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569 The First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Azacitidine Is Effective in MDS and AML Patients: Ongoing Phase 1b Results

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Combination Therapies
Hematology Disease Topics & Pathways:
Diseases, AML, Biological, antibodies, Adult, Therapies, Non-Biological, MDS, checkpoint inhibitors, chemotherapy, Cell Lineage, immune cells, immunotherapy, Study Population, Clinically relevant, Myeloid Malignancies, stem cells
Monday, December 9, 2019: 8:00 AM
W311EFGH, Level 3 (Orange County Convention Center)

David A Sallman, MD1,2, Adam S. Asch, MD3, Monzr M. Al Malki, MD4, Daniel J. Lee, MD5, William B. Donnellan, MD6, Guido Marcucci, MD7, Suman Kambhampati, MD8*, Naval G. Daver, MD9, Guillermo Garcia-Manero, MD9, Rami S. Komrokji, MD2,10,11, Joanna Van Elk12*, Ming Lin, PhD12*, Jens-Peter Volkmer, MD13*, Chris H Takimoto, MD, PhD13, Mark Chao, MD, PhD13* and Paresh Vyas, MD, PhD14

1Division of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL
2Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
3Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
4Department of Hematology/HCT, City of Hope National Medical Center, Duarte, CA
5Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY
6Tennessee Oncology / Sarah Cannon Research Institute, Nashville, TN
7Department of Hematologic Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope, Monrovia, CA
8HCA Midwest Health at Research Medical Center, Kansas City, KS
9University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX
10Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
11Division of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
12Forty Seven, Inc., Menlo Park, CA
13Forty Seven Inc., Menlo Park, CA
14MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom

Background

Magrolimab (previously named 5F9) is a first-in-class antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers. CD47 blockade induces tumor phagocytosis and eliminates leukemia stem cells (LSC) in AML models. Azacitidine (AZA) synergizes with magrolimab by inducing “eat me” signals on AML, to enhance phagocytosis. A Phase 1b trial of magrolimab+AZA was initiated in MDS/AML patients with preliminary reported results mainly from the safety cohort demonstrating high response rates in both diseases. Here we report data from the expansion cohort of this ongoing trial.

Methods

Results from this Phase 1b reported here focus on treatment of magrolimab+AZA in untreated intermediate to very high risk MDS patients by IPSS-R and untreated AML (induction chemotherapy ineligible) patients. A magrolimab priming/intrapatient dose escalation regimen (1-30 mg/kg weekly) was utilized to mitigate on target anemia. AZA dosing was 75mg/m2 days 1-7 on a 28 day cycle. Responses were assessed by IWG 2006 and ELN 2017 criteria for MDS and AML patients, respectively.

Results

43 patients (18 MDS and 25 AML) with a median of 73 years of age were treated with magrolimab+AZA. 19% were intermediate cytogenetic risk with 63% poor risk (19% unknown). 28% of patients harbored a TP53 mutation. Magrolimab+AZA was w­­­ell-tolerated with a safety profile similar to AZA monotherapy. Treatment-related AEs (>15% of patients) for magrolimab+AZA were anemia (37%), neutropenia (26%), and thrombocytopenia (26%). Treatment-related febrile neutropenia occurred in only 1 (2%) patient. Only 1 patient discontinued due to an AE. 29 patients were evaluable for efficacy at time of data cut. 13/13 (100%) untreated MDS patients had an objective response with 7 patients (54%) achieving a CR, 5 (39%) with marrow CR (3/5 also had hematologic improvement (HI)), and 1 (7%) with HI alone. In AML, 11/16 (69%) had an objective response; 8/16 (50%) with CR or CRi, 2 (13%) with PR, 1 (6%) with MLFS, and 5 (31%) with stable disease. Time to response was more rapid (median 1.9 mos) than expected for AZA alone. For those with abnormal cytogenetics at baseline, 40% and 44% of MDS and AML patients achieved a cytogenetic CR, respectively. 4/8 (50%) AML patients with CR/CRi and 2/12 (17%) MDS patients with CR or marrow CR were MRD negative by flow cytometry. 11/16 (69%) AML patients became RBC transfusion independent and 11/13 (85%) MDS patients had hematologic improvement.

Given that CD47 is an LSC marker on leukemic cells, CD34+CD38- putative LSC frequency was measured by flow cytometry in the bone marrow in 5F9+AZA treated AML/MDS patients. In data available for analysis, LSCs were completely eliminated in 10/16 (63%) of AML/MDS patients who had a clinical response. Lastly, mutational analyses are ongoing to correlate subgroups with response. Interestingly, 7/8 (88%) evaluable TP53 mutant patients (5/6 AML patients [5 CR/CRi], 2/2 MDS [1 CR, 1 marrow CR]) achieved an objective response, highlighting efficacy in a poor prognosis and therapy-refractory population. No median duration response or overall survival has been reached for either MDS or AML patients with a median follow-up of 4.9 months (range 3.1 – 8.8 months) for MDS and 5.8 months (range 1.9 – 9.5 months) for AML.

Conclusions

Magrolimab+AZA is a novel immunotherapy regimen that blocks a key macrophage checkpoint. The combination therapy continues to be well tolerated with robust activity in MDS and AML patients with an ORR of 100% and 69%, respectively. High rates of putative LSC eradication suggest potential durable responses, with no median duration of response yet reached. Initial data indicate that 5F9+AZA may be particularly effective in TP53 mutant patients, a treatment-refractory subgroup. Expansion cohorts are ongoing (NCT03248479) with registrational studies in MDS being initiated. Additional patients, follow-up, and mutational characterization will be reported at time of presentation. Funded by Forty Seven and the California Institute for Regenerative Medicine.

Disclosures: Sallman: Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Jazz: Research Funding; Novartis: Speakers Bureau; Abbvie: Speakers Bureau. Lee: Bayer: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Forty Seven, Inc.: Research Funding; Tolero: Research Funding. Daver: Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Pfizer: Consultancy, Research Funding; Servier: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; NOHLA: Research Funding; Astellas: Consultancy; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Glycomimetics: Research Funding. Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Komrokji: Novartis: Speakers Bureau; Incyte: Consultancy; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau. Van Elk: Forty Seven, Inc.: Employment, Equity Ownership. Lin: Forty Seven, Inc.: Employment, Equity Ownership. Takimoto: Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Chao: Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Vyas: Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Speakers Bureau; Abbvie: Speakers Bureau; Astellas: Speakers Bureau.

*signifies non-member of ASH