Exploratory Analyses from the Phase Three INDIGO Study Suggest Potential Mechanism of Seizure Control Through Tumor Volume Reduction Under Treatment With Vorasidenib
Katherine Peters1, Ingo Mellinghoff2, Wolfgang Wick3, Martin Van Den Bent4, Deborah Blumenthal5, Mehdi Touat6, Jennifer Clarke7, Joe Mendez8, Liam Welsh9, Warren Mason10, Andreas Hottinger11, Juan Sepulveda12, Riccardo Soffietti13, Dan Zhao14, Denise Yi14, Daniel Weidl15, Lori Steelman14, Islam Hassan14, Patrick Wen16, Timothy Cloughesy17
1Duke University Medical Center, 2Memorial Sloan Kettering Cancer Center, 3Universitätsklinikum Heidelberg, Heidelberg & German Cancer Research Center, 4Erasmus Medical Center, 5Tel Aviv Medical Center, Tel Aviv University, 6Pitié Salpêtrière Hospital, Assistance Publique – Hôpitaux de Paris (AP-HP) Sorbonne Université, 7UCSF, 8Huntsman Cancer, 9The Royal Marsden Hospital, 10Toronto General Hospital, 11University Hospital of Lausanne, 12Hospital Universitario 12 de Octubre, 13University of Turin, 14Servier Pharmaceuticals, 15Servier Deutschland GmbH, 16Dana-Farber/Brigham and Women'S Cancer Center, 17University of California Los Angeles
Objective:
We investigated potential relationships between vorasidenib/seizure rate and tumor volume/seizure activity in patients with isocitrate dehydrogenase 1/2 mutant (mIDH1/2) glioma.
Background:
Grade 2 mIDH1/2 gliomas are slow-progressing incurable brain tumors with poor long-term prognosis. Patients often experience seizures that impact daily life. Vorasidenib, an oral, brain-penetrant, dual mIDH1/2 inhibitor, demonstrated significant clinical benefits, including gradual tumor shrinkage, and a manageable safety profile in the Phase 3 INDIGO study (NCT04164901).
Design/Methods:
Patients aged ≥12 years with grade 2 mIDH1/2 oligodendroglioma or astrocytoma, no prior glioma treatment other than surgery, and no uncontrolled seizures, were randomized 1:1 to vorasidenib 40 mg or placebo daily. On-treatment seizure numbers were analyzed in patients with ≥1 seizure during baseline or on-treatment periods using a negative binomial regression model. Potential association between seizure activity and tumor volume was assessed using mixed-effect model with repeated measurements. Analyses were exploratory; P-values were not prespecified and should be interpreted with caution.
Results:
This analysis included 168 patients treated with vorasidenib (oligodendroglioma n=88; astrocytoma n=80) and 163 treated with placebo (oligodendroglioma n=84; astrocytoma n=79). Patients treated with vorasidenib versus placebo had lower on-treatment rates of seizures; model-estimated rate per person-year: 18.2 (95% confidence interval [CI] 8.4–39.5) vs 51.2 (95% CI 22.9–114.8); rate ratio: 0.36 (95% CI 0.14–0.89), P=0.0263. There was a highly positive association between tumor volume (log scale) and seizure number (estimate of coefficient: 0.7, standard error [SE]: 0.26, P=0.007). Sensitivity analyses per tumor volume suggest that vorasidenib was negatively associated with both number and severity of seizures (estimates of coefficient [SE], -4.81 [1.41], P=0.0008; -0.55 [0.25], P=0.0289, respectively).
Conclusions:
Vorasidenib was associated with lower seizure rate and severity than placebo in patients with mIDH1/2 glioma. Smaller tumor volume was associated with lower seizure rate. Our analyses suggest a potential mechanism of seizure control with vorasidenib through tumor size reduction.
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