INTRODUCTION: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in a spectrum of solid tumors and hematologic malignancies, with mutations in DNMT3A and NPM1 co-occurring with IDH1 most frequently (Molenaar et al. Leukemia 2015). AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme being evaluated in an ongoing, first-in-human, phase 1, open-label study (NCT02074839). We report data, including clinical activity and safety, based on patients from the completed dose escalation phase. Molecular profiling, including observations of co-occurring genomic alterations at baseline, and relationship with clinical activity is also presented.

METHODS: Patients with advanced IDH1 mutation-positive hematologic malignancies, diagnosed by local evaluation, receive AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously, in 28-day cycles. Bone marrow is examined on Days 15, 29, 57, and every 56 days thereafter. Primary objectives are safety, determination of maximum tolerated dose (MTD) and selection of a dose schedule for expansion cohorts and future phase 2 studies. Secondary objectives include clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML (Cheson et al). Molecular profiling was performed with the FoundationOne Heme next-generation sequencing (NGS) test on bone marrow and/or peripheral blood from all patients at pre-defined time points throughout the study.

RESULTS: As of July 1, 2015, 66 patients were treated in the dose escalation phase, of whom 25 remain on treatment. Therapy has been well tolerated and the MTD was not reached. Dosing in the first cohort was 100 mg BID. The long half-life of AG-120 supported QD dosing subsequently, and 1200 mg QD was the highest dose evaluated. Dose escalation is now closed. The majority of adverse events (AEs) were grade 1 and 2, the most common being diarrhea (23%), fatigue (22%), and pyrexia (22%); the most common Grade ≥3 AE was febrile neutropenia (11%). The majority of serious AEs were disease-related. Of the 66 patients, 61 are response evaluable (patients with a Day 28 or later response assessment or who discontinued earlier than Day 28 for any reason). In all response evaluable patients, an estimated 55% had treatment durations of at least 3 months. Objective responses have been observed in 22 subjects (11 complete remissions [CR], 1 CR with incomplete platelet recovery, 4 partial responses and 6 marrow CRs), with a CR rate of 18% and an overall response rate (ORR) of 36% (22/61). Responses are durable, with a median duration of response among responders of 5.6 months [1.9, NE], including responses ≥11 months. Molecular profiling data from screening bone marrow was available in 38 patients. Among these 38, the most common co-mutations associated with IDH1 mutation were DNMT3A (67%) and NPM1 (24%). Incidence of additional co-mutations was <22%, with FLT3 in 7 patients (21%). Additional samples for longitudinal NGS sequencing were further analyzed at specified time points throughout the study. Updates from the completed dose escalation phase and further molecular profiling analysis will be presented. Three dose expansion arms are currently enrolling at 500 mg QD in relapsed/refractory AML, untreated AML, or other IDH1 mutation-positive advanced hematologic malignancies (n=125, n=25, and n=25, respectively, as of July 1, 2015). In addition, safety and efficacy data from the ongoing study will be included as of an October 2015 data cut-off date.

CONCLUSION: AG-120, a potent, selective, oral inhibitor of mutant IDH1, is well tolerated in patients with advanced hematologic malignancies, and induces objective durable responses, with an ORR of 36%, including complete remissions. Molecular profiling may provide insights into the mechanisms of response and resistance. The data support the efficacy of AG-120 and provide continued validation of mutant IDH1 as a therapeutic cancer target.


DiNardo:Novartis: Research Funding. de Botton:Agios pharmaceuticals: Research Funding. Pollyea:Glycomimetics: Other: Member of data safety monitoring board; Pfizer: Consultancy; Karyopharm: Consultancy; Agios Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Ariad: Consultancy. Stein:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Altman:Astellas: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Derti:Agios Pharmaceuticals: Employment, Equity Ownership. Goldwasser:Agios Pharmaceuticals: Employment, Equity Ownership. Prahl:Agios Pharmaceuticals: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Agresta:Agios Pharmaceuticals: Employment, Equity Ownership. Stone:Agios: Consultancy; Novartis: Research Funding; AROG: Consultancy; Merck: Consultancy; Celator: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Juno: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.

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