Novel Oral Agent Induces Durable Responses in Relapsed/Refractory AML

The novel agent ivosidenib is well tolerated and induces durable responses in patients with high-risk, molecularly defined, relapsed/refractory acute myeloid leukemia (AML) and other advanced hematologic malignancies-a population with an unmet medical need-according to a new study.

IDH mutations are a target in AML. Ivosidenib, an investigational, first-in-class, potent, selective, oral small-molecule inhibitor of the mutant IDH1 protein, is under evaluation in multiple clinical trials as a single agent and in combinations, said lead author Courtney D. DiNardo, MD, MSc, of the University of Texas MD Anderson Cancer Center in Houston.

At the American Society of Hematology (ASH) Annual Meeting & Exposition, she reported on an ongoing single-arm, open-label, multicenter phase I trial to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mutant IDH1 hematologic malignancies (abstract 725). During dose escalation, patients received ivosidenib as a single agent orally once daily or twice daily in 28-day cycles.

The MTD was not reached and a 500-mg daily dose was selected as the recommended dose to be tested in 4 expansion cohorts: patients who relapsed after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapsed within 1 year of initial treatment (Arm 1); untreated AML (Arm 2); other advanced hematologic malignancies, including myelodysplastic syndrome (Arm 3); and patients with relapsed/refractory AML who were not eligible for Arm 1 (Arm 4).

A total of 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib; one-quarter of them continue on treatment. The median duration of exposure to ivosidenib was 3.5 months. Twenty-two (8.5%) patients discontinued treatment and proceeded to allogeneic stem cell transplantation.

Most common adverse events were grade 1 and 2 and were unrelated to treatment. The most common adverse events were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%).

Differentiation syndrome was observed in 29 of 258 (11.2%) patients, including grade 3 or higher in 14 (5.4%); no instances of differentiation syndrome led to permanent treatment discontinuation or death.

Among 125 Arm 1 relapsed/refractory AML patients receiving ivosidenib 500 mg daily across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 30.4%, including CR in 27 (21.6%) patients and CRh in 11 (8.8%) patients.

Median duration of CR plus CRh was 8.2 months, and duration of CR was 9.3 months. The overall response rate (ORR) was 41.6%.

Durable responses were also seen in patients with untreated AML, with CR and ORR rates of 20.6% and 55.9%, respectively.

In conclusion, DiNardo said, “In patients with relapsed/refractory AML, most of whom had received multiple prior AML treatments, ivosidenib induced durable responses. Additional benefits included transfusion independence across best response categories and decreased frequency of febrile neutropenia and infections in responders.”