P542: a phase i/ii study to assess safety, tolerability and preliminary efficacy of bexmarilimab in combination with standard of care in patients with myeloid malignancies (bexmab)

Background: Clever-1 constitutes a novel macrophage checkpoint. Its expression in AML BM cells is a prognostic factor for poor outcome and its suppression inhibits leukemia cell growth (1). Analyses suggests lower expression is associated with venetoclax sensitivity (2). Bexmarilimab (BEX), a humanized IgG4 monoclonal antibody, binds Clever-1 and alters the function of macrophages. BEX has been shown to increase antigen presentation, induce secretion of proinflammatory cytokines and increase activation of T cells (3). The therapeutic potential of BEX is supported by data from the MATINS study (NCT03733990) evaluating single agent activity in advanced solid tumors (n>200) that showed good tolerability as well a clinical activity. Recent data show that Clever-1 is expressed at high levels on malignant blasts and monocytes of AML and MDS patients. Treatment of AML bone marrow cells with BEX alone or in combination with azacitidine/venetoclax results in enhanced antigen presentation capacity and increased activation markers on effector T cells with synergistic effects (4). Aims: The PhI/II study evaluates safety, tolerability and preliminary efficacy of BEX plus standard of care in frontline or hypomethylating agent (HMA) failed MDS/CMML patients, newly diagnosed AML or in relapsed/refractory AML patients. Analyses of parameters for immunological and cellular read-outs and the association of predictive biomarker for BEX clinical activity in patient sub-groups is part of the exploratory endpoints. Methods: BEXMAB (NCT05428969) consists of a dose escalation PhI using a Bayesian Optimal Interval (BOIN) design to explore 4 dose levels of BEX in cohort sizes of n=5 with 1mg/kg as starting dose. BEX plus azacitidine (doublet) is assessed in a mixed cohort of MDS, CMML frontline and HMA-failure patients or r/r AML patients. Dose determination may then be performed in separate indications. BEX plus azacitidine/venetoclax (triplet) will follow a similar BOIN design for dose determination in patients with newly diagnosed AML unfit for induction chemotherapy. BEX is dosed in 28-day cycles Q1W during cycles 1-3 followed by Q2W dosing, until disease progression or intolerable toxicity. Standard of care therapy is administered as per label. During PhII, selected indications are explored for efficacy when BEX is administered at recommended phase 2 dose (RP2D) following a 2-Stage design with indication-specific target efficacy rates. Key eligibility includes patient ≥ 18 years of age presenting with morphologically confirmed diagnosis of either MDS (intermediate-very high rIPSS risk), CMML-2 with indication for azacitidine treatment; CMML and MDS patients with failure to HMA therapy, confirmed diagnosis of r/r AML following at least 1 prior treatment line or diagnosis of AML in patients unfit for induction therapy with indication for azacitidine/venetoclax. Approximately up to 181 patients at 10 US and EU sites will be enrolled. Results: As of 13Feb2023, 14 patients have been treated with BEX in the 1 and 3mg/kg doublet cohorts (n=5 each) and the 1mg/kg triplet cohort (n=4). The majority of AEs are Grade 1-2 and no bexmarilimab-related Grade ≥3 AEs or DLTs have been reported. Preliminary efficacy of the 1mg/kg doublet patients showed CR in frontline MDS, PR in HMA failure MDS, CRi in r/rAML and SD in r/r AML (n=2). Biomarker data (n=4) shows up to 70% reduction of sClever-1 in blood and decreased Clever-1 expression on BM blasts after BEX treatment in patients of the 1mg/kg doublet cohort. Summary/Conclusion: The initial data show that BEX treatment is well-tolerated without additional toxicity to standard treatment. Preliminary efficacy shows 3 responses out of 5 patients in the first dose cohort. The study is ongoing.Keywords: Acute myeloid leukemia, MDS, Macrophage, Immunotherapy