Vorasidenib Plus Temozolomide Demonstrates Safety in IDH1/2+ Glioma

The addition of vorasidenib (Voranigo) to temozolomide (Temodar) did not lead to any serious adverse effects (AEs) or dose-limiting toxicities (DLTs) for the treatment of patients with glioma harboring IDH1 or IDH2 mutations, according to data from the phase 1b IDHEAL-4U trial (NCT05592743) presented at the 2025 Society for Neuro-Oncology Annual Meeting.1

Findings demonstrated that, with a median treatment duration 5.5 months (range, 2.8-6.9), all patients (n = 7) experienced any-grade treatment-emergent AEs (TEAEs); 28.6% (n = 2) had grade 3 or higher TEAEs, which included decreased neutrophil count (14.3%) and decreased platelet count (28.6%). No patients discontinued treatment due to TEAEs, and all patients completed the DLT evaluation portion of the study. As of the September 8, 2025, data cutoff, 85.7% (n = 6) of patients remained on treatment with both study drugs.

TEAEs led to dose reductions in 42.9% of patients; notably, 14.3% required dose reductions of only vorasidenib, 28.6% needed dose reductions of only temozolomide, and no patients required dose reductions of both agents. Dose reductions of vorasidenib stemmed from increased alanine aminotransferase (ALT) levels (14.3%), and reductions of temozolomide were due to decreased platelet count (28.6%) and decreased neutrophil count (14.3%).

TEAEs 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 vorasidenib was interrupted in 14.3% of patients, and only temozolomide was interrupted in 57.1% of patients. TEAEs leading to dose interruptions of only vorasidenib included increased ALT levels (14.3%), and these included neutropenia (42.9%) and decreased platelet count (42.9%) for temozolomide only.

“Based on data from the May 6, 2025, data cutoff, the safety review committee declared vorasidenib [at] 40 mg as the recommended combination dose [RCD] to be given in combination with standard-of-care temozolomide,” lead study author Macarena de la Fuente, MD, 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 vorasidenib and temozolomide being evaluated as a combination strategy in IDH1/2-mutated glioma?

Although vorasidenib 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,2 treatment with IDH inhibitor monotherapy is unlikely to lead to disease control in patients with higher-grade, more aggressive gliomas.1

As such, de la Fuente and colleagues hypothesized that adding vorasidenib to temozolomide 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 temozolomide in the adjuvant setting after radiotherapy or at first disease recurrence.

Vorasidenib was first evaluated at 40 mg once per day in combination with temozolomide at 150 mg/m2 in cycle 1, then 200 mg/m2 in cycles 2 to 12. Vorasidenib 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 vorasidenib to 20 mg per day, or declare the RCD.

The incidence of DLTs during cycle 1 was the primary end point in phase 1b, along with the incidence and severity of AEs, serious AEs, and AEs of special interest.

What were the patient characteristics in phase 1b?

The 7 enrolled patients had a median age of 36 years (range, 29-67), 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 temozolomide.

References

1. de la Fuente MI, Cloughesy TF, Touat M, et al. Phase 1b safety results of vorasidenib in combination with temozolomide in patients with mutant IDH1 or IDH2 glioma. Presented at: 2025 SNO Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTNI-34.
2. Voranigo. Prescribing information. Servier Pharmaceuticals; 2025. Accessed November 21, 2025. https://d11vmvycldsjdg.cloudfront.net/7fffe4c3-9746-4e82-9582-df9879a712d5/5939acdd-1c44-41f5-b2f6-260ab3860288/5939acdd-1c44-41f5-b2f6-260ab3860288_source__v.pdf