Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study

Abstract

Purpose: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479).

Patients and methods: Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. 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 complete remission (CR) rate.

Results: Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53-mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS.

Conclusion: Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).

FIG 1.

Hemoglobin changes from baseline over time on treatment with magrolimab + azacitidine in patients with HR-MDS (N = 95). Data shown are median (Q1, Q3) change in blood samples drawn before each magrolimab dose. Analysis includes all patients who received at least one dose of magrolimab. HR-MDS, higher-risk myelodysplastic syndrome; Q1, first quartile; Q3, third quartile.

FIG 2.

Efficacy of magrolimab + azacitidine in patients with HR-MDS (N = 95). Assessments of efficacy were based on bone marrow aspirate and trephine bone marrow biopsy collected every two cycles starting with cycle 3 day 1, then every three cycles starting with cycle 7 day 1. Analyses include all patients who received at least one dose of magrolimab. (A) Best change from baseline in percent of bone marrow blasts for each patient. Bars are labeled by TP53 mutation status; those labeled as missing represent patients with TP53 mutation status unknown. (B) KM curves of PFS for the overall population and by TP53 mutation status. (C) KM curve of OS for the overall population and by TP53 mutation status. (D) KM curve of OS for patients who did and did not undergo allo-HSCT after magrolimab + azacitidine treatment. allo-HSCT, allogeneic hematopoietic stem-cell transplantation; HR-MDS, higher-risk myelodysplastic syndrome; KM, Kaplan-Meier; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 3.

Swimmer plot of response over time, treatment duration, and next treatment initiation for individual patients treated with magrolimab + azacitidine who achieved a CR. Y-axis indicates TP53-mut status for each patient. Time of first response assessment and results of subsequent response assessments are indicated by vertical lines. Stem-cell transplant is shown by black dots. Blue stars indicate time of next treatment initiation, and blue arrows show patients who were ongoing on magrolimab treatment at the time of data cutoff. CR, complete remission; mCR, marrow CR; mut, mutation; PD, progressive disease; PR, partial remission; Pt, patient; SCT, stem-cell transplantation; SD, stable disease; wt, wild-type.