Patients with previously untreated higher-risk myelodysplastic syndromes (MDS) did not experience improved outcomes with the addition of the anti-CD47 antibody magrolimab to azacitidine compared with azacitidine alone, according to the results of the phase III ENHANCE trial reported by Sallman et al in the Journal of Clinical Oncology.
Study Details
The international, randomized, double-blind trial enrolled 539 adults (median age = 70 years, range = 19–88 years) between September 2020 and October 2022. Study participants had previously untreated intermediate-, high-, or very-high-risk MDS according to the Revised International Prognostic Scoring System and were not immediately eligible for allogeneic stem cell transplantation.
Patients were randomly assigned 1:1 to receive magrolimab plus azacitidine (n = 268) or placebo plus azacitidine (n = 271). Magrolimab was administered using a priming and dose-escalation schedule followed by maintenance dosing every 2 weeks, while azacitidine was given at the standard dose of 75 mg/m² in 28-day cycles. The trial's dual primary endpoints were complete remission rate and overall survival.
The study initially incorporated an interim analysis of complete remission, followed by a prespecified futility analysis for overall survival if the remission endpoint was not met. After the first interim analysis failed to demonstrate an improvement in complete remission, the second interim analysis crossed the predefined futility boundary for overall survival, prompting termination of the trial. A final analysis was subsequently conducted after treatment discontinuation.
Key Results
At final analysis (in November 2023), the combination regimen failed to improve either primary endpoint. Complete remission was achieved in 21.3% of patients receiving magrolimab plus azacitidine vs 23.6% of those receiving placebo plus azacitidine (odds ratio = 0.876, 95% confidence interval [CI] = 0.585–1.312, P = .5218). Median overall survival was likewise not improved, at 15.9 months in the investigational arm compared with 18.6 months in the control arm (hazard ratio = 1.203, 95% CI = 0.947–1.528, P = .1299).
Treatment-related toxicity was substantially greater with the experimental regimen. Grade 3 or higher adverse events occurred in 92.8% of patients receiving magrolimab compared with 79.2% of those receiving placebo. Serious adverse events were reported in 71.9% vs 51.5% of patients, treatment discontinuations due to adverse events occurred in 24.0% vs 12.1%, and fatal adverse events occurred in 15.2% vs 9.8%. Higher rates of severe anemia, infections, infusion-related reactions, and neutropenia were observed with magrolimab, despite implementation of anemia-management protocols during the trial.
The investigators concluded: “ENHANCE did not meet the primary endpoints of [complete remission] rate and [overall survival], and showed more frequent severe [adverse events] in patients treated in the [magrolimab plus azacitidine] arm.”
David A. Sallman, MD, of Moffitt Caner Center, Tampa, Florida, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by Gilead Sciences, Inc. For full disclosures of the study authors, visit ascopub.org.
