Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: the phase I/II first-in-human MATINS trial
Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n=30) and no additional safety signals in part II (n=108). Disease control (DC) rates of 25%-40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon ? (IFN?) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFN? and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer. Overall design: Spatial transcriptomics profiling of pre- and post-treatment biopsies from MATINS trial patients with observed disease control (DC, n = 3) and without observed disease control (nDC, n = 3). Transcriptomes of macrophages (CD68+), vessels (CD31+) and remaining tumor area (CD68-CD31-) were analyzed separately from each region of interest using GeoMx Digital Spatial Profiler and GeoMx Human Whole Transcriptome Atlas (NanoString).