The Lynx Group

Magrolimab, First CD47 Antibody, Shows Promise in Combination with Azacitidine in Unfit Patients with Acute Myeloid Leukemia

February 2021, Vol 12, No 1

Magrolimab, a first-in-class investigational antibody targeting CD47, showed good efficacy when combined with azacitidine injection (Vidaza) regardless of TP53 mutation in patients with treatment-naïve acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, according to data presented at ASH 2020. The results also showed that this combination did not lead to significant immune-related side effects.

The results from this phase 1b study with magrolimab plus azacitidine showed an objective response rate (ORR) of 63% and a complete response rate of 42%, and were presented by David A. Sallman, MD, Assistant Member, Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Promising Antibody Targeting CD47

Magrolimab is a novel antibody targeting CD47, a potent macrophage immune checkpoint of “do not eat me” signal that enables cancer cells to evade the immune system. CD47 is overexpressed on solid and hematologic cancer cells, leading to macrophage immune invasion.

“Magrolimab eliminates tumor cells through macrophage phagocytosis,” said Dr Sallman. Azacitidine synergizes with magrolimab by increasing the “do not eat me” signals on leukemic blasts, thereby enhancing phagocytosis (or cell death).

The study included 64 treatment-naïve patients with AML ineligible for induction chemotherapy who received magrolimab plus azacitidine. A magrolimab priming or intrapatient dose-escalation regimen (1-30 mg/kg intravenous weekly followed by 30 mg/kg every 2 weeks) was used to mitigate on-target anemia. Azacitidine was dosed at 75 mg/m2 on days 1 to 7 of a 28-day cycle.

The median patient age was 71 years, 70% had poor cytogenetic risk, 53% had AML with myelodysplastic-related change, and 73% had TP53 mutations. Among patients with TP53 mutation, the median TP53 baseline variant allele frequency burden was 73.3%, “which we know has been shown to be highly concordant with having a dismal overall survival at approximately 6 months,” said Dr Sallman.

On-target anemia is expected from CD47 blockade, he explained. The initial priming dose resulted in a transient mean hemoglobin drop on the first dose of 0.9 g/dL, which returned to baseline.

In addition, 12% of patients achieved a complete response with an incomplete count recovery. The median time to response was 1.95 months, which is more rapid than azacitidine monotherapy. The ORR (63%) and complete response rate (42%) in patients with TP53 mutation were similar to the response rate in the overall cohort.

Of the total cohort, 68% of the patients achieved red blood cell transfusion-independence and 45% had a complete cytogenetic response, and these rates were similar in the population with TP53 mutation. Minimum residual disease negativity in patients with complete response was achieved in 35%. Responses were durable, said Dr Sallman; the median duration of response was 9.6 months in all patients, and 7.6 months in the patients with TP53 mutation. Multiple patients deepened their response over time.

The median overall survival (OS) was 18.9 months in patients without TP53 mutation, with a median of 12.5 months of follow-up, and 12.9 months in those with TP53 mutation, with a median follow-up of 4.7 months. The OS was superior to the OS recorded with venetoclax (Venclexta) plus hypomethylating combinations, Dr Sallman said.

Adverse Events

Treatment-related adverse events were observed in more than 15% of the patients and included anemia, fatigue, an increase in blood bilirubin, infusion-related reaction, neutropenia, thrombocytopenia, and an increase in alanine aminotransferase levels.

“We see no significant increase in cytopenias over azacitidine monotherapy, and no significant increase in infectious-related complications, and in opposition to traditional immune checkpoint therapy, we have not seen any immune-related adverse events,” Dr Sallman said.

Only 4.7% of patients had an adverse event leading to magrolimab dose reduction, and 4.7% of patients had treatment discontinuation because of drug-related adverse events.

Continued Development

Given the high unmet need in patients with unfit AML and TP53 mutation, a randomized phase 3 clinical trial of first-line magrolimab plus azacitidine versus venetoclax plus azacitidine in patients with AML and TP53 mutation is planned for early 2021, said Dr Sallman. He noted that broader development of magrolimab across all mutational subtypes in AML is indicated.

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