Low-grade gliomas are grade 1 and grade 2 tumors. And while grade 1 may be cured with surgery, most grade 2 gliomas are, in contrast, infiltrative. This means that the tumor cells do not remain concentrated in one area, and, as a result can generally not be cured with surgery.
The majority of grade 2 gliomas are slowly progressive, malignant brain tumors with a poor long-term prognosis. These gliomas have DNA mutations in the isocitrate dehydrogenase (IDH) 1 or 2 gene. IDH 1 occurs in approximately 80% of grade 2 gliomas, while IDH 2 occurs in approximately 4% of these tumors. IDH 1 and 2 are a disease defining characteristic in the World Health Organization (WHO) 2021 definition.
Compared to gliomas without IDH 1 and 2 mutations, gliomas with these mutations are generally are slowly progressive. Some grade 2 gliomas with an IDH mutation have an additional DNA irregularity called 1p/19q codeletion. These gliomas can respond well to chemotherapy.
Current treatments, which includes surgery followed by observation or adjuvant radiation and chemotherapy, are not curative and can be associated with short- and long-term toxicities.
Vorasidenib (AG-881), an oral, brain-penetrant, dual inhibitor of mutant isocitrate dehydrogenase (IDH) 1 or 2 (mIDH1/2) enzymes has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. The drug was developed for penetration across the blood–brain barrier. [1]
This treatment has also shown a significantly improved progression-free survival in patients with grade 2 gliomas. These findings, which represent a significant step forward in the treatment of grade 2 glioma with IDH mutations, were presented as a late breaking abstract at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023 in Chicago, Illinois, and simultaneously published in the New England Journal of Medicine. [1][2]
The study was funded by Servier Pharmaceuticals.
Study design
In a global, randomized, double-blind, placebo-controlled phase 3 study, 331 eligible patients (16-71 years) from 10 countries with grade 2 gliomas and IDH mutations were enrolled. Patients were stratified by 1p19q status and baseline tumor size.
The media age of the participating patients was 40.4 years (range, 16 to 71). The histological subtype included oligodendroglioma in 172 patients and 159 patients with astrocytoma. The median time from last surgery until randomization was 2.4 years.
The participating patients were randomized to receive a daily oral dose of vorasidenib or placebo in 28-day cycles, with 168 patients in the vorasidenib arm and 163 in the placebo arm.
The primary endpoint was progression-free survival based on centrally reviewed brain MRIs. The key secondary endpoint was time to next treatment. Crossover to vorasidenib from placebo was permitted upon confirmed imaging-based disease progression.
Study results
In patients with grade 2 gliomas with IDH mutations, vorasidenib treatment showed a significant improvement in progression-free survival (median was 27.7 months compared to 11.1 months for placebo and a delay in the time to next treatment (median time to next treatment not yet reached, compared to 17.4 months for placebo), as demonstrated by the results of the phase 3 INDIGO study, a registration-enabling Phase 3 global, randomized, double-blinded placebo-controlled study.
The study results demonstrated that vorasidenib was tolerable with a manageable safety profile, with reported side effects in both the placebo and treatment groups. Although there were adverse events in the treatment group (fatigue, headache, diarrhea, nausea, COVID-19, and reversible liver transaminase elevations), most of them were manageable and resolved with appropriate medical attention. The increase of liver enzyme alanine aminotransferase was the most common grade ≥3 adverse event, occurring in 9.6% of patients receiving vorasidenib.
“Our study shows that targeting IDH mutations with vorasidenib significantly delays tumor growth and the need for more toxic therapies. This is clinically meaningful because patients diagnosed with grade 2 glioma with IDH mutations are typically young, otherwise healthy individuals. The results of this trial offer a chance to change the treatment paradigm for this type of glioma and could bring the first new targeted therapy for low-grade glioma,” said lead author Ingo Mellinghoff, MD, FACP, of Memorial Sloan Kettering Cancer Center.
“The overwhelmingly positive INDIGO results convincingly demonstrate the impact of targeting IDH mutations early in cancer biology where a monotherapy approach can lead to a profoundly meaningful outcome for patients with recurrent or residual IDH-mutant grade 2 gliomas,” noted Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier.
“IDH mutations are disease defining alterations in IDH-mutant diffuse gliomas and these pivotal data coupled with vorasidenib’s especially high penetration of the blood-brain barrier, offer opportunities to evolve the treatment landscape for patients living with this malignancy. We look forward to working with the FDA on its review of vorasidenib as a potential therapy in IDH-mutant diffuse glioma,” Pandya added.
Regulatory development
Vorasidenib was granted fast track designation by the U.S. Food & Drug Administration (FDA) in March 2023. Servier is working to determine timelines for submission of a New Drug Application (NDA) for vorasidenib to the FDA.
“Patients with brain cancer live with the constant fear of what their future looks like. For over twenty years, the lack of new treatment options has put patients in a position of making the difficult decision to accept a treatment that has significant side effects or to preserve cognitive function for as long as possible,” said Brock Greene, Founder of Oligo Nation, a leading brain cancer patient organization.
“Servier’s positive clinical trial data for a targeted therapy in IDH-mutant glioma that may possibly improve outcomes for patients provides this community with new hope that they have been waiting decades for,” Greene concluded.
Next Steps
Vorasidenib is under evaluation in combination with pembrolizumab in an ongoing phase I study in grade 2/3 glioma. Future rational combination therapy efforts in both low- and high-grade glioma are under consideration.
Clinical research
Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO) – NCT04164901
References
[1] Mellinghoff IK, Penas-Prado M, Peters KB, Burris HA 3rd, Maher EA, Janku F, Cote GM, de la Fuente MI, Clarke JL, Ellingson BM, Chun S, Young RJ, Liu H, Choe S, Lu M, Le K, Hassan I, Steelman L, Pandya SS, Cloughesy TF, Wen PY. 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 Aug 15;27(16):4491-4499. doi: 10.1158/1078-0432.CCR-21-0611. Epub 2021 Jun 2. PMID: 34078652; PMCID: PMC8364866.
[2] Mellinghoff IK, Van Den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke JL, Mendez JS, Welsh L, et al. INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. J Clin Oncol 41, 2023 (suppl 17; abstr LBA1). DOI 10.1200/JCO.2023.41.17_suppl.LBA1
Feature image: NCI Director Dr Monica Bertagnolli during Opening Session of the ASCO annual meeting in the Chicago, IL – McCormick Place. Photo courtesy: © 2023 ASCO/Todd Buchanan. Used with permission.
