Background Clever-1 is an immunosuppressive scavenger receptor expressed on tumor-associated macrophages (TAM). High levels of Clever-1 are associated with poor survival, T-cell exclusion and dysfunction, and immunotherapy resistance.1 Bexmarilimab (FP-1305, Bex) is a novel humanized anti-Clever-1 IgG4-antibody capable of promoting an immune switch, potentially leading to intratumoral proinflammatory responses in patients. The ability to predict cancer drug response accurately is important to select patients who will benefit from treatment but to also allow patients who would not benefit the opportunity to have a more appropriate alternative.
Here, we highlight the development of a biomarker plan that allows for both patient selection for future clinical trials as well as confirming the mechanism of action (table 1). This was based on our first-in-human all-comer single agent Phase I/II study in advanced solid tumors; MATINS (NCT03733990) and is to be deployed prospectively in an upcoming Phase II study in combination with approved therapies; BEXCOMBO.
Methods The aim of this first-in-human trial was to study the safety and tolerability of Bex in patients with treatment-refractory solid tumors and to assess preliminarily antitumor efficacy, pharmacodynamics, and immunologic correlates. As part of this study, a plan to monitor and stratify patients and confirm the drug mechanism of action has been completed.
Results In the MATINS trial approximately 30% of subjects achieved immune activation, characterized by a systemic increase in IFNg, which associated with prolonged overall survival in landmark analysis.2 The responding patients had low baseline serum proinflammatory cytokines in comparison to patients not responding to Bex. The response was significantly associated with higher intratumoral Clever-1 positivity. Bex targeting of TAMs was further confirmed by digital spatial profiling (GeoMx), which showed a decrease in M2-like markers and T-cell activation in the responding patients.2
Conclusions Patient selection is important and impacts clinical development of novel agents. Our biomarker approach indicates Bex benefit in patients with low baseline immune activation and demonstrates proof-of-concept of Bex mode-of-action as a macrophage converting drug. While the data are preliminary, they can support a diagnostic/enrichment plan for future development of Bex in prospective and randomised studies.
Trial Registration MATINS (NCT03733990) BEXCOMBO is a study in planning and has not been added to ClinicalTrials.Gov
Hollmen M, Figueiredo CR, Jalkanen S. New tools to prevent cancer growth and spread: a ‘Clever’ approach. BJC. 2020;123:501-509
Rannikko JH, Verlingue L, de Miguel M, et al. Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: the phase I/II first-in-human MATINS trial. medRxiv. 2023. https://doi.org/10.1101/2023.04.17.23288693
Ethics Approval This study has recieved approved from the approporate ethics committees and institutional review boards where required at the multiple sites. These can be requested for review by the Editor of this journal
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