The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending approval of vorasidenib (Voranigo) for treating predominantly non-enhancing grade 2 astrocytoma or oligodendroglioma with IDH1 R132 or IDH2 R172 mutations in adult and adolescent patients aged 12 years and older who have undergone surgical resection and are not in immediate need of radiotherapy or chemotherapy.
The CHMP recommendation represents a significant milestone for patients with grade 2 IDH-mutant glioma, who have historically had limited treatment options. If approved by the European Commission, vorasidenib would become the first targeted therapy for this indication in the European Union.
Pivotal Trial Results Drive Regulatory Decision
The positive opinion is supported by findings from the phase 3 INDIGO trial, a global, randomized, double-blind, placebo-controlled study that evaluated vorasidenib in 331 patients with residual or recurrent grade 2 IDH-mutant glioma following surgery. Results published in The New England Journal of Medicine demonstrated that vorasidenib significantly improved progression-free survival compared with placebo, with a median PFS of 27.7 months versus 11.1 months, respectively (hazard ratio, 0.39; 95% CI, 0.27-0.56; P < .001).
The study also showed that time to next intervention was significantly delayed with vorasidenib treatment (HR, 0.26; 95% CI, 0.15-0.43; P < .001), indicating patients could defer additional cancer treatments for a longer period.
In the INDIGO trial, patients were randomized to receive vorasidenib 40 mg daily or placebo continuously in 28-day cycles. Of the 331 enrolled patients, 172 had oligodendroglioma and 159 had astrocytoma. The study's primary endpoint was progression-free survival, with time to next anticancer intervention serving as a key secondary endpoint.
Safety Profile and Tolerability
Grade 3 or higher adverse effects occurred in 22.8% of patients receiving vorasidenib compared with 13.5% in the placebo group. Elevated alanine aminotransferase levels of grade 3 or higher were reported in 9.6% of patients receiving vorasidenib and in none of the placebo-treated patients. Importantly, no treatment-related deaths were reported in the study.
Global Regulatory Progress
"Today's recommendation for European Union approval brings us one step closer to offering vorasidenib to patients in the EU with grade 2 IDH-mutant glioma who have historically had limited treatment options for this relentless disease," said Susan Pandya, MD, vice president of Clinical Development and global head of oncology LS/LCM at Servier.
The marketing authorization application for vorasidenib will now be reviewed by the European Commission, which has authority to approve medicines for use in the 27 member states of the EU. Decisions by the European Commission are also applicable in Norway, Liechtenstein, and Iceland.
This positive recommendation follows the FDA approval of vorasidenib in August 2024 for the treatment of IDH1/2-mutant grade 2 diffuse glioma following surgical resection. The drug has also received marketing authorization in Canada, Australia, Israel, the United Arab Emirates, Saudi Arabia, and Switzerland.
First-in-Class Targeted Therapy
Vorasidenib represents the first and only approved therapy designed to target mutant IDH enzymes in grade 2 glioma. The drug is an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor that offers patients the convenience of once-daily oral administration.
"We look forward to continuing conversations with the EMA and other regulatory bodies around the world to introduce vorasidenib as a potential new standard of care for patients with IDH-mutant gliomas," Pandya concluded.
Servier has also submitted marketing authorization applications in the United Kingdom, Japan, and various other regions, with reviews by the appropriate health authorities ongoing.
