Please “Eat me”: Can Magrolimab Put Higher-risk MDS Back on the Immunologic Menu?

Study Title: ENHANCE: A Randomized, Double-blind, Multicenter Study Comparing Magrolimab in Combination with Azacitidine versus Azacitidine Plus Placebo in Treatment-naïve Patients with Higher Risk Myelodysplastic Syndrome

Clinicaltrials.Gov Identifier: NCT04313881

Sponsor: Gilead Sciences, Inc.

Accrual Goal: This clinical trial plans to enroll approximately 520 participants, randomized 1:1 to the experimental or control arm.

Participating Centers: The study is currently open at 53 locations, planned for as many as 200 sites across the United States, Australia, and Europe.

Study Design: This trial is enrolling previously untreated adult patients (≥ 18 years of age) with intermediate-, high-, or very high-risk myelodysplastic syndrome (MDS) as defined by the Revised International Prognostic Scoring System (IPSS-R). This is a randomized, double-blind, placebo-controlled, international multicenter phase III trial in which participants are randomized (1:1) to receive either magrolimab in combination with azacitidine (experimental arm) or azacitidine plus placebo (control arm) as frontline therapy. Subjects will continue therapy until disease progression, loss of clinical benefit, or unacceptable toxicities occur. Participants are stratified according to 1) geographic region (U.S. vs. non-U.S. sites); 2) cytogenetic risk status; and 3) percentage of bone marrow blasts (≥ 10% vs. < 10% blasts). The primary objectives are to compare complete remission (CR) and overall survival (OS) rates between the combination arm and the monotherapy arm.

Rationale: Azacitidine is a long-standing but mediocre standard-of-care treatment for newly diagnosed high-risk MDS throughout the world. Single-agent treatment results in modest CR rates, and OS remains limited at only around 18 months.¹  Thus, there exists a pressing need for novel, effective therapies for MDS. In the current higher-risk arena, the standard trial design is to compare a new agent combined with a hypomethylating agent, to azacitidine monotherapy. The goal for the patients is improved response rate with maintenance of an adequate safety profile.

Magrolimab is a first-in-class macrophage immune checkpoint inhibitor that targets CD47, a key molecule mediating cancer cell evasion of phagocytosis by the innate immune system.²  CD47 appears to be an indispensable means by which cancer cells and cancer stem cells subvert the intrinsic expression of the prophagocytic “eat me” signal.^3,4  In preclinical models, blockade of CD47 via magrolimab led to phagocytosis and elimination of tumor cells. Furthermore, the combination of magrolimab with azacitidine resulted in synergy based upon the upregulation of prophagocytic signals including calreticulin on leukemic cells by azacitidine, combined with blockade of the antiphagocytic signal with magrolimab.⁵  A phase Ib single-arm study in untreated intermediate- to very high-risk MDS using this combination resulted in an overall response rate (ORR) of 92 percent and a CR rate of 50 percent in 24 patients with an acceptable safety profile.⁶  It has also been suggested that this combination has improved performance in TP53-mutated myeloid disease, another significant unmet MDS clinical need. This current placebo-controlled and double-blinded study will establish whether the combination of magrolimab and azacitidine will improve clinical activity and maintain an acceptable safety profile.

Comment: The investigators of ENHANCE aim to determine if the addition of a novel macrophage immune checkpoint inhibitor to azacitidine monotherapy will improve clinical efficacy without added toxicity, which would be a very welcome development given the dearth of progress for patients with this disease. The preclinical rationale for this combination is certainly enticing, as CD47 is upregulated in several cancers including acute myeloid leukemia (AML)/MDS as well as on leukemic stem cells, which may be further enhanced via azacitidine-induced calreticulin upregulation. Results from the phase Ib study (5F9005) demonstrated impressive outcomes as compared to either single-agent azacitidine or decitabine, which have historically demonstrated CR rates of approximately six to 17 percent and a median OS of only 18 months.^1,7  Importantly, combination therapy did not result in significant neutropenia or thrombocytopenia, with the majority of patients improving their neutrophil and platelet counts while undergoing therapy. There were also no significant increases in infection rates or immune-related adverse events.⁶  There exists a potential for on-target anemia induced by the pharmacodynamic effect of treatment with magrolimab, which can be mitigated by an initial priming dose that has been incorporated into the current phase III study. In fact, most patients on 5F9005 had a significant hemoglobin improvement and decrease in transfusion frequency over time.⁶  The ENHANCE study aims to expand upon these impressive results with the phase III, randomized, placebo-controlled, double-blinded study described herein.

In 2021 there are more phase III studies in higher-risk MDS than ever. This means competition for patient accrual and for validation as a new standard of care. The trials all share a similar design in their phase III registration studies with the novel product in combination compared to single-agent azacitidine. Each trial has reasonable earlier phase data, usually in both AML and higher-risk MDS, upon which they have based their current clinical investigations. Venetoclax (NCT04401748) will be studied in higher-risk MDS at a truncated dosing schema (14 days) relative to its AML trials. NCT04266301, studying dual targeting of immune effectors and leukemic cells by sabatolimab, is also a trial enrolling the same higher-risk patients. Finally, SY-1425, a selective RARα agonist called tamibaterone, is part of a biomarker driven study (NCT04797780) of those patients with MDS who overexpress RARα. These trials have the benefit of learning from previous combination trials in the MDS arena^8–10  where the field has yet to see replication of phase I or II results in a later-phase randomized trial. There is now greater attention than ever to non-overlapping and cumulative toxicities between azacitidine and its trial partner. Additionally, there is also keen awareness to avoid underdosing azacitidine, which may have compromised response and survival in combination arms in past protocols. Magrolimab has a combined endpoint with two clinically meaningful metrics, CR and OS, which will be valuable to the field. Its accrual may complete in the most efficient fashion amongst all the trials. The field is eager for doublets, and some are even thinking triplets, when we find combinations with complementary mechanisms of action. The ENHANCE phase III, randomized, placebo-controlled, double-blinded study with magrolimab in higher-risk MDS is well positioned for success. It is adequately powered to demonstrate an improvement in CR and OS as dual primary endpoints without marked added toxicity in the higher-risk group. Within this “smorgasbord” of options, the higher-risk MDS community has a great deal of hope for the next era of therapeutics, including immunotherapy.