Efficacy, molecular and translational analysis of TP53-mutated HR-MDS with bexmarilimab and azacitidine: Updated results from the bexmab Phase 1/2 study

Abstract

Abstract Introduction Bexmarilimab is a novel macrophage checkpoint inhibitor targeting Clever-1, a scavenger receptor expressed on malignant blasts and monocytes in myelodysplastic syndromes (MDS) bone marrow (BM). Tumor protein 53 (TP53) is mutated in 5-10% of de novo and in 30-40% of therapy-related MDS and is a frequent molecular abnormality in higher risk (HR) MDS. Mutated TP53 (mTP53) is a poor prognostic factor and treatment of mTP53 HR MDS represents a high unmet medical need. Hypomethylating (HMA) agents, including azacitidine are standard of care for mTP53 MDS, with complete response (CR) rate of 15-20% regardless of TP53 mutation, but mTP53 HR-MDS is associated with shorter responses, inferior median overall survival (OS) and high rate of relapse even after stem cell transplant (SCT) (Santini et al., 2024). BM immune system dysregulation, especially in the myeloid compartment, including defective antigen presentation has been suggested to be a driver for the poor prognosis in mTP53 MDS (Zambini et al., 2025). Bexmarilimab enhances macrophage antigen presentation and T cell activation. Thus, bexmarilimab may favourably alter the dysregulated BM immune microenvironment in mTP53 MDS. Simultaneously, bexmarilimab can increase the efficacy of cytotoxic agents, such as HMAs, by targeting Clever-1 on malignant blasts and altering energy production of the malignant cells. Aims 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, including mTP53 disease. Methods Twenty-one treatment-naïve and 32 HMA r/r MDS patients have been recruited in the BEXMAB study. Key inclusion criteria include indication for azacitidine treatment with a risk score of >3 based on IPSS-R and for r/r population, failure to achieve response after 4 cycles or disease progression during treatment with HMA or HMA containing regimen. Bexmarilimab (1-6mg/kg in Ph1; 3 or 6mg/kg in Ph2) was administrated weekly in 28-day cycles, in combination with a standard regimen of azacitidine (75 mg/m2 D1-7 each cycle). BM response was assessed at the end of cycles 1-6, followed by every third cycle, per IWG2006 (investigator assessment) and IWG2023 (central assessment) criteria. TP53 mutation status was analysed per local practice. Results From the treatment-naïve HR MDS and r/r MDS patients, 43% and 41%, respectively, had mTP53. TP53 mutation was biallelic in 67% of treatment-näive and 62% of r/r MDS patients. Preliminary overall response rates (ORR) with bexmarilimab and azacitidine (IWG2006) in treatment-naïve HR MDS are 78% in mTP53 (biallelic ORR: 83%) and 91% in wt TP53. Composite CR (cCR) rates per IWG2023 criteria are 44% (biallelic cCR: 50%) and 55% in mTP53 and wt, respectively. In r/r MDS, preliminary ORR (IWG2006) are 46% in mTP53 (biallelic ORR: 38%) and 74% in wt TP53. Composite complete response (cCR) rates per IWG2023 criteria are 8% (biallelic cCR: 13%) and 21% in mTP53 and wt. Median OS estimate in r/r MDS is 13.4 months, with 9.3 months in mTP53 subgroup (wt TP53; not reached). Six (27%) mTP53 patients have received SCT, of which four are still in follow-up. Updated response data from November 2025, including duration of response, will be reported from mTP53 and wt groups. Translational correlates have shown favorable immune activation in the BM with bexmarilimab plus azacitidine, including increased number of cytotoxic CD8 T cells and antigen-presenting molecule (human leukocyte antigen DR isotype) expression in flow cytometry and single-cell RNA sequencing analyses. Updated translational data comparing immunoprofiles and changes in pharmacodynamic markers in wt and mTP53 MDS after bexmarilimab plus azacitidine treatment, will be reported. Conclusion Bexmarilimab plus azacitidine shows encouraging activity in mTP53 HR MDS and translational data supports potential for altering the immune dysregulation in mTP53 MDS. Updated clinical and translational data will be reported.