Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: the phase I/II first-in-human MATINS trial

Clever-1 expression in macrophages contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial was designed to investigate the safety and tolerability of Clever-1 blockade in patients with treatment-refractory solid tumors and to assess preliminary anti- tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab was well tolerated with no observed 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% were observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor positive breast, and biliary tract cancers, which associated with improved survival in a landmark analysis. High pre-treatment intra-tumoral Clever-1 staining and low circulating TNFα correlated with DC. Digital spatial profiling of DC and non-DC tumors with next generation sequencing showed bexmarilimab-induced macrophage activation and robust stimulation of IFNγ 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 tumor control in late stage cancer. Highlights Targeting Clever-1 with bexmarilimab is well tolerated Disease control in late stage cancer can be achieved with bexmarilimab monotherapy Low baseline immune activation associates with bexmarilimab benefit Bexmarilimab converts intratumoral macrophages to support adaptive immune responses