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3706 Magrolimab + Azacitidine Versus Azacitidine + Placebo in Untreated Higher-Risk (HR) Myelodysplastic Syndrome (MDS): The Phase 3, Randomized, ENHANCE Study

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes — Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Adults, Biological therapies, Clinical Trials, Workforce, immune mechanism, Diseases, Therapies, Myeloid Malignancies, Biological Processes, Study Population
Monday, December 13, 2021, 6:00 PM-8:00 PM

Guillermo Garcia-Manero, MD1, Naval Daver, MD1, Jin Xu, PhD2*, Mark Chao, MD, PhD2, Trisha Chung, BS2*, Anderson Tan, PharmD, Rph2*, Yan V. Wang, Phd, MPH, MSE2*, Andrew H. Wei, MBBS, PhD3, Paresh Vyas, DPhil, FRCP, FRCPath, MRCP, MRCPath4 and David A. Sallman, MD5

1The University of Texas MD Anderson Cancer Center, Houston, TX
2Gilead Sciences, Inc., Foster City, CA
3The Alfred Hospital and Monash University, Melbourne, VIC, Australia
4University of Oxford, Oxford, United Kingdom
5Moffitt Cancer Center, Tampa, FL

Myelodysplastic syndrome (MDS) is a clonal myeloid disorder characterized by cytopenia and ineffective hematopoiesis. MDS primarily affects older individuals, with the median age of diagnosis at 70 years. Prognosis and treatment decisions are guided by the revised International Prognostic Scoring System (IPSS-R) criteria. Patients with intermediate-, high-, and very high-risk MDS (HR-MDS) have a median overall survival (OS) of 0.8 to 3.7 years. Despite the high unmet need in this patient population, azacitidine (AZA) is the only approved therapy for HR-MDS that has improved OS in clinical trials to date. However, AZA treatment is characterized by low complete response (CR) rates (10% to 17%) with limited OS (<2 years), indicating a need for alternative therapies. Magrolimab is a first-in-class monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, a “do not eat me” signal overexpressed on tumor cells. Binding of magrolimab to CD47 leads to phagocytosis of tumor cells. AZA increases expression of tumor cell prophagocytic “eat me” signals, facilitating synergy with magrolimab. In an ongoing Phase 1b study, the combination of magrolimab + AZA led to high response rates (overall response rate 91%, with a CR of 42%) and an acceptable safety profile without significant immune-related adverse events. ENHANCE (NCT04313881) is a Phase 3 trial comparing the efficacy and safety of magrolimab + AZA with that of AZA + placebo in previously untreated patients with HR-MDS.

Patients ≥18 years old with previously untreated intermediate- to very high-risk MDS by IPSS-R are eligible for ENHANCE. Randomization is 1:1 to magrolimab + AZA or AZA + placebo with no crossover allowed. Magrolimab or placebo is administered intravenously with an initial 1 mg/kg priming dose to mitigate on-target anemia. An intrapatient dose-escalation regimen up to 30 mg/kg is then administered through Cycle 1, 30 mg/kg weekly dosing in Cycle 2, and 30 mg/kg once every 2 weeks in Cycle 3 and beyond. AZA is administered per regional prescribing information. Patients may remain on treatment until disease progression, relapse, loss of clinical benefit, or until unacceptable toxicities occur. The 2 primary efficacy endpoints are CR rate and OS. For patients undergoing allogeneic stem cell transplantation (ASCT), data for the CR rate will be censored at the time of ASCT, and OS will be censored at the last known alive date. Secondary efficacy endpoints include red blood cell transfusion independence rate, event-free survival, minimal residual disease-negative rate, time to acute myeloid leukemia transformation, and patient-reported Functional Assessment of Cancer Therapy Anemia response rate. Biomarkers of immune cell recruitment, immune cell signaling, and bone marrow penetration of magrolimab will also be explored.

As of July 2021, there are 78 sites active globally. Patient enrollment began in September 2020, and as of July 2021, 172 patients have been enrolled in the trial. Planned enrollment is approximately 520 patients globally, and accrual is ongoing.

© 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved.

Disclosures: Daver: Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Amgen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Xu: Gilead Sciences, Inc.: Current Employment. Chao: Gilead Sciences, Inc.: Current Employment; Bioverge: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Foresite capital: Consultancy; Stanford University Medical School: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Iconovir Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; TigaTx: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties; Hepatx Inc: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Chimera Bioengineering: Current equity holder in publicly-traded company. Chung: Gilead Sciences, Inc.: Current Employment. Tan: Gilead Sciences, Inc.: Current Employment. Wang: Gilead Sciences, Inc.: Current Employment. Wei: Roche: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Vyas: Pfizer: Honoraria; Jazz: Honoraria; Novartis: Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Takeda: Honoraria. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding.

*signifies non-member of ASH