Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients: Phase Ib results.

Abstract

7507 Background: Magrolimab (Hu5F9-G4) is an antibody blocking CD47, a macrophage immune checkpoint and don’t eat me signal on cancers. It induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing eat me signals on leukemic cells, enhancing phagocytosis. We report Ph1b data including a potential MDS registration cohort. Methods: Magrolimab+AZA was given to untreated intermediate to very high risk IPSS-R MDS and intensive chemo unfit AML patients. A magrolimab priming/intrapatient dose escalation regimen (1-30 mg/kg QW, Q2W Cycle 3+) was used. AZA was dosed 75mg/m2 days 1-7. Efficacy was assessed by IWG 2006 (MDS) and ELN 2017 (AML) criteria. Results: 68 patients (39 MDS, 29 AML) with a median age of 72 were treated with magrolimab+AZA. 19% were intermediate cytogenetic risk with 68% poor risk (13% unknown). 27% were TP53 mutant. The combo was well-tolerated with safety similar to AZA alone. Common treatment-related AEs were anemia (38%), fatigue (21%), neutropenia (19%), thrombocytopenia (18%) and infusion reaction (16%). Treatment-related febrile neutropenia was 1.5%. Only 1 patient (1.5%) discontinued due to an AE. In RBC transfusion dependent patients, 58% of MDS and 64% of AML patients became transfusion independent. 30/33 (91%) efficacy evaluable MDS patients had an objective response (42% CR, 24% marrow CR (4/8 also with HI), 3% PR, 21% HI alone, 9% SD). MDS patient responses deepened on study, with a 56% CR rate in patients with ≥ 6 mo follow-up. In AML, 16/25 (64%) responded (40% CR, 16% CRi, 4% PR, 4% MFLS, 32% SD, 4% PD). In 12 TP53 mutant AML patients, 75% had a CR+CRi (42% CR, 33% CRi, 17% SD, 8% PD). Cytogenetic CR was seen in 35% and 50% of responding MDS and AML patients. 22% of MDS and 50% of AML patients with CR/CRi/marrow CR were MRD negative by flow cytometry. Median duration of response is not reached in either MDS or AML, including TP53 mutant AML, with a median follow-up of 5.8, 8.8 and 9.4 mos, respectively (range: 1.9 – 16.8 mos). 91% of MDS and 100% of AML responding patients are in response at 6 mos. The 6 mo overall survival estimate is 100% in MDS and 91% in TP53 mutant AML patients. Conclusions: Magrolimab is a macrophage targeting immunotherapy that with AZA is well tolerated with durable efficacy in MDS, AML, particularly TP53 mutant, a poor prognostic group. A potential registration single arm MDS cohort is ongoing (NCT03248479). ENHANCE, a randomized Ph3 MDS trial is planned. Additional patients/analyses will be reported. Funded by Forty Seven and CIRM. Clinical trial information: NCT03248479 .

Emerging treatment options for patients with high-risk myelodysplastic syndrome

“…Preliminary data from a phase Ib trial of 68 HMA-naive patients (39 MDS and 29 AML) treated with magrolimab + AZA showed an ORR of 91% (30 out of 33 evaluable patients) in MDS with 42% CR rate, a median duration of response that has not been reached at 5.8 months of median follow up, and a 100% 6-month OS estimate. 108 Notably, even in patients with TP53 mutations, ORR of 75% in both the AML and MDS patient cohort with 6-month OS estimates of 91% and 100%, respectively, have been shown. 108 Since CD47 is also expressed on erythrocytes and erythrocyte precursor cells, hemolytic anemia can be an on-target, off-leukemia adverse event seen with magrolimab.…”

“… 108 Notably, even in patients with TP53 mutations, ORR of 75% in both the AML and MDS patient cohort with 6-month OS estimates of 91% and 100%, respectively, have been shown. 108 Since CD47 is also expressed on erythrocytes and erythrocyte precursor cells, hemolytic anemia can be an on-target, off-leukemia adverse event seen with magrolimab. 111 However, the combination of AZA + magrolimab appeared to have a safety profile similar to that of AZA monotherapy with anemia (38%), fatigue (21%), neutropenia (19%), and thrombocytopenia (18%) being the most common treatment-related adverse events with only one patient discontinuing treatment due to adverse events.…”

“…Promising data for the frontline treatment of MDS have also been published for the combination of AZA with the anti-CD47 antibody magrolimab [ ClinicalTrials.gov identifier: NCT03248479]. 108 CD47 is an inhibitory immune checkpoint on macrophages inhibiting phagocytosis and has been shown to be upregulated by leukemic stem cells enabling immune escape and whose upregulation has been associated with adverse outcomes in AML patients. 109 , 110 Inhibiting CD47-mediated immune escape could therefore lead to enhanced phagocytosis of leukemic stem cells and AML blasts.…”

“… 111 However, the combination of AZA + magrolimab appeared to have a safety profile similar to that of AZA monotherapy with anemia (38%), fatigue (21%), neutropenia (19%), and thrombocytopenia (18%) being the most common treatment-related adverse events with only one patient discontinuing treatment due to adverse events. 108 Those promising results have led to a randomized phase III trial comparing AZA + magrolimab with AZA + placebo in untreated MDS patients [ ClinicalTrials.gov identifier: NCT04313881].…”

Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy

“…However, monoclonal antibodies are sometimes handicapped by their mechanism of action, in that their biodistribution could lead to an unfavorable pharmacokinetic profile, bottlenecking clinical efficacy. Indeed, though CD47 blockade therapies have achieved early therapeutic efficacy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients in clinical trials ( 79 , 80 ), this strategy has so far struggled in coping with solid tumors. Furthermore, it is possible that monotherapy acting on a single target is simply insufficient to overcoming the heterogeneous tumor microenvironment ( 81 ).…”