IDH Inhibitor Activity in Brain Cancer Persists With Longer Follow-Up

HOUSTON — Progression-free survival (PFS) in IDH-mutant low-grade glioma remained twice as high in adults who received vorasidenib (Voranigo) after surgery versus placebo, according to a follow-up analysis of a pivotal clinical trial.

After a median follow-up of 20 months, median PFS had yet to be reached in patients randomized to vorasidenib (lower range of estimate 22.1 months) as compared with 11.4 months in the placebo arm. The difference translated into a 65% reduction in the hazard for disease progression or death in favor of the IDH1/2 inhibitor (P=0.00000000013).

Similarly, median time to next intervention (TTNI) was not estimable with vorasidenib versus 20.1 months for the placebo group, reported Ingo K. Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center in New York City, at the Society for NeuroOncology (SNO) meeting.

“Vorasidenib treatment demonstrates consistently robust efficacy and a greater magnitude of PFS and TTNI with longer follow-up,” he said. “Vorasidenib continues to demonstrate a manageable safety profile, with no new safety signals, and was associated with better seizure control. Vorasidenib reduces tumor volume, causing tumor shrinkage, and the effect is observed after crossover to vorasidenib from placebo.”

The results mirrored those reported at the 2023 American Society of Clinical Oncology (ASCO) meeting, when median PFS had yet to be reached in the vorasidenib arm (estimated 27.7 months) versus 11.1 months in the placebo group. TTNI at that time was 17 months in the placebo arm but not yet estimable with vorasidenib. The results supported FDA approval of vorasidenib earlier this year for patients, ages 12 years or older, with grade 2 IDH-mutant astrocytoma or oligodendroglioma.

In a separate report at SNO, long-term follow-up from a phase I study of perioperative therapy showed promising results with vorasidenib and the IDH1 inhibitor ivosidenib (Tibsovo) in diffuse IDH1-mutant glioma. Patients who received vorasidenib before and after surgery, with or without radiotherapy (RT), had a median PFS of 41.4 months versus 38.3 months with ivosidenib, as reported by Timothy Cloughesy, MD, of UCLA Health in Los Angeles.

INDIGO

Mellinghoff reported updated results from the phase III INDIGO trial involving 331 patients, ages ≥12 years, who had IDH1/2-mutant grade 2 oligodendroglioma or astrocytoma. Additional eligibility criteria included one or more prior surgeries for glioma, measurable non-enhancing disease, and no immediate need for chemotherapy or RT.

Patients were randomized to vorasidenib or placebo and treated until disease progression, at which time patients had the option to cross over. The primary endpoint was PFS by independent review, and the key secondary endpoint was TTNI.

The trial met the primary endpoint at the first interim analysis reported in 2023, and the update provided confirmation, said Mellinghoff. With additional follow-up, the PFS hazard ratio in favor of vorasidenib increased from 0.39 to 0.35. Landmark analyses showed substantial advantages for vorasidenib at 12 months (77.3% vs 47.3%) and 24 months (58.8% vs 26.7%).

The PFS benefit remained consistent across all prespecified subgroups. PFS improved with vorasidenib regardless of baseline tumor volume or pretreatment tumor growth rate, said Mellinghoff.

The TTNI hazard was 0.25, almost identical to the earlier report (0.26). The TTNI at 12 months (90.3% vs 74.9%) and 24 months (80.3% vs 41.4%) showed substantial advantages in favor of vorasidenib.

Grade ≥3 treatment-emergent adverse events (TEAE) occurred more often with vorasidenib (26.9% vs 16.0%), particularly increased liver function tests (ALT 10.2% vs 1.2%; AST 4.8% vs 0%). Seizure occurred in a similar proportion of patients in the two groups (4.2% vs 3.1%). TEAE-related discontinuation rates were 4.2% with vorasidenib and 1.2% with placebo.

Seizures occurred in a similar number of patients treated with vorasidenib (n=54) or placebo (n=56). However, on-treatment seizure events occurred substantially more often in the placebo group (5,124 vs 1,541), resulting in a significantly lower ratio of rates favoring vorasidenib (0.36, P=0.263).

Tumor volume decreased by 1.3% in the vorasidenib arm but increased by 14.4% in the placebo group. Mellinghoff said tumor volume increased in patients before starting treatment and then decreased in the vorasidenib arm. Among 61 patients who crossed over from placebo to vorasidenib, tumor volume increased by 23.9% before crossover versus 0.9% after crossover.

Phase I Study

A 2023 report on the phase I comparison of vorasidenib and ivosidenib showed that both drugs reduced tumor levels of 2-hydroxyglutarate (2-HG) by more than 90%. Reduction in 2-HG was associated with favorable effects on multiple factors related to tumor growth. However, PFS data were not mature at that time, said Cloughesy. The updated report incorporated an additional 3.5 years of follow-up.

The study involved 49 patients with grade 2/3 non-enhancing IDH1-mutant gliomas. They were randomized prior to surgery to the two IDH inhibitors. The primary endpoint was 2-HG concentration in tumors resected after treatment with the assigned therapy. Secondary endpoints included safety and pharmacokinetics, as well as clinical activity as measured by the Response Assessment in Neuro-Oncology for low-grade gliomas (RANO-LGG). Three patients in the ivosidenib group did not continue therapy after surgery.

The updated results showed a response rate of 45.5% with vorasidenib and 31.8% with ivosidenib. Time to response and duration of response also favored vorasidenib. Treatment duration was almost twice as long with vorasidenib (44.67 vs 23.2 months).

In the subgroup of patients who had surgery but not RT, median PFS was 55.2 months with vorasidenib and 38.6 months with ivosidenib.

Overall, safety results were similar between the two groups, but almost twice as many patients in the vorasidenib group had grade ≥3 TEAEs (62.5% vs 32.0%). More patients in the ivosidenib group discontinued treatment because of TEAEs (8.0% vs 4.2%).

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