January 29, 2018
2 min read

Ivosidenib appears safe, effective in leukemia subtype

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ATLANTA — Ivosidenib monotherapy was well tolerated in patients with acute myeloid leukemia and an IDH1 mutation, according to results of a first-in-human phase 1 study presented at the ASH Annual Meeting and Exposition.

Additionally, ivosidenib (AG-120, Agios Pharmaceuticals), an IDH1 inhibitor, induced durable remissions and improved patient outcomes in a high-risk patient population with relapsed/refractory AML.

Recurrent IDH1 mutations typically occur in approximately 6% to 10% of patients with AML, according to study background.

Ivosidenib suppresses the abnormal production of oncometabolite 2hydroxyglutarate (2HG), leading to clinical responses via differentiation of malignant cells, Courtney D. DiNardo, MD, MSCE, an assistant professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during her presentation.

DiNardo said the aim of the study was to report safety and efficacy data from the use of ivosidenib in patients with IDH1-advanced hematologic malignancies, including relapsed/refractory AML.

Researchers assessed the safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics and clinical activity of the monotherapy.

Enrollment was from early 2014 to May 2017, DiNardo said.

Patients received ivosidenib orally once daily or twice daily in 28-day cycles during dose escalation. A maximum tolerated dose was not reached, and researchers selected 500 mg once daily as the recommended dose to be tested in the four expansion cohorts.

In all, 258 patients (78 dose escalation, 180 expansion) received ivosidenib. As of May 2017, 24% of patients remained on treatment. Median exposure to monotherapy was 3.5 months (0.1-33.5). Twenty-two patients discontinued therapy to undergo allogeneic stem cell transplant.

The most common adverse events of any grade, regardless of cause, included diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%) and febrile neutropenia (25%).

Most of the adverse events were reported as unrelated to treatment and were listed as grade 1 or grade 2.

Differentiation syndrome occurred in 11.2% of patients, including grade 3 or higher in 5.4% of patients. However, no instances of differentiation syndrome led to permanent treatment discontinuation or death.

Complete remission, according to modified IWG 2003 criteria, plus complete remission with partial hematologic recovery, defined as CR except absolute neutrophil count > 0.5 × 109/L [500/µL] and platelet count > 50 × 109/L [50,000/µL]), served as the primary efficacy endpoint for patients with relapsed/refractory AML (n = 125).

The CR plus CRh rate was 30.4% (95% CI; 22.5-39.3). The CR rate was 21.6% (95% CI; 14.7-29.8).

Median time to CR plus CRh was 2.7 months (0.9-5.6) and median duration of CR plus CRh was 8.2 months (5.5-12).


Overall response rate was 41.6% (32.9-50.8) and median time to first response was 1.9 months (0.8-4.7). Median duration of response was 6.5 months (4.6-9.3).

Median overall survival was 8.8 months (95% CI, 6.7-10.2) among all patients with best response in relapsed/refractory AML (n = 125). (95% CI, 13.8-NE) among CR plus CRh patients.

“The new IDH1-inhibitor, ivosidenib, is a well-tolerated, oral agent with a favorable safety profile,” DiNardo said. “In an older and relapsed/refractory population, daily ivosidenib induced durable responses.” – by Ryan McDonald


DiNardo CD, et al. Abstract 725. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.

Disclosures: DiNardo reports receiving honoraria and research funding from Abbvie, Agios Pharmaceuticals, Celgene, Daiichi-Sankyo and Novartis.