Magrolimab/Azacitidine Shows Tolerability, Efficacy in Higher-Risk MDS

Magrolimab may be a potentially tolerable and effective treatment in combination with azacitidine (Onureg) for patients with untreated higher-risk myelodysplastic syndromes (MDS), according to findings from a phase 1b trial (NCT03248479) published in the Journal of Clinical Oncology.

"Magrolimab offers a dual mechanistic approach not only to augment the innate immune response by macrophage-mediated phagocytosis but also to eradicate the underlying leukemia stem cell and augment adaptive immunity," according to the study authors.

The complete and overall response rates (CR; ORR) were 32.6% (95% CI, 23.4%-43.0%) and 74.7% (95% CI, 64.8%-83.1%), respectively. The median time to first response was 1.9 months (range, 0.7-10.9), and the median time to CR was 3.7 months (range, 1.7-7.2). The median durations of CRs and ORs were 11.1 months (95% CI, 7.6-13.4) and 9.8 months (95% CI, 8.8-12.9), respectively.

Additionally, the median progression-free survival (PFS) was 11.6 months (95% CI, 9.0-14.0), and the median overall survival (OS) was not reached (NR; 95% CI, 16.3-NR) after a median follow-up for survival of 17.1 months.

“Although immunotherapy has shifted the paradigm in solid tumors and Hodgkin lymphoma, targeting traditional immune checkpoints in patients with MDS or [acute myeloid leukemia]…with or without azacitidine has shown significant immune-related toxicities and no clear evidence of synergy, possibly because of a functionally abrogated T-cell response,” the investigators wrote. “Magrolimab offers a dual mechanistic approach not only to augment the innate immune response by macrophage-mediated phagocytosis but also to eradicate the underlying leukemia stem cell and augment adaptive immunity.”

Investigators of this single-arm, open-label, multicenter phase 1b studyenrolled 95 patients from July 10, 2018, to August 4, 2020. Most patients had an ECOG performance status of 1 (63.2%) and poor-risk cytogenetics (62.1%). Additionally, 27.4% had complex cytogenetics, defined as having 3 or more cytogenetic abnormalities. The proportion of patients with intermediate, high, and very high Revised International Prognostic Scoring System (IPSS-R) risk was 27.4%, 51.6%, and 21.1%, respectively.

The median patient age was 69 years old (range, 28-91). Most were male (65.3%) and White (89.5%), with other patients identifying as Black or African American (3.2%), Asian (2.1%), or American Indian or Alaska Native (1.1%).

Following the safety run-in cohort, patients in this trial received intravenous magrolimab at a priming dose of 1 mg/kg on days 1 and 4, 15 mg/kg on day 8, and 30 mg/kg on days 11, 15, and 22. This was followed by 30 mg/kg once weekly or once every 2 weeks beginning on the first day of the third cycle. They also received subcutaneous or intravenous azacitidine at a dose of 75 mg/m2 once daily on days 1 to 7 of each 28-day cycle.

The primary end points included adverse effects (AEs) and serious AEs (SAEs). Secondary efficacy end points included ORR, CR rate, PFS, and OS.

Patients with untreated MDS by World Health Organization classification and an IPSS-R risk category of intermediate, high, or very high were eligible for enrollment. Additional eligibility criteria included having an ECOG performance status of 0 to 2 and a glomerular filtration rate of at least 40 mL/min/1.73 m2.

The most common treatment-emergent AEs (TEAEs) of any grade were constipation (68.4%), thrombocytopenia (54.7%), anemia (51.6%), neutropenia (47.4%), nausea (46.3%), and diarrhea (43.2%). The most common grade 3/4 AEs were anemia (47.4%), neutropenia (46.3%), and thrombocytopenia (46.3%), and the most common serious TEAEs were febrile neutropenia (24.2%), pneumonia (9.5%), and anemia (8.4%).

Immune-related reactions potentially related to magrolimab occurred in 2.1% of patients. Magrolimab-related anemia occurred in 37.9%, with grade 3 events reported in 34.7%. Among these patients, 33.3% had grade 1, 50.0% had grade 2, and 13.9% had grade 3 anemia at baseline.

Investigators detected antidrug antibodies in 2.2% of patients, but they were transient, not neutralizing, and without clinical sequelae.

“To our knowledge, this phase 1b study represents the largest, most comprehensive data set for magrolimab with azacitidine in myeloid malignancies,” the investigators concluded. “If [future trials are] successful, this combination could be an important addition for patients with higher-risk [MDS], a population of significant unmet need.”

A more comprehensive comparison of this regimen with a matched placebo is underway in the phase 3 ENHANCE trial (NCT04313881) based on these phase 1b findings.

Reference

Sallman DA, Al Malki MM, Asch AS, et al. Magrolimab in combination with azacitidine in patients with higher-risk myelodysplastic syndromes: final results of a phase Ib study. J Clin Oncol. Published online March 8, 2023. doi:10.1200/JCO.22.01794