IDH Inhibitor Efficacy in Brain Cancer Continues with Longer Follow-Ups

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

After a median follow-up of 20 months, median PFS had not yet been reached in patients randomized to the vorasidenib group (minimum prediction interval 22.1 months), compared with 11.4 months in the placebo arm. The difference translated into a 65% reduction in the hazard of disease progression or death in favor of the IDH1/2 inhibitor (P.=0.00000000013).

Dr. from Memorial Sloan Kettering Cancer Center in New York City. Ingo K. Mellinghoff similarly reported that mean time to next intervention (TTNI) was not predictable with vorasidenib, compared with 20.1 months for the placebo group. NeuroOncology Association (SNO) meeting.

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

The results reflected these reported At the 2023 American Society of Clinical Oncology (ASCO) meeting, median PFS was not yet reached in the vorasidenib arm (estimated at 27.7 months) while it was 11.1 months in the placebo group. At that time, TTNI was 17 months in the placebo arm but was not yet predictable with vorasidenib. Results support FDA approval of vorasidenib at the beginning of this year For patients 12 years and older, grade 2 IDH-mutant astrocytoma or oligodendroglioma.

In a separate report in SNO, long-term follow-up The stage I am working on Results of perioperative treatment have shown promising results, commonly with vorasidenib and the IDH1 inhibitor ivosidenib (Tibsovo). IDH1-mutant glioma. As reported by Timothy Cloughesy, MD, of UCLA Health in Los Angeles, the median PFS of patients receiving vorasidenib with or without radiotherapy (RT) before and after surgery was 41.4 months compared with 38.3 months with ivosidenib. was.

INDIGO

Mellinghoff reported updated results from the phase III INDIGO study, which included 331 patients aged ≥12 years. IDH1/2-mutant grade 2 oligodendroglioma or astrocytoma. Additional eligibility criteria included one or more previous surgeries for glioma, measurable non-progressive disease, and no need for immediate chemotherapy or radiotherapy.

Patients were randomized to vorasidenib or placebo and treated until disease progression; At this time, patients had the option to switch. The primary endpoint was PFS by independent review and the primary secondary endpoint was TTNI.

The trial met the primary endpoint in the first interim analysis reported in 2023, and the update provides approval, Mellinghoff said. With additional follow-up, the PFS hazard ratio in favor of vorasidenib increased from 0.39 to 0.35. Milestone analyzes showed significant benefits for vorasidenib at 12 months (77.3% versus 47.3%) and 24 months (58.8% versus 26.7%).

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

The TTNI hazard was 0.25, almost the same as the previous report (0.26). At 12 months (90.3% versus 74.9%) and 24 months (80.3% versus 41.4%), TTNI showed significant advantages in favor of vorasidenib.

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred more frequently with vorasidenib (26.9% vs 16.0%), particularly increased liver function tests (ALT 10.2% vs 1.2%) ; AST 4.8% vs 0%). Seizures occurred at similar rates in patients in both 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 voradidenib (n=54) or placebo (n=56). However, seizure events during treatment occurred significantly more frequently in the placebo group (5,124 vs. 1,541), resulting in significantly lower odds favoring vorasidenib (0.36, P.=0.263).

Tumor volume decreased by 1.3% in the vorasidenib arm and increased by 14.4% in the placebo group. Tumor volume increased in patients before they started treatment, then decreased in the vorasidenib arm, Mellinghoff said. Among 61 patients who switched from placebo to vorasidenib, tumor volume increased by 23.9% before switching and 0.9% after switching.

Phase I Study

A. 2023 report A phase I comparison between vorasidenib and ivosidenib showed that both drugs reduced 2-hydroxyglutarate (2-HG) levels in the tumor by more than 90%. The reduction in 2-HG was associated with positive effects on many factors associated with tumor growth. But Cloughesy said PFS data was not mature at that time. An additional 3.5-year follow-up was included in the updated report.

2/3 to study. 49 patients with poor contrast enhancement were included. IDH1-mutant gliomas. They were randomized to two IDH inhibitors before surgery. The primary end point was the concentration of 2-HG in resected tumors after treatment with the assigned therapy. Secondary endpoints include safety and pharmacokinetics, as well as clinical activity as measured by: Response Evaluation in Neuro-Oncology for low-grade gliomas (RANO-LGG). Three patients in the ivosidenib group did not continue treatment after surgery.

Updated results showed a response rate of 45.5% with vorasidenib and 31.8% with ivosidenib. Duration of 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 underwent 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 due to TEAEs (8.0% vs 4.2%).