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Foran, J. M.1; DiNardo, C. D.2; Watts, J. M.3; Stein, E. M.4; de Botton, S.5; Fathi, A. T.6; Prince, G. T.7; Stein, A. S.8; Stone, R. M.9; Patel, P. A.10; Tallman, M. S.4; Choe, S.11; Wang, H.11; Zhang, V.11; Dai, D.11; Fan, B.11; Yen, K. E.11; Kapsalis, S. M.11; Hickman, D.11; Agresta, S. V.11; Liu, H.11; Wu, B.11; Attar, E. C.11; Kantarjian, H. M.2

doi: 10.1097/01.HS9.0000563628.38037.c3
Poster Session II: Myelodysplastic syndromes - Clinical

1Mayo Clinic, Jacksonville

2University of Texas MD Anderson Cancer Center, Houston

3Sylvester Comprehensive Cancer Center, University of Miami, Miami

4Memorial Sloan Kettering Cancer Center, New York, United States

5Institut Gustave Roussy, Villejuif, France

6Massachusetts General Hospital Cancer Center, Boston

7Johns Hopkins Hospital, Baltimore

8City of Hope Medical Center, Duarte

9Dana-Farber Cancer Institute, Boston

10University of Texas Southwestern Medical Center, Dallas

11Agios Pharmaceuticals, Inc., Cambridge, United States

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Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ˜4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO; AG-120) is an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory (R/R) AML. Through inhibition of mIDH1, IVO suppresses production of the oncometabolite 2-hydroxyglutarate, leading to clinical responses via differentiation of malignant cells.

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To report safety and efficacy data from patients with R/R MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839).

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This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of IVO. Enrollment was completed on May 8, 2017. In dose escalation, patients received single-agent IVO orally (dose range, 200-1200 mg daily) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose for expansion. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR (mCR) according to International Working Group 2006 criteria for MDS. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%).

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Baseline characteristics of the 12 patients with R/R MDS who received 500 mg IVO once daily were: 9 men/3 women; median age 72.5 years (range 52-78), and 42% were ≥75 years of age; median number of prior therapies 1 (range 1-3). As of Nov 2, 2018, 3 of 12 (25.0%) patients remained on treatment; 9 (75.0%) had discontinued (one for allogeneic stem cell transplantation). Median duration of exposure to IVO was 11.4 months (range 3.3-42.5). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n = 4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n = 3 each, 25.0%). No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome was observed in 1 of 12 (8.3%) patients (grade 2). Electrocardiogram QT prolonged was reported in 2 of 12 patients (17%; grade 1 in 1 patient and grade 2 in 1 patient). Five of 12 patients achieved CR (41.7%; 95% CI 15.2%, 72.3%), 1 achieved PR (8.3%), and 5 achieved mCR (41.7%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median duration of CR was not estimable (NE) at the time of datacutoff and the median duration of response was 21.4 months (95% CI 2.3, NE). At 12 months, 60.0% of patients remained in CR. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for ≥56 consecutive days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels will be presented.

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In patients with mIDH1 R/R MDS, IVO monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.