Ivosidenib (AG-120) is a first-in-class, oral, potent, reversible, targeted inhibitor of the mutant-IDH1 enzyme which is able to decrease the production of 2-HG, which provides clinical benefit via differentiation of malignant cells containing mutant-IDH1. In July 2018, the US Food and Drug Administration (FDA) approved ivosidenib for relapsed/refractory acute myeloid leukemia (AML) with IDH1 mutation.
At the 60th Annual Society of Hematology Annual Meeting and Exposition, Gail J. Roboz (co-chair of our North American Steering Committee) from Weill Cornell Medical College, New York, US, presented data from a first-in-human phase I dose-escalation and expansion study (NCT02074839) of ivosidenib (AG-120) in patients with IDH1-mutant advanced hematologic malignancies, including those with previously untreated AML. The aims of the study were to evaluate the safety and efficacy of single-agent ivosidenib in patients with untreated AML enrolled in this study.
In total, 258 patients (78 in dose escalation, 180 in expansion) with advanced hematologic malignancies were enrolled in this single-arm, open-label, phase I, multicenter trial. Of these, 34 patients had previously untreated AML (median age = 76.5 years, range: 64–87). Patients received ivosidenib 500 mg orally once daily (QD) and 8 (23.5%) remained on treatment at the time of data cut-off (11 May 2018). The median duration of treatment for all patients was 4.3 months (range: 0.3–35.1). The primary efficacy endpoint was complete remission (CR) plus CR with partial hematologic recovery (CRh).
- Most common adverse events (AEs) occurring in ≥ 25% of patients include diarrhea (52.9%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%) and peripheral edema (26.5%)
- Grade ≥3 leukocytosis occurred in 3% (1/34) patients
- Electrocardiogram QT prolongation occurred in 17.6% (6/34) of patients, with grade ≥3 events occurring in 8.8% (3/34) patients
- Differentiation syndrome (DS) was observed in 17.6% (6/34) of patients, with grade ≥ 3 DS occurring in 8.8% (3/34) of patients
- CR+CRh rate: 42% (95% CI, 6.5–NE)
- Median duration of CR+CRh: not estimable
- Overall response rate: 58% (95% CI, 39.2–74.5)
- Median duration of follow-up: 23.1 months (range: 0.6–35.1)
- Median overall survival: 12.6 months (95% CI, 4.5–25.7)
- IDH1 mutational clearance
- Ivosidenib induced IDH1 mutation clearance in bone marrow mononuclear cells in 64% (9/14) of patients who achieved CR+CRh
- Ivosidenib therapy resulted in transfusion independence across response categories in patients who were dependent at baseline
In summary, ivosidenib monotherapy induces durable responses and is well tolerated in patients with IDH1-mutant AML. Gail Roboz discusses the results of this study in an interview with the AML Global Portal (AGP) here.