Tolerability and Efficacy of the First-in-Class Anti-CD47 Antibody Magrolimab Combined With Azacitidine in Frontline Patients With TP53-Mutated Acute Myeloid Leukemia: Phase 1b Results

Introduction:
Patients with -mutated acute myeloid leukemia (AML) have a poor prognosis, poor survival outcomes, and limited responses to currently available therapies, representing a significant unmet medical need. Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cells in cancers such as AML. Blocking CD47 induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. Here we report tolerability and efficacy data from a phase 1b trial of frontline magrolimab + AZA in patients with -mutated AML unsuitable for intensive chemotherapy (NCT03248479).
Methods:
Patients received magrolimab IV starting with a priming dose (1 mg/kg) followed by ramp up to 30 mg/kg QW or Q2W as the maintenance dose. AZA 75 mg/m was given IV or SC on days 1-7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by European LeukemiaNet 2017 criteria.
Results:
72 patients (median age, 73 years) with mutated AML were treated. At baseline, 85% of patients had ECOG PS scores 0 or 1, and 79% had adverse cytogenetic risk. Common all-grade treatment-emergent adverse events (TEAEs) were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), and nausea (43.1%). The most common grade ≥3 TEAEs were febrile neutropenia (37.5%), anemia (29.2%; grade 3, 26.4%; grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). No grade 4 hemolysis was reported, and grade 3 hemolysis was reported in 1 patient (1.4%). Objective response rate was 48.6% (CR, 33.3%; CR with incomplete hematologic recovery [CRi]/CR with partial hematologic recovery [CRh], 8.3%; morphological leukemia-free state [MLFS], 1.4%; partial remission, 5.6%). Stable disease was reported in 16.7% of patients, and progressive disease (PD) was reported in 5.6%. Mortality rates at 30 and 60 days were 8.3% and 18.1%, respectively. Response assessments were unavailable in 4.2% of patients who discontinued due to AEs and 6.9% who discontinued for other reasons prior to the cycle 3, day 1 assessment. Median time to CR/CRi was 2.2 months (range, 1.7-7.2 months) and to CR was 3.0 months (range, 1.8-9.6 months); 14/31 (45.2%) evaluable patients with CR/CRi/CRh/MLFS achieved negative MRD by flow cytometry (investigator reported). 8/24 patients with CR had a longitudinal variant allele frequency (VAF) assessment, and 5/8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to stem cell transplant (9 [12.5%]), PD (26 [36.1%]), death (8 [11.1%]), AE (13 [18.1%]), and other (14 [19.4%]). Median durations of CR and CR/CRi were 7.7 months (95% CI, 4.7-10.9 months) and 8.7 months (95% CI, 5.3-10.9 months), respectively. Median overall survival (OS) was 10.8 months (95% CI, 6.8-12.8 months) with median follow-up of 8.3 months. 9 patients proceeded to transplant, with a median OS of not reached, compared with 8.4 months in 63 patients who did not receive a transplant.
Discussion:
Frontline magrolimab + AZA showed durable responses and encouraging OS in a single-arm study in high-risk patients with mutated AML unsuitable for intensive chemotherapy. A phase 3 trial of this combination vs standard of care in mutated AML (ENHANCE-2; NCT04778397) is ongoing.