New Agents Show Promise in Treating Patients with IDH1-Mutant Low-Grade Glioma

Ingo K. Mellinghoff, MD

Single-agent vorasidenib or ivosidenib (Tibsovo) led to brain penetrance and 2-hydroxyglutarate (2-HG) suppression in patients with low-grade glioma who harbor IDH1 mutations, according to updated data from an ongoing, 2-cohort, perioperative study (NCT03343197) that were presented at the 2019 Society for Neuro-Oncology Annual Meeting.

Findings were available from 42 efficacy-evaluable patients on vorasidenib (n = 21) or ivosidenib (n = 21). Among those who received postoperative vorasidenib at 50 mg, 4 (31%) patients achieved objective tumor responses, which comprised 2 partial responses (PRs) and 2 minor responses, according to the investigator by Response Assessment in Neuro-Oncology for low-grade glioma (RANO-LGG).

The objective response rate was also 31% for patients who received 500 mg of ivosidenib in the postoperative setting, also according to investigator by RANO-LGG. This included 2 PRs and 2 minor responses. Moreover, stable disease was achieved in 15 and 16 patients on vorasidenib and ivosidenib, respectively, which led to respective disease control rates of 90% and 95%.

Vorasidenib is an investigational, oral, selective IDH1/IDH2 inhibitor that is designed to enhance brain penetrance and has been in clinical development in IDH mutant low-grade glioma.

Ivosidenib is currently approved by the FDA for the treatment of adult patients with relapsed/refractory IDH1-mutant acute myeloid leukemia (AML), and for the first-line treatment of adult patients with IDH1-mutant AML, as detected by an FDA-approved test, who are ≥75 years old or are ineligible to receive intensive induction chemotherapy.

In the ongoing trial, vorasidenib and ivosidenib are being evaluated as single agents in patients with IDH1-mutant grade 2/3 glioma. Patients are randomized to receive 500 mg of ivosidenib once daily, 50 mg vorasidenib once daily, or the control arm of no treatment in cohort 1. In the second cohort, patients receive either 250 mg of ivosidenib twice daily or 10 mg of vorasidenib once daily. Patients are treated for 4 weeks prior to surgery and can continue postoperative treatment until disease progression.

The primary endpoint is 2-HG concentration in tumors resected following neoadjuvant treatment with vorasidenib and ivosidenib compared with the untreated control tumors.

As of the July 26, 2019, data cutoff, 49 patients were randomized before surgery and 39 remain on treatment. The median duration of postoperative treatment for all doses was 5.42 months (0.9-13.5) for vorasidenib and 6.93 months (1.0-13.2) for ivosidenib.

The baseline characteristics were similar across arms in each cohort. Overall, 88% of patients had World Health Organization classified grade 2 tumors; less than one-third of patients had prior radiation therapy and approximately half of patients previously received systemic therapy.

Results also showed that vorasidenib and ivosidenib each demonstrated brain penetrance. The mean brain-plasma ratios were 3.16, 1.74, 0.13, and 0.10 for the 10-mg vorasidenib, 50-mg vorasidenib, 250-mg ivosidenib, and 500-mg ivosidenib arms, respectively. The mean percent reduction in 2-HG were 92.6% (95% CI, 76.1-97.6) in the 50-mg vorasidenib group and 91.1% (95% CI, 72.0-97.0) in the 500-mg ivosidenib arms, relative to untreated samples.

A safety analysis was conducted for all 49 patients as of the data cutoff, which showed that both vorasidenib and ivosidenib had favorable safety profiles. In the vorasidenib arm, the most common adverse events (AEs) occurring in >25% of patients were diarrhea (29.2%), fatigue (29.2%), and nausea (29.2%). The most common AEs on the ivosidenib arm were headache (32%), diarrhea (28%), and anemia (28%).

A total 8.3% of patients on vorasidenib developed transaminase elevations, including one grade 3 transaminase elevation at 50 mg daily; this was resolved with dose interruption. Grade ≥3 AEs occurred in 6 (25.0%) vorasidenib-treated patients and 4 (16.0%) patients on ivosidenib; the majority of these were related to postoperative complications. No patients discontinued treatment due to AEs.

“Having now demonstrated brain penetrance, robust 2-HG suppression and an encouraging disease-control rate with vorasidenib, we’re confident in our ability to make a difference for patients with IDH mutant low-grade glioma and are on track to initiate the phase III INDIGO study next month.” Chris Bowden, MD, chief medical officer at Agios Pharmaceuticals, Inc., the developer of these agents, stated in the press release.

The double-blind, phase III INDIGO study will randomize 366 patients with IDH-mutant, grade 2 non-enhancing glioma 1:1 to receive either 50 mg of vorasidenib once daily or placebo. The primary endpoint of the trial, which is expected to initiate at the end of 2019, is progression-free survival.

A version of this article originally appeared on OncLive^® as, “Vorasidenib, Ivosidenib Show Encouraging Activity in IDH1-Mutant Low-Grade Glioma”.

Reference

Agios presents new pharmacodynamic and response data from both cohorts of the perioperative study of vorasidenib and Tibsovo (ivosidenib) in patients with IDH1 mutant positive low-grade glioma. Agios Pharmaceuticals. Published November 22, 2019. https://bit.ly/34lHPL7. Accessed November 25, 2019.