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 Glenn Lesser, MD, FASCO, ASCO Expert.
Vorasidenib, an oral dual inhibitor of mutant IDH1/2 enzymes, significantly improved progression-free survival in patients with grade 2 gliomas, a type of malignant brain tumor with poor long-term prognosis. This treatment delayed disease progression and was well-tolerated. These findings represent a significant step forward in the treatment of grade 2 glioma with IDH mutations.
Study at a Glance
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Focus |
Evaluating vorasidenib, an oral, brain-penetrant dual inhibitor of mutant IDH1/2 enzymes, as a treatment for grade 2 gliomas. |
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Population |
331 eligible patients (16-71 years) from 10 countries with grade 2 gliomas (oligodendroglioma or astrocytoma) with IDH mutations who had undergone surgery but no other treatment. |
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Findings |
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Significance |
Vorasidenib is a well-tolerated and effective treatment that could delay the disabling long-term effects of current therapies. The potential approval of vorasidenib would represent a new targeted therapy for low-grade glioma. |
Key Findings
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 III INDIGO study. 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.
About the Study
In this global, randomized, double-blind, placebo-controlled phase III study, 331 eligible patients (16-71 years) from 10 countries with grade 2 gliomas and IDH mutations were enrolled. 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.
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.
