Vorasidenib, an oral dual inhibitor of mutant IDH1/2 enzymes, significantly improved progression-free survival in patients with grade 2 gliomas. This treatment delayed disease progression and was well tolerated. These findings from the INDIGO trial represent a significant step forward in the treatment of patients with grade 2 glioma with IDH mutations. The research was presented by Ingo Mellinghoff, MD, FACP, and colleagues at the 2023 ASCO Annual Meeting (Abstract LBA1) and simultaneously published in The New England Journal of Medicine.
Ingo Mellinghoff, MD, FACP
About the INDIGO Study
A total of 331 eligible patients aged 16 to 71 years from 10 countries with grade 2 gliomas and IDH mutations were enrolled in the global, randomized, double-blind, placebo-controlled phase III INDIGO study. Patients were randomly assigned 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 magnetic resonance imaging scans. The key secondary endpoint was time to next treatment. Crossover to vorasidenib from placebo was permitted upon confirmed imaging-based disease progression.
Key Findings
In patients with grade 2 gliomas with IDH mutations, vorasidenib showed a significant improvement in progression-free survival (median of 27.7 months vs 11.1 months for placebo) and a delay in the time to next treatment (not yet reached vs 17.4 months for placebo). 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 the 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 Dr. Mellinghoff, of Memorial Sloan Kettering Cancer Center.
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.
ASCO Perspective
"This study highlights the significant benefits of vorasidenib in minimizing the disabling long-term effects of current therapies for low-grade gliomas, particularly in younger patients, and has the potential to revolutionize care for this disease,” said ASCO expert Glenn Lesser, MD, FASCO.
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
