Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results

Abstract

Purpose: Magrolimab is a first-in-class humanized monoclonal antibody against cluster of differentiation 47, an antiphagocytic signal used by cancer cells to evade phagocytosis. Azacitidine upregulates prophagocytic signals on AML cells, further increasing phagocytosis when combined with magrolimab. We report final phase Ib data for magrolimab with azacitidine in patients with untreated AML ineligible for intensive chemotherapy (ClinicalTrials.gov identifier: NCT03248479).

Patients and methods: Patients with previously untreated AML, including TP53-mutant AML, received magrolimab intravenously as an initial dose (1 mg/kg, days 1 and 4), followed by 15 mg/kg once on day 8 and 30 mg/kg once weekly or every 2 weeks as maintenance. Azacitidine 75 mg/m² was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and proportion with complete remission (CR).

Results: Eighty-seven patients were enrolled and treated; 72 (82.8%) had TP53 mutations with a median variant allele frequency of 61% (range, 9.8-98.7). Fifty-seven (79.2%) of TP53-mutant patients had European LeukemiaNet 2017 adverse-risk cytogenetics. Patients received a median of 4 (range, 1-39) cycles of treatment. The most common treatment-emergent adverse events included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). Thirty (34.5%) experienced anemia, and the median hemoglobin change from baseline to first postdose assessment was -0.9 g/dL (range, -3.6 to 2.5 g/dL). Twenty-eight (32.2%) patients achieved CR, including 23 (31.9%) patients with TP53 mutations. The median overall survival in TP53-mutant and wild-type patients were 9.8 months and 18.9 months, respectively.

Conclusion: Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML.

FIG 1.

Hb change from baseline and RBC/whole blood transfusion over time. (A) Hb (g/dL) change from baseline over time. Median (IQR) shown for all patients (n = 87). Numbers below the graph indicate the number of patients with Hb assessment at that time point. (B) RBC/whole blood units transfused over time in patients remaining on treatment from the overall study population (n = 87); median (IQR). Numbers below the graph indicate the number of patients who received a transfusion at that time point. ^*Time points with at least five patients. Hb, hemoglobin.

FIG 2.

Responses to magrolimab + azacitidine in patients with untreated AML who were unfit for intensive chemotherapy. (A) Waterfall plot of best change from baseline in percent of bone marrow blasts in evaluable patients. (B) Kaplan-Meier curve of the duration of complete remission by TP53 mutation status. Censored patients are represented by vertical tick marks in the Kaplan-Meier curve. CR, complete remission.

FIG 3.

Kaplan-Meier curves. (A) OS of all patients (left) and by TP53 mutation status (right); (B) OS of patients who received allo-HSCT and patients who did not, including all patients (left), and patients with TP53 mutations (right) using landmark analysis to control for lead-time bias, with 10 months as the landmark time point to include all patients with TP53 mutations who received allo-HSCT. Patients who discontinued or were lost to follow-up before the landmark time point were excluded from the analyses. The allo-HSCT group includes all patients who had allo-HSCT by the landmark time point. The no allo-HSCT group includes all patients who did not receive allo-HSCT or received allo-HSCT after the landmark time point (n = 1). Among patients bridged to allo-HSCT, the median (range) age was 68 (51-73) years, and ECOG performance status at screening was 0 in 3 of 10 (30%), 1 in 5 of 10 (50%), and 2 in 2 of 10 (20%). Eight patients had adverse-risk cytogenetics, one had intermediate-I risk, and one had unknown risk; three had AML related to previous chemotherapy or radiation; and seven were RBC transfusion-independent at baseline. Allo-HSCT was entirely at the discretion of the investigator, and patients took off-trial treatment before conditioning, so no additional information is available. Censored patients are represented by vertical tick marks in the Kaplan-Meier curve. Allo-HSCT, allogeneic hematopoietic stem-cell transplantation; ECOG, Eastern Cooperative Oncology Group; NA, not available; OS, overall survival.