As reported in The Lancet Oncology by Cloughesy et al, vorasidenib was associated with improvement in some secondary and exploratory outcomes vs placebo in the phase III INDIGO trial in patients with residual or recurrent IDH1-mutant or IDH2-mutant low-grade glioma.
Initial reports at second interim analysis of the trial showed that vorasidenib was associated with a significant improvement in progression-free survival on masked independent review committee assessment (primary endpoint) and time to next intervention, resulting in subsequent unblinding of the study.
Study Details
In the double-blind trial, 331 patients aged 12 years or older from sites in Canada, France, Germany, Israel, Italy, Japan, the Netherlands, Spain, Switzerland, the United Kingdom, and the United States were randomly assigned between January 2020 and February 2022 to receive vorasidenib at 40 mg (n = 168) or placebo (n = 163) once daily in continuous 28-day cycles until disease progression or unacceptable toxicity.
The current report includes 6 months of additional double-blind data and associations of vorasidenib with volumetric tumor growth rate, health-related quality of life (HRQOL), neurocognitive function, and seizure control.
Key Findings
Overall, median follow-up was 20.1 months (interquartile range = 15.9–23.8 months).
With an additional 6 months of follow-up, the vorasidenib group maintained significantly better progression-free survival and time to next intervention. Median progression-free survival was not reached (95% confidence interval [CI] = 22.1 months to not reached) in the vorasidenib group vs 11.4 months (95% CI = 11.1–13.9 months) in the placebo group (hazard ratio [HR] = 0.35, 95% CI = 0.25–0.49). Median time to next intervention was not reached (95% CI = not reached to not reached) in the vorasidenib group vs 20.1 months (95% CI = 17.5–27.1 months) in the placebo group (HR = 0.25, 95% CI = 0.16–0.40).
The 6-month tumor growth rate was –1.3% (95% CI = –3.2% to 0.7%) in the vorasidenib group vs 14.4% (95% CI = 12.0%–16.8%) in the placebo group (difference = 15.9%, 95% CI = 12.6%–19.3%).
HRQOL assessed as Mean Functional Assessment of Cancer Therapy–Brain total scores was similar in the two groups at baseline (158.2 vs 158.8) and end of treatment (154.2 vs 153.2). No differences between groups were observed in neurocognitive domains of verbal learning, executive function, attention, working memory, and psychomotor function from baseline through end of treatment.
The number of seizures per person-year was 18.2 (95% CI = 8.4–39.5) in the vorasidenib group vs 51.2 (95% CI = 22.9–114.8) in the placebo group.
Grade 3 or worse adverse events occurred in 27% vs 16% of patients, with the most common in the vorasidenib group being increased alanine aminotransferase (10%), increased aspartate aminotransferase (5%), and seizures (4%). Serious adverse events occurred in 12% vs 6% of patients. No treatment-related deaths were reported.
The investigators concluded: “Vorasidenib reduced tumour growth rate and improved seizure control compared with placebo, with no observed negative effects on HRQOL or neurocognition. Additional follow-up supported the robustness of progression-free survival and time to next intervention in patients with grade 2 IDH1/2-mutant diffuse glioma. These findings support the use of vorasidenib in patients with grade 2 IDH1/2-mutant gliomas who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy.”
Ingo K. Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center, New York, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Servier. For full disclosures of all study authors, visit thelancet.com.
