Ivosidenib, New IDH1 Inhibitor, Elicits Complete Response in Relapsed Acute Myeloid Leukemia

Wayne Kuznar

Emerging Therapies, Web Exclusives

Atlanta, GA—Treatment with ivosidenib, an IDH1 inhibitor, resulted in an objective response rate (ORR) of 41.6% in a phase 1 dose-escalation and expansion clinical trial in patients with relapsed or refractory acute myeloid leukemia (AML) and IDH1 mutation.

Ivosidenib induced a complete response (CR) or a CR with a partial hematologic recovery (CRh) in 30.4% of the study population. The results were presented by Courtney D. DiNardo, MD, MSCE, Assistant Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, at ASH 2017.

Ivosidenib demonstrates “impressive single-agent efficacy, with durable responses in these high-risk patients with relapsed or refractory AML,” said Dr DiNardo. “Important measures of clinical benefit for patients treated with ivosidenib were also observed, and include increases in transfusion independence, and a decrease in the frequency of comorbidities, such as febrile neutropenia and infections in responding patients,” she said.

In this study, patients with hematologic malignancies and IDH1 mutation were enrolled in a dose-escalation stage in which ivosidenib was given at 100 mg twice daily, or in doses ranging from 200 mg to 1200 mg once daily. A subsequent dose-expansion cohort was treated with 500 mg daily of ivosidenib. The dose-expansion cohort consisted of 4 arms—(1) 126 patients who had a second relapse after stem-cell transplantation, had disease refractory to previous therapy, or had AML with IDH1 mutation that relapsed within 1 year; (2) 25 patients with untreated AML; (3) 11 patients with non-AML relapsed or refractory hematologic malignancies and IDH1 mutation; and (4) 18 patients with IDH1 mutation and relapsed or refractory AML who were not eligible for arm 1.

Study Results

The ORR in the primary analysis was 41.6%, with a CR rate of 21.6% and a CRh rate of 8.8%. The median duration of response was 9.3 months for patients who achieved a CR, 8.2 months for those who achieved a CR/CRh, and 6.5 months for all responders. The median time to first response was 1.9 months, median time to CR was 2.8 months, and the median time to CR/CRh was 2.7 months.

At the time of data cut-off (14.8 months of follow-up), the median overall survival (OS) was not yet reached for patients who achieved a CR/CRh. For responders who did not achieve a CR/CRh, the median OS was 9.3 months.

All patients who were transfusion-dependent at baseline and achieved a CR became independent of platelet transfusions, and 84.6% became independent of red blood cell (RBC) transfusions during any 56-day postbaseline. Of those who were transfusion-dependent at baseline and achieved a CRh, 71.4% became independent of platelet transfusions, and 75% became independent of RBC transfusions. Among the entire study cohort, 39.1% and 39.7% of patients, respectively, were independent of platelet transfusions and RBC transfusions.

In arm 2, 34 patients with AML had responses, including a 55.9% ORR and 20.6% CR. In arm 3, 12 patients with myelodysplastic syndrome achieved a 91.7% ORR and 41.7% CR.

The most common adverse events were diarrhea (33.3%), elevated levels of white blood cells (30.2%), nausea (29.5%), fatigue (28.7%), and febrile neutropenia (25.2%); 10 (8%) of 125 patients had grade 3 QT prolongation.

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