Perioperative Study of Vorasidenib Shows Promise for Patients with Low-Grade Glioma

November 26, 2019

A perioperative study confirmed brain penetrance and robust biomarker suppression in patients with low-grade glioma with an IDH1 mutation.

A perioperative study in low-grade glioma with an IDH1 mutation suggested brain penetrance and robust biomarker suppression with treatment of single agent vorasidenib (AG-881) or ivosidenib (Tibsovo), according to Agios Pharmaceuticals.1

The data were presented at the Society for Neuro-Oncology (SNO) Annual Meeting in Phoenix.

In the cohort of 49 patients, 15 patients treated with vorasidenib and 16 patients treated with ivosidenib experienced stable disease, resulting in disease control rates of 90% and 95%, respectively.

“It is encouraging that the safety profile continues to be consistent, and preliminary efficacy data show objective tumor responses and durable disease control with postoperative treatment. These data support the selection of vorasidenib for pivotal development and help establish the potential role for IDH inhibitors in the treatment of low-grade glioma,” study investigator Ingo Mellinghoff, MD, Memorial Sloan Kettering Cancer Center, said in a press release.

Patients in cohort 1 were randomized to 500 mg ivosidenib, 50 mg vorasidenib once daily, or the control arm. In cohort 2, patients were given 250 mg ivosidenib twice daily or 10 mg vorasidenib once daily. Patients were treated for 4 weeks prior to surgery and were given the option to continue postoperative treatment until disease progression.

Vorasidenib and ivosidenib demonstrated brain penetrance, with mean brain to plasma ratios of 3.16 in patients given 10 mg vorasidenib, 1.74 in those who received 50 mg vorasidenib, 0.13 in patients given 250 mg ivosidenib, and 0.10 for those who received 500 mg ivosidenib.

Among patients treated postoperatively with 50 mg vorasidenib, 4 patients (31%) achieved objective tumor responses (2 achieved a partial response and 2 achieved a minor response). Among patients treated postoperatively with 500 mg ivosidenib, 4 patients (31%) achieved confirmed responses (2 achieved a partial response and 2 achieved a minor response).

The most common adverse events (AEs) occurring in >25% of patients in the vorasidenib arm were diarrhea (29.2%), fatigue (29.2%), and nausea (29.2%). In the ivosidenib arm, the most commons AEs were headache (32%), diarrhea (28%), and anemia (28%). No patient discontinued treatment due to an AE.

“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, said in a press release.

In the phase III INDIGO study, researchers will evaluate 366 patients with IDH-mutant grade 2 non-enhancing glioma in a 1:1 double-blind randomization, giving patients either 50 mg of vorasidenib once daily or placebo.

The primary endpoint is progression free survival, as assessed by a blinded independent review committee. Secondary endpoints include safety and tolerability, tumor growth rate as assessed by volume, overall response rate, time to next intervention, and quality of life.

The phase III INDIGO study will initiate by the end of 2019. Vorasidenib and ivosidenib are not currently approved in any country for the treatment of patients with low-grade glioma.

References:
1. 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 [news release]. Phoenix, Arizona. Published November 22, 2019. investor.agios.com/news-releases/news-release-details/agios-presents-new-pharmacodynamic-and-response-data-both. Accessed November 25, 2019.