PS1023 MUTANT IDH1 INHIBITOR IVOSIDENIB (AG‐120) IN COMBINATION WITH AZACITIDINE FOR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA
Authors: DiNardo C.D. , Stein A.S. , Stein E.M. , Fathi A.T. , Frankfurt O. , Schuh A.C. , Döhner H. , Martinelli G. , Patel P.A. , Raffoux E. , Tan P. , Zeidan A. , de Botton S. , Kantarjian H.M. , Stone R.M. , Lam D. , Wang X. , Gong J. , Kapsalis S.M. , Hickman D. , Zhang V. , Winkler T. , Wu B. , Vyas P. 
Published: June 2019

Background:

Mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6–10% of patients with acute myeloid leukemia (AML). Ivosidenib (IVO; AG‐120) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory AML. In vitro, combination treatment of mIDH1 leukemic cell lines with IVO and azacitidine (AZA) enhanced cellular differentiation and apoptosis.

Aims:

We report results from an ongoing phase 1b study of patients with mIDH1 newly diagnosed (ND) AML who were ineligible for intensive treatment, and who received IVO in combination with AZA (NCT02677922).

Methods:

Patients received IVO 500 mg once daily continuously, and subcutaneous AZA 75 mg/m2 on Days 1–7 in 28‐day cycles. Overall response rate (ORR) comprised complete remission (CR) + CR with incomplete hematologic or platelet recovery (CRi/CRp) + partial remission + morphologic leukemia‐free state (MLFS). CR with partial hematologic recovery (CRh) was defined as CR with absolute neutrophil count >0.5 × 109/L (500/μL) and platelets >50 × 109/L (50,000/μL). Exploratory analysis included digital PCR assessment of mIDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity).

Results:

As of Oct 9, 2018, 23 patients had received IVO+AZA (11 men; median age 76 years [range, 61–88]). Median duration of exposure was 11 months (range, 0.3–25.3); 12 patients remained on treatment at data cutoff. All‐grade adverse events (AEs) regardless of cause in ≥30% of patients were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included electrocardiogram (ECG) QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% of patients were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18), including a CR rate of 57%, a CRi/CRp rate of 13%, and an MLFS rate of 9%. The CR+CRh rate was 70% (n = 16). Median time to response was 1.8 months (range, 0.7–3.8) and to CR was 3.5 months (range, 0.8–6.0); median response duration not yet reached. mIDH1 clearance was seen in 10 of 16 patients (63%) with CR/CRh, including 9 of 13 (69%) with CR.

Summary/Conclusion:

IVO+AZA was well tolerated, and had a safety profile consistent with IVO or AZA monotherapy. All‐grade cytopenia‐related AEs were infrequent relative to other nonintensive therapies. CR rate and ORR exceeded those of AZA alone (Dombret et al. Blood 2015) and a majority of responders achieved mIDH1 mutation clearance. Based on these findings, a phase 3 double‐blind placebo‐controlled study of IVO+AZA (AGILE, NCT03173248) is actively enrolling patients.