S166: MAGROLIMAB IN COMBINATION WITH AZACITIDINE FOR PATIENTS WITH UNTREATED HIGHER-RISK MYELODYSPLASTIC SYNDROMES (HR MDS): 5F9005 PHASE 1B STUDY RESULTS

Abstract

Background: 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 (pts) with HR MDS. Aims: To report the final safety/tolerability and efficacy data from a phase 1b trial of magrolimab + AZA in pts with untreated HR MDS (NCT03248479). Methods: Pts with previously untreated intermediate, high, or very high–risk MDS per the Revised International Prognostic Scoring System (IPSS-R) received magrolimab IV as a priming dose (1 mg/kg) followed by ramp-up to a 30-mg/kg QW or Q2W maintenance dose. AZA 75 mg/m2 was administered IV or SC on days 1-7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate. Results: A total of 95 pts (median age, 69 y [range, 28-91 y]) were treated. IPSS-R risk was intermediate, high, or very high in 27%, 52%, and 21% of pts. MDS was therapy related in 22% of pts; 26% had a TP53 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 (44%). The most common grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and white blood cell count decreased (30%). Six pts discontinued treatment due to AEs. The 60-day mortality rate was 2%. Median hemoglobin change from baseline (BL) at first postdose sample was −0.7 g/dL (range, −3.1 to 2.4 g/dL). CR and objective response (OR) rates were 33% and 75%, with 31% of OR-evaluable pts with abnormal cytogenetics at BL having cytogenetic CR. Median time to first OR, duration of CR (DCR), duration of OR, and progression-free survival (PFS) were 1.9, 11.1, 9.8, and 11.6 mo. Overall survival (OS) rates at 12 and 24 mo were 75% and 52%; median OS was not reached (NR) with 17.1 mo of follow-up (figure). In pts evaluated with sequential whole-exome sequencing with a variant allele frequency (VAF) cutoff of 5%, 3 of 3 pts with TP53 mutation who achieved CR had TP53 VAF <5% by cycle 5 day 1. Favorable outcomes were observed both in pts with TP53 mutation (CR rate, 40%; median OS, 16.3 mo) and wild-type TP53 (CR rate, 31%; median OS, NR) (table). Table. - Outcomes in patients with previously untreated HR MDS treated with magrolimab + AZA Outcome All patients N=95 a Wild-type TP53 n=61 TP53 mutation n=25 OR rate, % b 75 79 68 CR rate (95% CI), % 33 (23-43) 31 (20-44) 40 (21-61) Marrow CR rate, % 32 38 20 Stable disease with HI rate, % 11 10 8 Median DCR (95% CI), mo 11.1 (7.6-13.4) 12.9 (8.0-NR) 7.6 (3.1-13.4) Marrow CR rate with HI/any HI, % 17/59 20/61 12/56 Converted to red blood cell transfusion independence, % 14 10 24 Median PFS (95% CI), mo 11.6 (9.0-14.0) 11.8 (8.8-16.6) 11.0 (6.3-12.8) Median OS (95% CI), mo NR (16.3-NR) NR (21.3-NR) 16.3 (10.8-NR) a a 9 patients had missing TP53 status. b Defined as CR+PR + marrow CR+SD with HI.HI, hematologic improvement. Image:Summary/Conclusion: Magrolimab + AZA was well tolerated with promising efficacy in pts with untreated HR MDS, including those with TP53-mutated and –wild-type disease. A phase 3 trial of magrolimab/placebo + AZA (ENHANCE: NCT04313881) is ongoing.