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561 Ivosidenib (AG-120) Induced Durable Remissions and Transfusion Independence in Patients with IDH1-Mutant Untreated AML: Results from a Phase 1 Dose Escalation and Expansion Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Targeted Therapy
Hematology Disease Topics & Pathways:
Adult, AML, Diseases, Non-Biological, Therapies, Biological Processes, Study Population, epigenetics, Clinically relevant, Myeloid Malignancies
Monday, December 3, 2018: 7:30 AM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Gail J. Roboz, MD1, Courtney D. DiNardo, MD, MSc2, Eytan M. Stein, MD3, Stephane de Botton, MD, PhD4*, Alice S. Mims, MD5, Gabrielle T. Prince, MD6*, Jessica K. Altman, MD7, Martha L. Arellano, MD8, William B. Donnellan, MD9, Harry P. Erba, MD, PhD10, Gabriel N. Mannis, MD11, Daniel A Pollyea, MD12, Anthony S. Stein, MD13, Geoffrey L. Uy, MD14, Justin M. Watts, MD15, Amir T. Fathi, MD16, Hagop M. Kantarjian, MD2, Martin S. Tallman, MD3, Sung Choe, PhD17*, David Dai, PhD17*, Bin Fan, PhD17*, Hongfang Wang, PhD17*, Vickie Zhang, PhD17*, Katharine E. Yen, PhD17*, Stephanie M. Kapsalis, OTR17*, Denice Hickman, RN17*, Hua Liu, PhD17*, Samuel V. Agresta, MD17*, Bin Wu, PhD18*, Eyal C. Attar, MD18 and Richard M. Stone, MD19*

1Weill Cornell Medical College, New York, NY
2University of Texas MD Anderson Cancer Center, Houston, TX
3Memorial Sloan Kettering Cancer Center, New York, NY
4Institut Gustave Roussy, Villejuif, France
5Comprehensive Cancer Center, The Ohio State University, Columbus, OH
6Johns Hopkins Hospital, Baltimore, MD
7Northwestern University, Chicago, IL
8Winship Cancer Institute of Emory University, Atlanta, GA
9Sarah Cannon Research Institute, Nashville, TN
10University of Alabama at Birmingham, Birmingham, AL
11UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
12University of Colorado School of Medicine, Aurora, CO
13City of Hope Medical Center, Duarte, CA
14Washington University School of Medicine, St Louis, MO
15Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
16Massachusetts General Hospital Cancer Center, Boston, MA
17Agios Pharmaceuticals, Inc., Cambridge, MA
18Agios Pharmaceuticals Inc., Cambridge, MA
19Dana-Farber Cancer Institute, Boston, MA

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations are seen in 6–10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for mIDH1 AML. Ivosidenib suppresses production of the oncometabolite 2‑hydroxyglutarate (2‑HG), leading to clinical responses via differentiation of malignant cells.

AIM: To determine the safety and efficacy of single-agent ivosidenib in patients with untreated AML enrolled in the first-in-human, phase 1, dose escalation and expansion study of patients with mIDH1 advanced hematologic malignancies (NCT02074839).

METHODS: This ongoing study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Enrollment completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. MTD was not reached; 500 mg QD was selected as the dose for expansion cohorts. Overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). 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%). Here, we present data for all patients with untreated AML whose starting dose was 500 mg QD.

RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 34 patients with untreated AML (9 from dose escalation, 25 from expansion) who received ivosidenib 500 mg QD. Baseline characteristics for these 34 patients were: 19 male/15 female with median age 76.5 years (range 64–87); 56% were ≥75 years of age; 79% had secondary AML and 53% had prior MDS; 41% had ≥1 hypomethylating agent for antecedent hematologic disorder. As of 10Nov2017, 9 of 34 (26.5%) patients remained on treatment. Three (8.8%) patients discontinued treatment for allogeneic stem cell transplantation. Median duration of exposure to ivosidenib was 4.3 months (range 0.3–29.1). Treatment was well tolerated; the most common adverse events (AEs) (n=34) of any grade, irrespective of causality, occurring in ≥20% of patients were diarrhea (50.0%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%), peripheral edema (26.5%), dyspnea (23.5%), thrombocytopenia (23.5%), hypomagnesemia (23.5%), constipation (20.6%), dizziness (20.6%), and insomnia (20.6%). The majority of AEs were grade 1–2 and reported as unrelated to treatment. IDH differentiation syndrome (IDH-DS) was seen in 6 of 34 (17.6%) patients, and was grade ≥3 in 3 (8.8%); ivosidenib was held due to IDH-DS in 3 patients (8.8%), but IDH-DS did not lead to permanent treatment discontinuation or death. CR rate was 26.5% (95% CI 12.9%, 44.4%), CR+CRh rate was 41.2% (95% CI 24.6%, 59.3%), and ORR 58.8% (95% CI 40.7%, 75.4%; 20/34 patients). Median durations of CR, CR+CRh, and overall response were not estimable (lower bound of 95% CI 4.2, 6.5, and 4.2 months, respectively); 12-month durations of response were 75.0%, 56.4%, and 54.3%, respectively. Of patients who were transfusion dependent at baseline, 38.1% became transfusion independent for ≥56 consecutive days on treatment. Longitudinal mIDH1 VAF data were available for 23 patients with untreated AML in expansion: IDH1 mutation clearance was seen in 6 of 11 patients who achieved CR+CRh, including 3 of 7 patients with CR and 3 of 4 with CRh. The relationship between baseline co-occurring mutations and response will be presented.

CONCLUSION: Ivosidenib monotherapy was well tolerated in patients with untreated mIDH1 AML, and induced durable remissions and transfusion independence in a molecularly defined, poor prognosis, elderly patient population with high rates of secondary AML, and prior hypomethylating agent exposure. These results support the role of ivosidenib as an effective, oral, targeted treatment for patients with untreated mIDH1 AML who are not eligible for intensive chemotherapy.

Disclosures: Roboz: Argenx: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Eisai: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy. DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Stein: Novartis: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Pfizer: Consultancy. de Botton: Celgene: Honoraria, Research Funding; Agios: Research Funding. Mims: Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Altman: Bayer: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Astellas Pharma: Other; Epizyme: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Arellano: Cephalon: Research Funding. Mannis: Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Pollyea: Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein: Celgene: Speakers Bureau; Amgen: Speakers Bureau. Uy: GlycoMimetics: Consultancy; Curis: Consultancy. Watts: Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Fathi: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Boston Biomedical: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Medimmune: Consultancy; Exelexis: Research Funding. Kantarjian: AbbVie: Honoraria; Actinium: Honoraria; Amgen: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Astex: Research Funding; BMS: Honoraria, Research Funding; Immunogen: Honoraria; Novartis: Research Funding; Orsenix: Honoraria; Pfizer: Honoraria, Research Funding. Tallman: Orsenix: Other: Advisory board; Cellerant: Research Funding; BioSight: Other: Advisory board; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding. Choe: Agios: Employment, Equity Ownership. Dai: Agios: Employment, Equity Ownership. Fan: Agios: Employment, Equity Ownership. Wang: Agios: Employment, Equity Ownership. Zhang: Agios: Employment, Equity Ownership. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Hickman: Agios: Employment, Equity Ownership. Liu: Agios: Employment, Equity Ownership. Agresta: Agios: Employment, Equity Ownership. Wu: Agios: Employment, Equity Ownership, Patents & Royalties. Attar: Agios: Employment, Equity Ownership. Stone: Otsuka: Consultancy; Cornerstone: Consultancy; AbbVie: Consultancy; Arog: Consultancy, Research Funding; Amgen: Consultancy; Merck: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Fujifilm: Consultancy; Astellas: Consultancy; Ono: Consultancy; Orsenix: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Pfizer: Consultancy; Sumitomo: Consultancy.

*signifies non-member of ASH