Encouraging Efficacy of Bexmarilimab with Azacitidine in Relapsed or Refractory MDS in Bexmab Ph1/2 Study
Authors: Kontro Mika , Stein Anthony S. , Pyörälä Marja , Rimpiläinen Johanna , Siitonen Timo , Rannikko Jenna H , Mickos Jesper , Turpin Rita , Hakoniemi Milja , Berns Birge , Aakko Sofia , Pawlitzky Inka , Hollmén Maija , Zeidan Amer M. , Daver Naval 
Published: December 2024

Introduction
Treatment of myelodysplastic syndrome (MDS) with primary refractory disease or relapse after frontline treatment (r/r MDS) represents a high unmet medical need. Hypomethylating (HMA) agents, including azacitidine, are used in the frontline setting for higher-risk (HR) MDS patients with response rate reported as 16%1. After HMA-failure, the median overall survival (mOS) is poor, with 5.6 months.2 Bexmarilimab, a macrophage checkpoint inhibitor, blocks Common lymphatic and vascular endothelial receptor-1 (Clever-1) to enhance macrophage antigen presentation and T cell activation. In myeloid malignancies, Clever-1 is also abundant on myeloid blasts. Pre-clinical data suggests that by blocking Clever-1 on blasts, bexmarilimab hampers the energy production of the malignant cells, allowing enhanced killing of generally resistant blasts by cytotoxic agents, such as HMAs. Thus, bexmarilimab may alter the bone marrow (BM) microenvironment making the blasts susceptible to other available therapies, thereby enhancing their effectiveness in patients with MDS, including r/r MDS.
Methods
As of 15 May 2024, 14 patients with r/r MDS were enrolled in the ongoing Phase 1 dose escalation and Phase 2 dose optimization of the BEXMAB study (NCT05428969). All patients had IPSS-R &gt;3.5 and 7/14 were TP53 mutated. Bexmarilimab was administrated weekly in 28-day cycles, at 1,3, and 6 mg/kg, in combination with a standard regimen of azacitidine (75 mg/m2 D1-7 each cycle). Bayesian optimal interval (BOIN) design was used for dose escalation and r/r MDS was selected as the population for dose optimization and expansion following a Simon's 2-stage design. The primary objectives of the study are to evaluate safety, tolerability, and preliminary efficacy of bexmarilimab plus azacitidine. BM was evaluated at the end of Cycles 1, 3 and then every third cycle for response and exploratory biomarkers.
Results
Altogether, 113 treatment-emergent adverse events (TEAE) were reported, of which 74 (65%) were grade 1-2. Seventeen serious adverse events (SAE) were reported from 7 r/r MDS patients, with febrile neutropenia as most frequent event (n=9). Four bexmarilimab-related events were reported from 3 r/r MDS patients (fever, infusion related reaction, intermittent nausea and peripheral edema), all grade 1.
The objective response rate (ORR) was 79% in r/r MDS patients (11/14). The responses consisted of 1 complete remission (CR), 7 marrow CRs (mCR), 1 partial response (PR) and 2 hematological improvements (HI). In addition, 2 responses of stable disease (SD) and 1 progressive disease (PD) were reported. Clinical activity was observed across all dose levels. Two patients proceeded to allogenic stem cell transplantation. The current median overall survival estimate (mOS) for the 14 Phase 1 r/r MDS patients is 13.4 months.
Supporting our hypothesis of modulation of the BM microenvironment, the expression of human leukocyte antigen DR isotype (HLA-DR), was increased up to 6-fold on BM monocytes upon treatment. In addition, the number of CD4 and CD8 T cells was increased in the BM compared to baseline in 50% and 75% of patients, respectively. Both HLA-DR and T cell increases were observed in most patients after one treatment cycle. For further insight on the MoA of bexmarilimab plus azacitidine in r/r MDS, single-cell RNA sequencing analysis of pre- and post-treatment (Cycle 1 and 3) BM samples is ongoing. Preliminary data suggest significant changes in the expression of genes related to blast cell energy production and macrophage activity induced by bexmarilimab and azacitidine treatment.
Conclusions
Bexmarilimab plus azacitidine is well tolerated and results in promising clinical efficacy in r/r MDS patients after HMA failure.
1 Hasegawa et al. Azacitidine Monotherapy in Patients With Treatment-Naïve Higher-risk Myelodysplastic Syndrome: A Systematic Literature Review and Meta-analysis.Clin Lymphoma Myeloma Leuk. 2023.
2 Prébet et al. Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure. J Clin Onc. 2011.