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1070 Determination of IDH1 Mutational Burden and Clearance Via Next-Generation Sequencing in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Inhibitor of Mutant IDH1

Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: FLT3 and IDH Targeted Therapies in AML
Monday, December 5, 2016: 4:45 PM
San Diego Ballroom AB (Marriott Marquis San Diego Marina)

Courtney D. DiNardo, MD, MSCE1, Stéphane de Botton2*, Eytan M Stein3, Gail J. Roboz4, Ronan T Swords, MD, PhD, FRCPI, FRCPath5, Daniel A Pollyea, MD6, Amir T. Fathi, MD7, Robert Collins8, Jessica K. Altman, MD9, Ian W. Flinn, MD, PhD10, Gabriel N Mannis11, Alice S. Mims, MD, MSCR12, James M. Foran, MD13, Arnaud Pigneux, MD14*, Gabrielle T Prince, MD15, Geoffrey L Uy, MD16, Martin S. Tallman, MD17*, Hagop M. Kantarjian, MD18, Hua Liu19*, Eyal C Attar19, Jennifer Sacolick19*, Katharine Yen19*, Jonathan B Hurov19*, Sung Choe19*, Bin Wu19* and Richard M. Stone, MD20

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Institut Gustave Roussy, Villejuif, France
3Memorial Sloan Kettering Cancer Center, New York, NY
4Weill Cornell Medical College, New York, NY
5University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL
6University of Colorado Cancer Center, Aurora, CO
7Massachusetts General Hospital, Boston, MA
8University of Texas Southwestern Medical Center, Dallas, TX
9Robert H Lurie Comprehensive Cancer Center, Chicago, IL
10Blood Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN
11University of California, San Francisco School of Medicine, San Francisco, CA
12Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
13Mayo Clinic, Jacksonville, FL
14Hôpitaux du Haut Lévéque CHU Bordeaux, Pessac, France
15Johns Hopkins Hospital, Baltimore, MD
16Department of Medicine, Washington University School of Medicine, St. Louis, MO
17Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
18Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
19Agios Pharmaceuticals, Inc., Cambridge, MA
20Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

INTRODUCTION

Recurrent 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 multiple solid tumors and hematologic malignancies. Approximately 6-10% and 9-13% of adults with acute myeloid leukemia (AML) carry mutations in IDH1 (mIDH1) or IDH2 (mIDH2), respectively. AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme under evaluation in multiple ongoing single agent and combination clinical trials [NCT02074839, NCT02073994, NCT02632708, NCT02677922]. This is the first report of IDH1 mutation clearance assessed by variant allele frequency (VAF) analysis using next-generation sequencing (NGS) in patients treated on the dose escalation portion of the first-in-human phase 1 study [NCT02074839].

METHODS

Patients with advanced mIDH1-positive hematologic malignancies received AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously in 28-day cycles. Primary objectives were determination of safety, maximum tolerated dose (MTD), and selection of a dose schedule for expansion cohorts and future studies. Secondary objectives included clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML. Determination of mIDH1 VAF was performed using the FoundationOne® Heme test on mononuclear cells from the bone marrow or peripheral blood at screening and subsequent time points on study. This NGS assay reports IDH1 mutations for samples with VAF ≥1%, with median coverage 500X. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having mIDH1 at baseline and at least one on-study sample with no reported mIDH1.

RESULTS

Seventy-eight patients were treated in the dose escalation portion, which is now closed to enrollment. As of the data cut-off of May 12, 2016, the median duration on treatment was 3.2 months and 9 (11.5%) patients remain on treatment, with an additional 8 (10.3%) patients transitioned to stem cell transplant. Doses ranged from 300-1200 mg QD with 1 cohort at 100 mg BID. Though the MTD was not reached, the recommended phase 2 dose was determined to be 500 mg QD. The majority of adverse events (AEs) were grade 1 and 2, the most common (≥30%) being diarrhea, fatigue, and nausea; the most common grade ≥3 AEs (≥15%) were febrile neutropenia, anemia, leukocytosis and pneumonia. The most common serious AEs were febrile neutropenia (16.7%) and pneumonia (12.8%). The overall response rate (ORR) was 38.5% (n=30), with 17.9% (n=14) achieving a complete remission (CR). Longitudinal mIDH1 VAF data were available for 51 patients; of these, 22% (n=11) achieved a CR. IDH1-MC was observed in 27.3% (3/11) patients who achieved CR (Figure 1). In contrast, only 1/40 patients who did not achieve CR experienced IDH1-MC. This occurred in a patient with an initially low mIDH1 VAF who had clinical progression despite IDH1-MC (Figure 1, bottom right). In all 3 patients with CR who achieved IDH1-MC, an initial increase in mIDH1 VAF, or early peak, was observed prior to IDH1-MC, suggesting that early clonal expansion might have occurred as part of the mechanism of action of AG-120.

CONCLUSION

This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance as determined by NGS. Further analysis of the mutational profiles is planned. AG-120, a potent, selective, oral inhibitor of mIDH1 continues to demonstrate a well-tolerated safety profile in patients with advanced hematologic malignancies, and induced objective single-agent durable responses. The data continue to support the efficacy and safety of single agent AG-120 and provide evidence that the underlying biology of the disease is altered by treatment.

Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120

Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample

 

Disclosures: DiNardo: Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. de Botton: Novartis: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy. Stein: Agios: Other: advisory board; Celgene: Other: advisory board; Novartis: Other: advisory board. Roboz: Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Pollyea: Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Ariad: Other: advisory board; Glycomimetics: Other: DSMB member; Celgene: Other: advisory board, Research Funding. Fathi: Bexalata: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding. Altman: BioLineRx: Other: Was funding to the institution for clinical trial, Research Funding; Cyclacel: Other: Was funding to the institution for clinical trial, Research Funding; CSL Limited: Other: Was funding to the institution for clinical trial, Research Funding; Pfizer: Other: Was funding to the institution for clinical trial, Research Funding; Agios: Other: Was funding to the institution for clinical trial, Research Funding; Astellas: Other: Was funding to the institution for clinical trial, Research Funding; MethylGene: Other: Was funding to the institution for clinical trial, Research Funding; Boehringer Ingelheim: Other: Was funding to the institution for clinical trial, Research Funding; Syros: Other: advisory board; Seattle Genetics: Other: advisory board; Ariad: Other: advisory board; Spectrum: Other: advisory board; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: advisory board; Celgene: Other: Was funding to the institution for clinical trial, Research Funding; Genentech: Other: Was funding to the institution for clinical trial, Research Funding; Epizyme: Other: Was funding to the institution for clinical trial, Research Funding. Flinn: Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Pigneux: Sunesis: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Kantarjian: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Sacolick: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yen: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hurov: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Choe: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Wu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Stone: Amgen: Consultancy; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy.

*signifies non-member of ASH