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Long-term follow-up results show vorasidenib prolongs PFS and reduces tumor progression vs placebo in IDH-mutant grade 2 glioma.
Vorasidenib (Voranigo) maintained a durable treatment benefit over placebo in patients with grade 2 IDH1/2-mutant glioma following surgical resection, according to long-term follow-up data from the phase 3 INDIGO trial (NCT04164901), published in The Lancet Oncology.1,2
The newly published analysis included an additional 6 months of placebo-controlled, double-blind data collected between the second interim analysis on September 6, 2022, and trial unblinding on March 7, 2023. At a median follow-up of 20.1 months, vorasidenib significantly improved progression-free survival (PFS), the primary end point of the trial. The median PFS was not estimable (NE; 95% CI, 22.1-NE) in the vorasidenib arm compared with 11.4 months (95% CI, 11.1-13.9) in the placebo arm (HR, 0.35; 95% CI, 0.25-0.49; P < .0001). Imaging-based disease progression per blinded independent review committee occurred in 32% of patients receiving vorasidenib vs 64% of those receiving placebo.
Key Findings: INDIGO Trial Long-Term Follow Up
“These longer-term results from the INDIGO trial build upon [vorasidenib’s] previously demonstrated clinical benefits and demonstrate reductions in tumor volume and seizure frequency in patients with IDH-mutated gliomas," Becky Martin, PhD, chief of Medical at Servier Pharmaceuticals, said in a news release.1 “One year after the FDA approval of [vorasidenib], we're immensely proud to have delivered this first-of-its-kind targeted therapy to thousands of patients living with IDH-mutated glioma, offering them clinically meaningful and durable treatment benefits supported by more than a decade of research.”
The INDIGO trial was a global, randomized, double-blind, placebo-controlled study evaluating vorasidenib in patients with residual or recurrent grade 2 IDH1/2-mutant diffuse glioma who had undergone surgery as their only prior treatment.3 Conducted across 11 countries—including the United States, United Kingdom, Canada, France, Germany, Italy, Spain, Switzerland, Israel, Japan, and the Netherlands—the trial enrolled patients aged 12 years or older with a Karnofsky performance scale score (for patients at least 16 years of age) or a Lansky play performance scale score (for patients younger than 16 years of age) of at least 80%, a history of at least 1 prior surgery, and no prior chemotherapy or radiotherapy.
A total of 331 patients were randomly assigned 1:1 to receive oral vorasidenib at 40 mg once daily (n = 168) or placebo (n = 163) in continuous 28-day cycles until disease progression or unacceptable toxicity. Randomization was stratified by locally determined chromosome 1p/19q codeletion status and baseline tumor size.1,2 Among patients in the enrolled population, 172 had oligodendroglioma (vorasidenib, n = 88; placebo, n = 84) and 159 had astrocytoma (n = 80; n = 79).1
The primary end point was progression-free survival (PFS) assessed by a masked independent review committee.3 The key secondary end point was time to next intervention (TTNI). Additional prespecified secondary and exploratory end points included tumor growth rate (defined as the change in tumor volume every 6 months), health-related quality of life (HRQOL; as assessed by the Functional Assessment of Cancer Therapy–Brain), neurocognitive function, and seizure activity.
Prespecified subgroup analyses from the INDIGO trial demonstrated that the PFS benefit with vorasidenib was consistent across all evaluated patient subgroups, uniformly favoring the investigational agent over placebo.1 In addition to prolonging PFS, vorasidenib significantly improved the key secondary end point of TTNI. The median TTNI was NE with vorasidenib compared with 20.1 months with placebo (HR, 0.25; 95% CI, 0.16-0.40; P < .0001), reflecting a sustained delay in the need for subsequent cytotoxic therapy and confirming the regimen’s durable disease control.
Vorasidenib was also associated with a reduced tumor growth rate and lower seizure frequency compared with placebo, without detrimental effects on HRQOL or neurocognitive function. Exploratory analyses revealed that among patients who experienced 1 or more seizures, the rate of on-treatment seizures per person-year was significantly lower with vorasidenib (18.2 seizures per person per year; 95% CI, 8.4-39.5) than with placebo (51.2 seizures per person per year; 95% CI, 22.9-114.8; P = .026).
The most frequently reported grade 3 or higher treatment-emergent adverse effects (TEAEs) included elevations in alanine aminotransferase levels (10%), elevations in aspartate aminotransferase levels (5%), seizures (4%), and elevated gamma-glutamyltransferase levels (3%). These effects were manageable with standard supportive measures and dose modifications when necessary. Fewer than 5% of patients discontinued therapy due to AEs, and no treatment-related deaths occurred during the study period.
“For decades, patients with grade 2 IDH-mutated gliomas had limited treatment options. While surgery was often the first-line treatment option for glioma, total resection was rarely achievable because tumors continue to grow and infiltrate the brain even after surgery,” Timothy Cloughesy, MD, of the David Geffen School of Medicine Department of Neurology at UCLA and an investigator for the INDIGO trial, shared in the news release. “The longer-term data from the INDIGO trial demonstrate that targeted IDH inhibition can fundamentally alter the growth trajectory of certain gliomas, leading to gradual tumor shrinkage.”
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