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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 .

e15098 Background: Magrolimab (Hu5F9-G4) is a monoclonal IgG4 antibody that binds to CD47 receptor and blocks its interaction with SIRPA, thereby enabling tumor cell phagocytosis and activation of an anti-tumor T-cell response. Magrolimab has shown encouraging efficacy and tolerable safety profiles in treatment-naïve myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) patients on an every week (QW) maintenance dosing schedule. Reduced dosing frequency (e.g. every other week – Q2W) is desired to enhance patient convenience and quality of life. Methods: Interim pharmacokinetic (PK) and CD47 receptor occupancy (RO) data from study 5F9005 (Clinical Trial: NCT03248479) were used for this analysis. A previously developed population PK (PopPK) model of magrolimab was verified with observed PK data from study 5F9005. The PK model was linked to peripheral blood and bone marrow blast CD47 RO. The model-predicted RO was validated with observed RO data. Simulations of PK and RO were conducted to justify the proposed reduced dosing frequency of Q2W starting in Cycle 3 onward. Simulations were compared with preliminary observed RO data from the ongoing 5F9005 study after switching to Q2W dosing. Results: The results showed that observed magrolimab PK in study 5F9005 was consistent with model predictions. Model predicted RO was aligned with observed RO data. PK and RO simulations based on the model indicated > 99% RO in peripheral blood and ~90% RO in bone marrow are expected after switching to Q2W dosing regimen from Cycle 3 onward. Preliminary observed RO data confirmed these predictions. Conclusions: Magrolimab PK in AML/MDS is consistent with other patient populations including solid tumors and lymphomas. Model-based simulations and preliminary RO data support Q2W dosing of magrolimab from Cycle 3 onward as optimal RO is expected with the proposed dosing regimen. Clinical trial information: NCT03248479 .

114 Background: Magrolimab (M, Hu5F9-G4) is an antibody targeting CD47, a macrophage “don’t eat me” signal that demonstrates preclinical synergy with cetuximab (C) in refractory KRAS wild type (KRASwt) and KRAS mutant (KRASm) colorectal (CRC) tumors. Methods: Phase (Ph) 1 doses of M+C were escalated in solid tumor patients (pts) and Ph 2 efficacy was explored in previously treated KRASwt and KRASm CRC patients. Day 1 priming with 1 mg/kg of M was used to mitigate on-target anemia followed by maintenance doses ranging from 10 to 45 mg/kg in combination with C. Ph 2 pts were treated with 30 or 45 mg/kg of M and 400/250 mg/m2 of C. Results: In 78 treated pts (32 Ph 1 and 46 Ph 2), the median age was 59 years (range 19-82), and median prior therapies was 5 (range 1-14). No maximum tolerated dose was reached. Treatment-related adverse events (TRAEs) of any Grade (G) included dermatitis acneiform 36%, dry skin 33%, fatigue 32%, infusion reactions 31%, headache 30%, diarrhea 23%, nausea 23%, chills 23%, and anemia 22%. There were no fatal TRAEs and 3/78 (4%) discontinued M treatment due to any adverse events. In the combined Ph 1+2 study, 2 of 30 evaluable KRASwt CRC pts had confirmed PRs for 7.0 and 12.5 months (mo), for a 6.7% objective response rate (ORR). Both had prior C treatment. The median progression-free survival (mPFS) and median overall survival (mOS) was 3.6 mo (95%CI 1.8-5.4) and 10.1 mo (95%CI: 6.9-14.4), respectively. In 40 evaluable KRASm pts, there were no responses but 45% had stable disease (SD) and the mPFS and mOS were 1.9 mo (95%CI: 1.8-3.5) and 10.4 mo (95%CI: 5.7-16.4), respectively. In 28 KRASm pts who were TAS102/regorafenib naïve, preliminary mOS was 12.4 mo (95%CI: 5.9-not reached) which is longer than that reported for historical controls. Tumor biopsies showed treatment-related increases in macrophage immune cell infiltrates in SD pts, and baseline T cell infiltration was associated with longer OS. Pharmacokinetic profiles will be presented. Conclusions: M+C is a novel, well-tolerated combination immunotherapeutic treatment regimen. Responses were observed in two previously treated CRC pts and survival is encouraging in KRASm pts. Funded by Forty Seven and California Institute for Regenerative Medicine. Clinical trial information: NCT02953782.