Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.
DiNardo CD., Stein AS., Stein EM., Fathi AT., Frankfurt O., Schuh AC., Döhner H., Martinelli G., Patel PA., Raffoux E., Tan P., Zeidan AM., de Botton S., Kantarjian HM., Stone RM., Frattini MG., Lersch F., Gong J., Gianolio DA., Zhang V., Franovic A., Fan B., Goldwasser M., Wu B., Winkler T.
<h4>Purpose</h4>Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of <i>IDH1</i>-mutant (m<i>IDH1</i>) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis.<h4>Patients and methods</h4>This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m<sup>2</sup> on days 1-7 in 28-day cycles in patients with newly diagnosed m<i>IDH1</i> AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922).<h4>Results</h4>Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m<i>IDH1</i> clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission.<h4>Conclusion</h4>Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m<i>IDH1</i> mutation clearance.