-Author name in bold denotes the presenting author
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331 Flotetuzumab As Salvage Therapy for Primary Induction Failure and Early Relapse Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia: Novel Therapies and Treatment Approaches
Hematology Disease Topics & Pathways:
AML, Biological, antibodies, Diseases, Therapies, Myeloid Malignancies, Clinically relevant
Sunday, December 6, 2020: 9:45 AM

Ibrahim Aldoss, MD1, Geoffrey L Uy, MD2, Norbert Vey, MD3, Ashkan Emadi, M.D., Ph.D.4, Peter H. Sayre, MD, PhD5, Roland B. Walter, MD, PhD, MS6, Matthew C Foster, MD7, Martha L. Arellano, MD8, John E. Godwin, MD9, Matthew J. Wieduwilt, MD, PhD10, Michael T. Byrne, DO11, Laura C. Michaelis, MD12, Patrick J. Stiff, MD13, Matteo Giovanni Carrabba, MD14*, Patrice Chevalier, MD, PhD15*, Emmanuel Gyan, MD, PhD16, Christian Recher, MD, PhD17, Anjali S Advani, MD18, Martin Wermke19*, Harry P. Erba20, Fabio Ciceri, MD21*, Geert Huls, MD, PhD22, Mojca Jongen-Lavrencic, MD, PhD23, Max S. Topp, MD24, Antonio Curti, MD PhD25, Farhad Ravandi, MBBS26, Michael P. Rettig, PhD27, John Muth, MS28*, Mary Beth Collins29*, Erin Timmeny30*, Kuo Guo, MSc31*, Jian Zhao, PhD31*, Kathy Tran28*, Patrick Kaminker, PhD32*, Priyanka Patel, PharmD29*, Ouiam Bakkacha, MD33*, Teia Curtis34*, Kenneth Jacobs, MD35*, Maya Kostova, PhD31*, Jennifer Seiler, PhD, RAC29*, Bob Lowenberg, MD, PhD36, Sergio Rutella, MD, PhD, FRCPath37, Ezio Bonvini, MD32, Jan K Davidson-Moncada, MD, PhD38 and John F. DiPersio, MD2

1Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA
2Washington University School of Medicine, Saint Louis, MO
3Hematologie clinique, Institut Paoli Clamettes, Marseille, France
4University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
5University of California, San Francisco, San Francisco, CA
6Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
7Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, Chapel Hill, NC
8Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
9Providence Portland Medical Center, Portland, OR
10Moores Cancer Center, University of California, San Diego, La Jolla, CA
11Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN
12Division of Hematology/Oncology, Department of Medicine, The Medical College of Wisconsin Inc., Milwaukee, WI
13Loyola University Chicago Stritch School of Medicine, Maywood, IL
14Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
15Department of Hematology and Cell Therapy, CHU Nantes, Nantes, France
16CHU de Tours - Hôpital Bretonneau, Tours, France
17Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
18Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH
19NCT/UCC Early Clinical Trial Unit, University Hospital Carl Gustav Carus, Dresden, Germany
20Duke University School of Medicine, Durham, NC
21Haematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
22Department of Hematology, University Medical Center Groningen, Groningen, GZ, Netherlands
23Erasmus University Medical Center, Rotterdam, Netherlands
24Medizinische Klinik Und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
25Hematology/Oncology "L. e A. Seràgnoli", Sant’Orsola-Malpighi University Hospital, Bologna, Bologna, Italy
26Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
27Department of Internal Medicine, Division of Oncology, Washington Univ. School of Med., Saint Louis, MO
28MacroGenics, Inc., Rockville, MD
29MacroGenics, Rockville
30MacroGenics, Inc., ROCKVILLE, MD
31MacroGenics, Rockville, MD
32Macrogenics, Rockville, MD
33Macrogenics,Inc, ROCKVILLE, MD
34MacroGenics, Inc., Frederick, MD
35MacroGenics, Inc, Rockville, MD
36Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
37John van Geest Cancer Centre School of Science and Technology, Nottingham Trent University, Nottingham, ENG, United Kingdom
38MacroGenics, Inc., Washington, DC

Introduction. Approximately 40% of patients (pts) with newly diagnosed AML either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission (CR1 <6 months). While these primary induction failure (PIF) and early relapse (ER) pts are treated collectively with late relapse (LR) pts (CR1 >6 months), the probability of response for PIF/ER pts is particularly poor (~12%) with median expected overall survival of ~3.5 month and no approved therapy for this specific population. We have recently shown that increased immune infiltration of the tumor microenvironment (TME) is associated with induction failure and poor prognosis; conversely, an infiltrated TME predisposes for immunotherapy response1. We provide an update of the first-in-human study of flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule currently in clinical development for PIF/ER AML pts.

Methods. In this phase of the study, PIF is defined as being refractory to induction with: ≥1 high-intensity cytarabine-based chemotherapy (CTx) cycles, or ≥2 but ≤4 Bcl-2 inhibitor-based combinations, or gemtuzumab ozogamicin only. ER is defined as relapse following CR1 < 6 months. Pts who receive up to one prior salvage attempt are included. Pts whose AML recurred following HSCT are excluded. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day administered as a continuous infusion in 28-day cycles following a step-up (‘priming’) lead-in dose during Cycle 1 Week 1. Disease status is assessed by modified IWG criteria. Duration of response is measured from initial response to relapse or death.

Results. As of July 1, 2020, 38 PIF/ER (as defined above) AML patients have been treated at the RP2D (median age 63yrs [range 28-81]; 31.6% [12] pts female). Most pts (63.2%, 24/38) were PIF and the large majority (94.7%, 36/38) had non-favorable risk by ELN 2017 criteria (25 pts adverse, 11 pts intermediate); 34.2% (13/38) had secondary AML. For ER pts, median duration of CR1 was 2.9 months (range: 0.7-4.0 months). Cytokine release syndrome (CRS) was the most frequently reported treatment related adverse event (TRAE), with all pts experiencing mild-to-moderate (grade ≤ 2) CRS. No grade ≥ 3 CRS events have been reported in this cohort. Most CRS events (51.5%) occurred in the first week of treatment during step-up dosing. The incidence of CRS progressively decreased during dosing at RP2D (34.8% in week 2, 4.5% in week 3, and 6.1% in week 4), allowing outpatient treatment in most cases. Neurologic AEs have been infrequent, with the most prominent event being grade 1 or grade 2 headache in 23.7% (9/38) treated at the RP2D. Two pts experienced grade 3 confusion of short duration (1-2 days) that was fully reversible. Over half (57.9%) of pts had evidence of antileukemic activity (reduction in blast count) with a median decrease of 92.7% in BM blasts (Fig. 1). The overall complete response rate (CRR, <5% bone marrow blast) was 42.1% (16/38; 7 CR, 4 CRh, 4 CRi, and 1 MLFS), with 68.8% (11/16) subsequently undergoing stem cell transplant. PIF pts showed a CRR of 45.8% (11/24; 5 CR, 3 CRh, and 3 CRi); CRR for ER pts was 35.7% (5/14; 2 CR, 1 CRh, 1CRi and 1 MLFS). Median time to first response was 1 cycle (range: 1-3 cycles). Sixty-nine percent (11/16) of responders normalized PB counts while on FLZ. Transfusion independence was achieved in 35.7% (10/28) of pts for whom data were available. Preliminary, median duration of response (mDOR) was 3.1 months (range 0.4-30.0 months) with many pts (29%, 11/38) still ongoing. With a median follow up time of 10.8 months, median overall survival (mOS) was 4.5 months (95% confidence interval [CI]: 2.9, 8.8). In pts that responded (CRR) the mOS was 7.7 months (95% confidence interval [CI]: 2.9, NA). Overall 6 and 12-month survival rates are 41 % (22.1%, 59.0%) and 24 % (6.1%, 42.5%), respectively.

Conclusion: FLZ demonstrated encouraging activity in pts with PIF/ER AML, a population with poor prognosis and high unmet medical need, with 42.1% achieving CRR and over half of those receiving a stem cell transplant. Treatment is tolerable with a minimum 8 day inpatient treatment. The study is currently enrolling patients [NCT02152956]

1 Vadakekolathu J, Minden MD, Hood T, Church SE, Reeder S, Altmann H et al. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Trans Med 2020.

Disclosures: Aldoss: abbvie: Consultancy, Research Funding; agios: Honoraria; kite: Consultancy; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Uy: Genentech: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Emadi: Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Walter: Aptevo Therapeutics: Research Funding. Foster: Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Arellano: Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cephalon Oncology: Research Funding. Wieduwilt: Amgen: Research Funding; Macrogeneics: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Michaelis: Jazz Pharmaceuticals: Research Funding. Stiff: Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Advani: Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Abbvie: Research Funding; Macrogenics: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding; Takeda: Research Funding. Wermke: MacroGenics: Honoraria. Erba: AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; Glycomimetics: Other: member of Scientific Steering Committee; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy. Topp: Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Ravandi: Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding. Muth: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins: IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.; MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics. Guo: Macrogenics: Current Employment. Tran: MacroGenics: Current Employment. Kaminker: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel: MacroGenics: Current Employment. Bakkacha: MacroGenics: Current Employment. Jacobs: MacroGenics: Current Employment. Seiler: MacroGenics: Current Employment. Rutella: Kura Oncology: Research Funding; MacroGenics Inc.: Research Funding; NanoString Technologies Inc.: Research Funding. Bonvini: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada: Macrogenics: Current Employment. DiPersio: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH