Among patents with IDH1- or IDH2-mutant glioma, the treatment combination of Voranigo (vorasidenib) plus Temodar (temozolomide) did not lead to any serious side effects or dose-limiting toxicities (DLTs), clinical trial results have shown.
Data from the phase 1b IDHEAL-4U trial were presented at the 2025 Society for Neuro-Oncology Annual Meeting.
Findings demonstrated that, with a median treatment duration 5.5 months, all patients (seven patients) experienced any-grade treatment-emergent side effects; 28.6% (two patients) had grade 3 (severe) or higher treatment-emergent side effects, which included decreased neutrophil count (14.3%) and decreased platelet count (28.6%). No patients discontinued treatment due to treatment-emergent side effects, and all patients completed the DLT evaluation portion of the study. As of the Sept. 8, 2025, data cutoff, 85.7% (six patients) remained on treatment with both study drugs.
Treatment-emergent side effects led to dose reductions in 42.9% of patients; notably, 14.3% required dose reductions of only Voranigo, 28.6% needed dose reductions of only Temodar, and no patients required dose reductions of both agents. Dose reductions of Voranigo stemmed from increased alanine aminotransferase (ALT) levels (14.3%), and reductions of Temodar were due to decreased platelet count (28.6%) and decreased neutrophil count (14.3%).
Treatment-emergent side effects required study drug interruption in 57.1% of patients, including 28.6% who needed dose interruptions of both treatments, which was due to increased ALT levels (28.6%). Only Voranigo was interrupted in 14.3% of patients, and only Temodar was interrupted in 57.1% of patients. Treatment-emergent side effects leading to dose interruptions of only Voranigo included increased ALT levels (14.3%), and these included neutropenia (42.9%) and decreased platelet count (42.9%) for Temodar only.
“Based on data from the May 6, 2025, data cutoff, the safety review committee declared [Voranigo at] 40 mg as the recommended combination dose [RCD] to be given in combination with standard-of-care [Temodar],” lead study author Dr. Macarena de la Fuente and colleagues wrote in a poster presentation of the data.
de la Fuente is 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.
Why are Voranigo and Temodar being evaluated as a combination strategy in IDH1/2-mutated glioma?
Although Voranigo is approved by the FDA for the treatment of adult and pediatric patients 12 years of age and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, as detected by an FDA-approved test, following surgery including biopsy, sub-total resection, or gross total resection, treatment with IDH inhibitor monotherapy is unlikely to lead to disease control in patients with higher-grade, more aggressive gliomas.
As such, de la Fuente and colleagues hypothesized that adding Voranigo to Temodar could, “exploit the molecular vulnerabilities of higher-grade [IDH1/2-mutant] gliomas while controlling more rapidly proliferative tumor cells.”
IDHEAL-4U is a multicenter phase 1b/2 trial designed to evaluate the combination, with phase 1b focusing on safety, and the ongoing phase 2 portion looking at preliminary efficacy, safety, and tolerability for the RCD in patients with grade 4 astrocytoma harboring IDH1/2 mutations.
In phase 1b, investigators enrolled patients at least 12 years of age with grade 2 to 4 gliomas with IDH1/2 mutations who were eligible for Temodar in the adjuvant setting after radiotherapy or at first disease recurrence.
Voranigo was first evaluated at 40 mg once per day in combination with Temodar at 150 mg/m2 in cycle 1, then 200 mg/m2 in cycles 2 to 12. Voranigo was continued until disease progression. After safety review committee input and analysis of DLT rate and BOIN design, investigators could dose de-escalate to evaluate Voranigo to 20 mg per day, or declare the RCD.
What were the patient characteristics in phase 1b?
The seven enrolled patients had a median age of 36 years, and 57.1% were female. Karnofsky performance status at baseline included 100 (14.3%), 90 (57.1%), 80 (14.3%) and 70 (14.3%). Patient tumor types included frontline grade 3 astrocytoma (42.9%), frontline grade 4 astrocytoma (14.3%), recurrent grade 4 astrocytoma (14.3%), frontline grade 3 oligodendroglioma (14.3%) and recurrent grade 4 oligodendroglioma (14.3%).
All patients had received prior radiation therapy. Three patients (42.9%) received prior systemic therapy, which was exclusively Temodar.
Reference
- “Phase 1b safety results of vorasidenib in combination with temozolomide in patients with mutant IDH1 or IDH2 glioma” by Dr. Macarena de la Fuente et al., presented at: 2025 SNO Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTNI-34.
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