Vorasidenib shows promising results in IDH1- or IDH2-Mutant low-grade gliomas: NEJM

New research revealed that Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes significantly improves progression-free survival and delayed the time to the next intervention. The trial was published in the journal The New England Journal of Medicine.

Gliomas are the most common and diffusively infiltrative central nervous system tumors that originate from the glial cells. Gliomas are classified into low-grade, atypical, and high-grade tumors based on cell morphology, mitotic activities, and molecular marker. Grade 2 gliomas with IDH mutations are malignant brain tumors that result in severe impairment and early death. In preliminary studies, Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes has shown good results in IDH-mutant gliomas. Hence researchers conducted a double-blind, phase 3 trial to assess the effect of the drug on gliomas.

Patients with residual or recurrent grade 2 IDH-mutant glioma who had not undergone any previous treatment other than surgery were recruited to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. Assessing the imaging-based progression-free survival according to blinded assessment by an independent review committee was the primary endpoint of measurement. The key secondary endpoint was the duration of the next anticancer intervention. Participants could crossover to vorasidenib from placebo based on confirmation of imaging-based disease progression. Apart from this, safety was also assessed.

Key findings:

• Out of 331 patients who were assigned to receive vorasidenib (168 patients) or placebo (163 patients), 226 patients (68.3%) were continuing to receive vorasidenib or placebo at a median follow-up of 14.2 months.
• Vorasidenib group showed significant improvement in the progression-free survival as compared with the placebo group (27.7 months vs. 11.1 months).
• There was a significant improvement in the time to the next intervention in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26).
• Both the groups showed adverse events of grade 3 or higher. They occurred in 22.8% of the patients in the vorasidenib group and in 13.5% of those in the placebo group.
• An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo.

Thus, vorasidenib is the first targeted drug developed specifically for people with brain cancer and it has become a promising treatment option for low-grade gliomas.

Further reading: Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma [published online ahead of print, 2023 Jun 4]. N Engl J Med. 2023;10.1056/NEJMoa2304194. doi:10.1056/NEJMoa2304194