Treatment with vorasidenib (AG-881) monotherapy led to an improvement in progression-free survival (PFS) in patients with residual or recurrent IDH-mutant low-grade glioma, meeting the primary end point of the phase 3 INDIGO trial (NCT04164901).1
Results from the prespecified interim analysis also showed that the INDIGO study met a key secondary end point of time to next intervention. The achievements were both statistically significant and clinically meaningful.
“These results from the INDIGO provide a new opportunity to provide tumor control in IDH mutant beyond traditional chemotherapy and radiation therapy. This will give our patients to delay the use of radiation therapy, particularly in this IDH mutant tumor population enriched with younger patients, Katherine B. Peters, MD, PhD, FAAN, associate professor, neurology and neurosurgery, director of supportive care, and program director, neuro-oncology fellowship, Preston Robert Tisch Brain Tumor Center at Duke University School of Medicine, told Targeted Oncology™.
Vorasidenib is an oral, potent, reversible, brain penetrant dual inhibitor of the IDH1 and IDH2 enzymes.2 The agent was previously granted breakthrough therapy designation by the FDA for the treatment of IDH1/IDH2-mutant low-grade glioma. The FDA has now granted a fast track designation to the agent for the treatment of this patient population.
In a prior phase 1 dose-escalation and expansion study (NCT02481154), vorasidenib appeared well-tolerated in patients with IDH-mutant low-grade gliomas and demonstrated preliminary anti-tumor activity.3
Fifty-two patients were enrolled and treated with vorasidenib given orally, once daily, in a 28-day cycles until disease progression or unacceptable toxicity. The objective response rate (ORR) shown with vorasidenib was 18%, which included 1 partial response and 3 minor responses. The median PFS observed with the agent was 36.8 months (95% CI, 11.2-40.8) among patients with non-enhancing glioma, and 3.6 months (95% CI, 1.8-6.5 months) among those with enhancing glioma. Moreover, sustained tumor shrinkage was observed in multiple patients.
Dose-limiting toxicities were seen in the study. Specifically, elevated transaminases occurred in patients treated with at 100 mg dose of vorasidenib, but the toxicity was reversible. Overall, the agent had a favorable safety profile.
INDIGO is a phase 3, multicenter, randomized, double-blind, placebo-controlled study. Patients aged 12 years or older were eligible to enroll if they had grade 2 oligodendroglioma or astrocytoma per WHO 2016 criteria that did not need immediate treatment and without high-risk features, centrally confirmed IDH1 or IDH2 mutation status, received 1 or more surgery for glioma between 1 to 5 years before randomization, had a Karnofsky performance status of ≥ 80%, and centrally confirmed measurable non-enhancing disease that is evaluable by MRI.2
The study excluded patients who received prior anticancer therapy other than surgery for the treatment of glioma. Patients with high-risk features were also excluded.
The 366 eligible patients enrolled in the INDIGO study were randomized 1:1 to receive vorasidenib 40 mg once daily in continuous 28-day cycles or matching placebo. Patients in the placebo arm had the option to crossover to the vorasidenib arm upon centrally confirmed radiographic disease progression. All patients were stratified by 1p19q status (intact v co-deleted) and their baseline tumor size (≥ 2 cm v < 2 cm).
The study is 80% powered to detect a PFS of 18 months in the vorasidenib arm with a hazard ratio of 0.667 (1-sided P =.025).
In addition to PFS and time to next intervention, the study is assessing the ORR of vorasidenib, overall survival, tumor growth rate, safety/tolerability, health-related quality-of-life (HRQOL) by Functional Assessment of Cancer Therapy-Brain Questionnaire, and plasma pharmacokinetics as secondary end points. The exploratory end points of the study include seizure activity, HRQOL by EuroQol 5 Dimension 5 Level, neurocognitive function, and patient global impression of change.
“It will be essential to see long-term outcomes regarding overall survival. I am particularly excited to see the results of exploratory end points on seizure control and neurocognitive outcomes, as these are critical challenges in our IDH1-mutant low-grade glioma patients,” Peters said.
To assess ORR, radiographic assessment by MRI will be conducted every 3 months during months 3 through 36 months, every 6 months from month 37 to 62, and every year thereafter.
Investigators will conduct HRQOL and neurocognitive assessments every 3 months during month 3-36 and every 6 months thereafter. For seizure analysis, patients will be evaluated every month during months 2 through 6 followed by every 2 months thereafter.
"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 endpoint of progression-free survival and the key secondary endpoint of time to next intervention, presents an opportunity to shift the treatment paradigm for patients with IDH mutant low-grade glioma by potentially delivering the first targeted therapy," said Susan Pandya, MD, vice president Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology of Servier, in a press release.
1. Servier's pivotal phase 3 INDIGO trial 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://prn.to/3ZLeiY9
2. Mellinghoff IK, van den Bent M, Clarke JL, et al. INDIGO: A global, randomized, double-blind, phase III study of vorasidenib (VOR; AG-881) vs placebo in patients with residual or recurrent grade II glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation. Presented at: American Society of Clinicl Oncology (ASCO) Annual Meeting 2020 Annual Meeting; May 29–31, 2022. Abstract TPS2574. Virtual.
3. 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;15;27(16):4491-4499. doi: 10.1158/1078-0432.CCR-21-0611.