Efficacy of macrophage checkpoint Clever-1 inhibition with bexmarilimab plus azacitidine in myelodysplastic syndrome: Results from the ph1/2 BEXMAB study.

6513 Background: Treatment of higher-risk (HR) myelodysplastic syndrome (MDS) represents an unmet medical need. Hypomethylating (HMA) agents, including azacitidine, are used in the frontline setting for HR MDS patients with complete remission rate reported as 16% (Hasegawa et al., 2023) After HMA-failure, including primary refractory disease or relapse after frontline treatment (r/r MDS), the reported median overall survival (mOS) is <6 months (Prébet et al., 2011). Bexmarilimab, a first-in-class macrophage checkpoint inhibitor, blocks Common lymphatic and vascular endothelial receptor-1 (Clever-1) to enhance macrophage antigen presentation and T cell activation. In the MDS bone marrow (BM), Clever-1 is also abundant on malignant blasts. Translational data suggest that by inhibiting blast Clever-1, bexmarilimab hampers the energy production of the malignant cells. Thus, bexmarilimab may alter the BM immune microenvironment and make the blasts susceptible to other cytotoxic agents, such as HMAs, thereby enhancing their effectiveness in patients with HR MDS, both in frontline and r/r setting. Methods: The Phase 1/2 (Ph1/2) BEXMAB study investigates safety, tolerability and preliminary efficacy of bexmarilimab in combination with standard-of-care, azacitidine, in HR MDS. Key inclusion criteria include indication for azacitidine treatment with a risk score of >3 based on the revised International Prognostic Scoring System (IPSS-R) and for r/r MDS, failure to achieve response to or disease progression during treatment with HMA or HMA containing regimen. In Ph1, Bayesian optimal interval (BOIN) design was used for dose escalation to identify recommended dose for expansion (RDE). Ph1 studied 1, 3 and 6mg/kg bexmarilimab, administrated weekly in 28-day cycles, in combination with a standard regimen of azacitidine (75 mg/m 2 D1-7 each cycle). r/r MDS was selected as the first population for Ph2 dose optimization and expansion following a Simon’s 2-stage design, with subjects randomized to RDE (6mg/kg) and RDE-1 (3mg/kg). After dose escalation, Ph1 expansion cohorts were used to enrich frontline MDS population at RDE and RDE-1. Results: Safety and efficacy data from 20 frontline HR MDS and 35 r/r MDS patients, comparing bexmarilimab dose levels, will be reported. Previous analysis per IWG2006 criteria indicated an overall response rate (ORR) of 100% in 5 frontline MDS patients and 80% in 20 r/r MDS patients (65% per IWG2023). Simultaneously, a median overall survival estimate of 13.4 months, was reported for the r/r MDS population. During dose escalation, no dose limiting toxicities (DLT) were reported during the 28-day DLT period. Ongoing safety follow-up indicates a total of 277 treatment-emergent adverse events, of which 38 (13.7%) are considered bexmarilimab-related. Conclusions: Enrolment for both dose finding and randomized dose optimization parts (n=55) of the BEXMAB Phase 1/2 study has been completed. Safety and efficacy results for both populations will be reported for the first time. Clinical trial information: NCT05428969 .