Dr de la Fuente on Safety Data With Vorasidenib Plus Temozolomide in IDH-Mutant Glioma

"This is a study that combined vorasidenib with temozolomide for patients with IDH-mutant glioma. It is the first time that we’ve seen this combination [evaluated] in IDH-mutant tumors. We are excited about the safety profile of the combination and moving it forward to the phase 2 part of the study."

Macarena de la Fuente, MD, an associate professor of neuro-oncology, chief of the Neuro-Oncology Division, clinical service leader for Neuro-Oncology Service Line - Sylvester Comprehensive Cancer Center, chair of the Neuro-Oncology Site Disease Group, director of the Neuro-Oncology Fellowship Program, and oncology clinical service leader for Neuro-Oncology at the Miller School of Medicine of University of Miami in Florida, shared early safety data from the phase 1b IDHEAL-4U trial (NCT05592743), which evaluated the addition of vorasidenib (Voranigo) to temozolomide (Temodar) in patients with glioma harboring IDH1 or IDH2 mutations.

Vorasidenib is a brain penetrant dual IDH inhibitor that has been approved by the FDA for treating adult and pediatric patients with grade 2 astrocytoma or oligodendroglioma possessing a susceptible IDH1 or IDH2 mutation following surgery, de la Fuente began. However, standard care for more aggressive, higher-grade gliomas involves radiation with chemotherapy, and prior to this study, no safety or efficacy data existed for this combination, she noted.

IDHEAL-4U is a multicenter phase 1b/2 trial, with the phase 1b portion focusing specifically on safety. Investigators enrolled patients at least 12 years of age with grade 2 to 4 IDH1/2-mutant gliomas who were eligible for temozolomide in the adjuvant setting or at first recurrence.

Findings presented at the 2025 Society for Neuro-Oncology Annual Meeting showed that combining vorasidenib and temozolomide did not lead to any serious adverse effects (SAEs) or dose-limiting toxicities (DLTs), de la Fuente reported. Although all 7 patients experienced any-grade treatment-emergent adverse effects (TEAEs) over a median duration of 5.5 months, only 28.6% (n = 2) had grade 3 or higher TEAEs, including decreased neutrophil count (14.3%) and decreased platelet count (28.6%). Crucially, no patients discontinued treatment due to TEAEs, and all patients completed the DLT evaluation.

Accordingly, the recommended combinatory dose (RCD) was established as 40 mg of vorasidenib administered daily, combined with a standard dose of temozolomide, de la Fuente shared. This dose combination is currently being evaluated in the phase 2 portion of the study. Researchers expressed excitement over the safety profile, as this is the first time this specific combination has been studied in IDH-mutant tumors, she concluded.