Vorasidenib first ‘game changer’ in 20 years for patients with IDH-mutant grade 2 glioma
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Key takeaways:
- Researchers reported median PFS of 27.7 months with the agent vs. 11.1 months with placebo.
- Vorasidenib represents the first new viable treatment option for this patient population in over 2 decades.
CHICAGO — Vorasidenib significantly improved PFS while delaying time to next intervention among certain patients with grade 2 isocitrate dehydrogenase 1- or 2-mutant glioma, according to data presented at ASCO Annual Meeting.
The findings, published simultaneously in The New England Journal of Medicine, showed efficacy across all patient subgroups.
“We haven’t had a new drug in this disease for over 20 years,” Ingo K. Mellinghoff, MD, FACP, a neuro-oncologist at Memorial Sloan Kettering Cancer Center, told Healio. “This is also the first molecularly targeted therapy in this patient population. It’s a game changer based on both of those things just by the effect size.”
Background and methodology
Vorasidenib (Servier), an oral, brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase (IDH)1 and IDH2 enzymes, has shown activity in IDH-mutant gliomas with manageable toxicities.
The double-blind, randomized phase 3 INDIGO trial assessed the efficacy of vorasidenib among patients with residual or recurrent grade 2 IDH1/2-mutant glioma who had no prior treatment except surgery.
The study enrolled 331 patients at 77 centers in 10 countries. Among them, 172 had oligodendroglioma and 159 had astrocytoma.
Researchers assigned patients to receive 40 mg vorasidenib once daily (n = 168) or placebo (n = 163) on matched 28-day cycles.
Imaging-based PFS according to blinded independent review committee served as the primary endpoint, and time to next anticancer intervention served as a key secondary end point.
Protocol permitted crossover from vorasidenib to placebo upon confirmation of disease progression through imaging.
Most patients (68.3%) remained on vorasidenib or placebo at median follow-up of 14.2 months.
Results, next steps
The vorasidenib group demonstrated significant improvement compared with the placebo group in median PFS (27.7 months vs. 11.1 months; HR = 0.39; 95% CI, 0.27-0.56) and time to next intervention (median, not reached vs. 17.8 months; HR = 0.26; 95% CI, 15-0.43).
Adverse events of grade 3 or higher occurred among 22.8% of patients who received vorasidenib and 13.5% of patients who received placebo. The most common grade 3 or higher adverse events in the vorasidenib vs. placebo group included increased alanine aminotransferase (9.6% vs. 0%), increased aspartate aminotransferase (4.2% vs. 0%) and seizure (4.2% vs. 2.5%).
“Vorasidenib really has the potential to change the landscape of this disease ... and it will open the door for additional studies in the future,” Mellinghoff said.
References:
- Mellinghoff IK, et al. Abstract LBA1. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
Perspective
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Ashley L. Sumrall, MD, FACP
I was thrilled to see these data.
It has been years since we’ve had a new drug to use for patients with glioma. In particular, we’ve really never had a drug to treat the lower-grade gliomas. These tumors primarily affect younger patients, and for that patient population, maintenance and improvement of quality of life is very important.
If this will allow us to delay brain radiation and the cognitive effects that come from that, then it is really a revolutionary tool that we have.
Healio | HemOnc Today Editorial Board Member
Perspective
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Daniel Orringer, MD
Though slowly progressing, adult-type diffuse gliomas are the most common malignant tumors that arise from the brain, and they cannot be cured with existing therapies.
Our understanding of low-grade gliomas has developed profoundly in the last decades as we’ve learned more about their genetic basis. Specifically, a mutation in a key metabolic pathway enzyme (IDH in glioma cells) has been identified in 85% to 90% of low-grade diffuse gliomas. The presence or absence of this mutation is now used to define this subtype of diffuse gliomas.
IDH-mutant tumors (as opposed to IDH wild-type tumors) have a distinct biology and develop specific genomic and epigenetic alterations which, over-time, lead to malignant transformation.
Given the relatively long survival of many patients with IDH-mutant low-grade glioma, the impact of vorasidenib on OS could not be assessed in this study to date and will be reported at a future date. Follow-up studies will likely focus on new ways to combine vorasidenib with other treatments that are known to prolong survival in patients with low-grade IDH-mutant glioma, and potentially on the use of IDH inhibitors as maintenance therapy among patients with higher grade IDH-mutant tumors necessitating upfront therapy. However, the early signs of success with vorasidenib reported today represent a major step toward progress in the treatment of diffuse low-grade glioma.
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Mellinghoff IK, et al. Abstract LBA1. Presented at: ASCO Annual Meeting 2023; June 2-6, 2023: Chicago.
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