Magrolimab in Combination With Azacitidine for Patients With Untreated Higher-Risk Myelodysplastic Syndromes: 5F9005 Phase 1b Study Results

Introduction:
Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal overexpressed on cancer cells. CD47 blockade by magrolimab induces macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine (AZA) in the upregulation of “eat me” signals. A high unmet need exists to build on current standard-of-care AZA frontline therapy to increase efficacy while maintaining a tolerable safety profile in patients with higher-risk myelodysplastic syndromes (HR MDS). Here we report the final safety/tolerability and efficacy data from a phase 1b trial of magrolimab + AZA in patients with untreated HR MDS (NCT03248479).
Methods:
Patients with previously untreated, intermediate-, high-, or very high–risk MDS per the Revised International Prognostic Scoring System (IPSS-R) received magrolimab intravenously (IV) as a priming dose (1 mg/kg) followed by ramp-up to a 30-mg/kg once-weekly or every-2-weeks maintenance dose. AZA 75 mg/m was administered IV or subcutaneously on days 1 to 7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate.
Results:
A total of 95 patients (median age, 69‚Äâyears [range, 28-91‚Äâyears]) were treated. IPSS-R risk was intermediate in 27% of patients, high in 52%, and very high in 21%. MDS was therapy related in 22% of patients; 26% had a mutation, and 62% had poor-risk cytogenetics. Median number of cycles was 6 (range, 1-27). The most common treatment-emergent adverse events (TEAEs) included constipation (68%), thrombocytopenia (55%), anemia (52%), neutropenia (47%), nausea (46%), and diarrhea (43%). The most common grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and decreased white blood cell count (30%). Six patients discontinued treatment due to AEs. The 60-day mortality rate was 2%. Median hemoglobin change from baseline at first postdose sample was ‚àí0.7 g/dL (range, ‚àí3.1 to 2.4 g/dL). CR and objective response (OR) rates were 33% and 75%, with 31% of OR-evaluable patients with abnormal cytogenetics at baseline having cytogenetic CR. Median time to first OR, duration of CR, duration of OR, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Overall survival (OS) rates at 12 and 24 months were 75% and 52%; median OS was not reached (NR) with 17.1 months of follow-up. In patients evaluated with sequential whole-exome sequencing with a variant allele frequency (VAF) cutoff of 5%, 3 of 3 patients with mutation who achieved CR had VAF Discussion:
Magrolimab + AZA was well tolerated with promising efficacy in patients with untreated HR MDS, including those with -mutated and –wild-type disease. A phase 3 trial of magrolimab/placebo + AZA (ENHANCE: NCT04313881) is ongoing.