Vorasidenib delays disease progression or death in grade 2 glioma with IDH1/2 mutation
INDIGO is the first prospective, randomised, phase III study of a targeted therapy in grade 2 glioma with IDH1/2 mutation. Vorasidenib, an oral inhibitor of mutant IDH1 and IDH2 demonstrated clinical benefit and a manageable safety profile in this patient population for whom chemotherapy and radiotherapy are being delayed. As such, vorasidenib is an effective treatment that could delay the disabling long-term effects of current therapies.
Grade 2 gliomas are slowly progressive, malignant brain tumours with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and chemotherapy) are not curative and can be associated with short- and long-term toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease defining characteristic in the World Health Organization (WHO) 2021 definition. Median age of patients with IDH1/2-mutant diffuse gliomas is approximately 40 years. Vorasidenib is an oral inhibitor of mutant IDH1 and IDH2 that is specifically designed for brain penetrance.
Study design
In the randomised, double-blind, placebo-controlled phase III INDIGO study, patients were randomly allocated (1:1 ratio) to receive vorasidenib 40 mg daily or placebo daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumour size. Key eligibility criteria included: age ≥12 years, Karnofsky performance score >80, residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma, measurable non-enhancing disease, no prior treatment for glioma with most recent surgery 1-5 years from randomisation and not in immediate need of chemotherapy/radiation. Primary endpoint is radiographic progression-free survival (PFS), based on centrally reviewed brain MRIs. Key secondary endpoint is time to next intervention (TTNI).
Results
In total, 168 patients were randomised to the vorasidenib arm and 163 patients to the placebo arm. Median age of the patients was 40.4 years and the median time from last surgery until randomisation was 2.4 years. The study unblinded in March 2023 following IMDC recommendation based on early demonstration of efficacy, after which the majority of patients randomised to placebo crossed over to vorasidenib. After a median follow-up of 14.0 months with vorasidenib and 14.3 months with placebo, median PFS was significantly longer in the vorasidenib arm as compared to the placebo arm (27.7 vs. 11.1 months, HR[95%CI]: 0.39[0.27-0.56], one-sided p= 0.000000067). Time to next intervention was not reached for patients receiving vorasidenib and was 17.8 months for patients receiving placebo (HR[95%CI]: 0.26[0.15-0.43], one-sided p= 0.000000019).
All-grade adverse events occurring in more than 20% of patients receiving vorasidenib or placebo were alanine aminotransferase increased (38.9% vs. 14.7%), COVID-19 (32.9% vs. 28.8%), fatigue (32.3% vs. 31.9%), aspartate aminotransferase increase (28.7% vs. 8.0%), headache (26.9% vs. 27.0%), diarrhoea (24.6% vs. 16.6%) and nausea (21.6% vs. 22.7%). The increase of liver enzyme alanine aminotransferase was the most common grade ≥3 adverse event, occurring in 9.6% of patients receiving vorasidenib. Treatment interruption due to treatment-emergent adverse events (TEAEs) were reported in 29.9% of patients in the vorasidenib arm and in 22.7% of patients receiving placebo. Dose reductions due to TEAEs occurred in respectively 10.8% vs. 3.1% while treatment discontinuations due to TEAEs were reported in 3.6% vs. 1.2% of patients. No fatal TEAEs occurred.
Conclusion
Diffuse gliomas with IDH1/2 mutations are not curable with current therapies and infiltrate the brain in the absence of treatment. Vorasidenib is an oral inhibitor of the mutant IDH1/2 enzymes with proven brain penetrance. Treatment with vorasidenib significantly improved imaging-based PFS and TTNI with a manageable safety profile in patients who were not in need of immediate chemotherapy or radiotherapy.
Reference
Mellinghoff I, et al. INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. Presented at ASCO 2023; Abstract LBA1.
