Magrolimab Plus Azacitidine Achieves Complete Responses in Higher-Risk MDS

David Sallman, MD

The combination of magrolimab plus azacitidine (Onureg) demonstrated promising efficacy and safety in a phase 1b trial (NCT03248479) of patients with higher-risk myelodysplastic syndrome (MDS), according to a report published in the Journal of Clinical Oncology.¹

The open-label, multicenter, single-arm study of 95 patients with intermediate or higher-risk previously untreated MDS met its primary efficacy end point with a complete remission (CR) rate of 32.6% (95% CI, 23.4-43.0), and the combination was well tolerated.

“This phase 1b study represents the largest, most comprehensive data set for magrolimab with azacitidine in myeloid malignancies,” David A. Sallman, MD, lead study author and associate member of the malignant hematology department at Moffitt Cancer Center, said in a press release.²

Higher-risk MDS has survival rates below 2 years and is associated with poor outcomes including a high likelihood of developing acute myeloid leukemia (AML).² Treatment options for MDS include hypomethylating agents such as azacitidine. Investigators hypothesized that magrolimab, a monoclonal antibody that binds to CD47, would block signals that prevent immune cells from killing cancer cells, and this immune response would be enhanced by azacitidine.

The phase 1b trial enrolled 95 patients including with 26 with intermediate risk (27.4%), 49 with high risk (51.6%), and 20 with very high (21.1%) prognostic scores.¹ The median age was 69, and 69.5% had ECOG performance scores of 1 or 2, versus 30.5% with a score of 0. Poor-risk cytogenetics were present in 62.1% and 27.4% had complex cytogenetics. Twenty-five patients (26.3%) had a TP53 mutation.

The study included a safety run-in cohort with a standard 3 + 3 design to determine the best dosing approach and dose-limiting toxicities, followed by a dose expansion phase. In the expansion phase, patients received an intravenous magrolimab 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, followed 30 mg/kg once weekly in the initial expansion cohort or once every 2 weeks in the additional expansion cohort beginning in cycle 3. Azacitidine was administered at 75 mg/m2 once daily in the first week of a 28-day cycle. Treatment continued until unacceptable toxicity, progression, or death.

The primary end points included CR rate, duration of CR, rate of occurrence of adverse events (AEs), and independence from red blood cell transfusions. Secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The most common treatment-emergent adverse events (TEAEs) of any grade included were constipation in 68.4% of patients, thrombocytopenia in 54.7%, anemia in 51.6%, neutropenia in 47.4%, nausea in 46.3%, and diarrhea in 43.2%. The most common grade 3/4 TEAEs were anemia in 47.4%, neutropenia in 46.3%, and thrombocytopenia in 46.3%. Grade 3 anemia related to magrolimab was observed 34.7% of patients, though a significant portion of these patients had anemia at baseline. TEAEs led to dose interruptions of magrolimab and azacitidine of 52.6% and 49.5%, respectively, and led to discontinuation of treatment in 10 patients (10.5%).

The overall response rate was 74.7% (95% CI, 64.8-83.1). The median DOR was 9.8 months (95% CI, 8.8-12.9) and the median duration of complete response was 11.1 months (95% CI, 7.6-13.4). Minimal residual disease (MRD) negativity by flow cytometry was achieved in 41.9% of those who had CRs. Thirty-seven patients (38.9%) were transfusion dependent at baseline, and 13 of these (35.1%) became transfusion independent with a median duration of 5.2 months (range, 1.9-18.0) as of data cut-off.

At 17.1 months median follow-up, median PFS was 11.6 months (95% CI, 9.0-14.0) and median OS was not reached (95% CI, 16.3-not reached). Fourteen patients (14.7%) progressed to AML with a median time to progression of 26.0 months (95% CI, 26.0-not reached). Ten patients with a TP53 mutation (40%) had a CR. A complete cytogenic response was achieved in 19 of 47 (40.4%) evaluable patients with abnormal cytogenetics, and 12 out of 26 patients with complex cytogenetics(46.2%) achieved a complete cytogenic response.

At data cut-off, only 4 patients remained on treatment with 40 in follow-up. Discontinuation of treatment was due to progressive disease in 30.5%, AEs in 13.7%, patient decision, physician decision, or lack of efficacy in 5.3% each, consent withdrawn in 4.2%, and discontinuation due to receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in 35.8%.

In the 34 patients who went on to receive allo-HSCT, median OS was not reached. The investigators noted that historically, less than 10% of patients with MDS proceed to allo-HSCT, and they believed that deep MRD responses would improve OS with allo-HSCT. Investigators considered the combination’s potential to enable allo-HSCT for 4 patients with a TP53 mutation a promising development for these patients that they intend to monitor in expanded studies.

“These phase 1b trial results helped us launch a larger phase 3 randomized trial called ENHANCE [NCT04778397] evaluating magrolimab plus azacitidine versus placebo plus azacitidine,” said Sallman.² “If our results are confirmed, this would become our new standard-of-care treatment approach for patients with high-risk MDS moving forward and we eagerly await the readout of this study.”

_REFERENCES

_{1. Sallman DA, Malki MM, Asch AS, Wang ES, Jurcic JG, Bradley TJ. 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 08, 2023. doi: 10.1200/JCO.22.01794}

_{2. Magrolimab plus azacitidine results in promising activity in higher-risk MDS patients. News release. Moffitt Cancer Center. March 9, 2023. Accessed March 13, 2023. https://bit.ly/429NHW9}