First-in-class macrophage immune checkpoint inhibitor in AML

Magrolimab, a first-in-class macrophage immune checkpoint inhibitor targeting CD47, plus azacitidine was clinically effective in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Dr David Sallman (H. Lee Moffitt Cancer Center and Research Institute, Florida, USA) presented new data of the phase 1b 5F9005 study evaluating this combination in untreated patients with MDS or AML, including TP53-mutant AML [1].

CD47 provides a “do not eat me” signal and is overexpressed in multiple cancers including AML. CD47 blockade of these signals with magrolimab leads to enhanced phagocytosis. Azacitidine synergises with magrolimab by inducing “eat me” signals, such as calreticulin, on cancer cells [2].

In the presented phase 1b study, 52 AML patients with a median age of 73 years (range 31-89) were treated with magrolimab plus azacitidine. The patient population was specifically enriched for poor-risk cytogenetics, with 65% of patients having TP53 mutations.

Encouraging efficacy was observed with magrolimab plus azacitidine in untreated AML patients unfit for intensive chemotherapy, regardless of TP53-mutation status. In the full patient population, overall response rate (ORR) was 63% and complete remission (CR) rate 42%; in patients who were TP53-mutant, ORR was 69% and CR rate 45%. Preliminary median overall survival in TP53-wildtype (18.9 months) and TP53-mutant (12.9 months) is quite promising in this treatment setting in terms of historical treatment, according to Dr Sallman [1].

Most frequent treatment-related adverse events (AEs) for magrolimab plus azacitidine were anaemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%), and nausea (15%). “The combination with azacytidine has overall been well tolerated, with notably no significant immune-related AEs,” Dr Sallman concluded. “In addition, there was no significant worsening of neutropenia or thrombocytopenia, and a quite robust haematological improvement over time, correlating with robust responses. We do see on-target anaemia, but this has been mitigated with a priming/maintenance dose strategy and a higher transfusion threshold. Notably, patients do not have transfusion-related issues on chronic therapy.”

Given the high unmet need in this patient population, a randomised phase 3 trial of magrolimab plus azacitidine compared with venetoclax plus azacitidine in frontline TP53-mutant AML patients is planned for early 2021. Furthermore, broader development of magrolimab across all mutational subtypes in AML is warranted and ongoing (NCT03248479).

1. Sallman et al. The First-in-Class Anti-CD47 Antibody Magrolimab Combined with Azacitidine Is Well-Tolerated and Effective in AML Patients: Phase 1b Results. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 330.
2. Feng D, et al. Combination Treatment with 5F9 and Azacitidine Enhances Phagocytic Elimination of Acute Myeloid Leukemia. 60^th ASH Annual Meeting, 1-4 December 2018. Abstract 616.

Posted on 18 February 202122 February 2021