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

Abstract

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.

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization

“…Tumor-infiltrating macrophages play a critical role in promoting tumor growth, immune evasion, and therapeutic resistance 5,101 highlighting macrophages as a promising target for therapeutic intervention 10,[102][103][104][105][106][107][108] . In solid tumors, including breast cancer, tumor-infiltrating macrophages undergo two fundamental phenotypic alterations; (i) they adopt wound healing-associated activities in response to complex microenvironmental signals 16,99 , and (ii) regain their proliferative capacity in response to mitogenic signals to accumulate in situ 12,45 .…”

Bexmarilimab Activates Human Tumor-Associated Macrophages to Support Adaptive Immune Responses in Interferon-Poor Immune Microenvironments

“…Tumor biopsies were obtained from participants of the first-in-human phase I/II MATINS trial investigating bexmarilimab therapy ( 13 ). The trial was run according to Good Clinical Practice and the Declaration of Helsinki, and approved by local institutional review boards and national medicinal agencies (NCT03733990, EudraCT 2018–002732–24); written informed consents were obtained from the participants.…”