MDS-197: Magrolimab + Azacitidine Versus Azacitidine + Placebo in Untreated Higher-Risk (HR) Myelodysplastic Syndromes (MDS): The Phase 3, Randomized, ENHANCE Study

Context: Myelodysplastic syndromes (MDS) are myeloid clonal disorders characterized by cytopenia that primarily affect older individuals. Prognosis and treatment are guided by the Revised International Prognostic Scoring System (IPSS-R) criteria. Patients with intermediate-, high-, and very high-risk MDS (HR-MDS) have a median overall survival (OS) of 0.8–3.7 years. Despite the high unmet need for these patients, azacitidine (AZA) is the only approved therapy for HR-MDS that has improved OS in clinical trials to date. However, AZA monotherapy leads to low complete response (CR) rates with limited OS, indicating a need for alternative therapy. The monoclonal antibody magrolimab blocks the macrophage inhibitory immune checkpoint CD47, which is overexpressed on tumor cells. AZA increases expression of prophagocytic signals, facilitating synergy with magrolimab. In an ongoing phase 1b study, magrolimab + AZA led to high response rates and an acceptable safety profile without significant immune-related adverse events. Objective: To compare the efficacy and safety of magrolimab + AZA vs AZA + placebo in previously untreated patients with HR-MDS. Design: ENHANCE (NCT04313881) is a randomized, phase 3, double-blind, multicenter study. Interventions: Randomization is 1:1 to magrolimab + AZA or AZA + placebo with no crossover. Patients or Other Participants: Patients aged ≥18 years with previously untreated intermediate- to very high-risk MDS by IPSS-R are eligible. Magrolimab or placebo is administered intravenously with an initial 1 mg/kg priming dose to mitigate on-target anemia. An intrapatient dose-escalation regimen up to 30 mg/kg is administered through cycle 1, 30 mg/kg weekly dosing in cycle 2, with 30 mg/kg dosing every 2 weeks in cycle 3 and beyond. AZA is administered per regional prescribing information. Patients may remain on treatment until disease progression, relapse, loss of clinical benefit, or until unacceptable toxicities occur. Main Outcome Measures: The two primary efficacy endpoints are CR rate and OS. Secondary efficacy endpoints include red blood cell transfusion-independence rate, event-free survival, minimal residual disease-negative rate, time to acute myeloid leukemia transformation, and patient-reported Functional Assessment of Cancer Therapy-Anemia response rate. Results: Trial in progress. Conclusions: Patient enrollment began in September 2020; accrual is ongoing. Planned enrollment is approximately 520 patients globally. Funding Source: Gilead Sciences, Inc., Foster City, CA, USA.