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

Abstract

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 γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and 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 immune activation and tumor control in late-stage cancer.

Trial registration: ClinicalTrials.gov NCT03733990.

Keywords: Clever-1; GeoMx; Stabilin-1; cancer; first-in-man; immune activation.

Graphical abstract

Figure 1

Bexmarilimab responses in patients showing DC (A) Swimmer plot analysis for treatment durations and tumor responses in melanoma, gastric, and hepatocellular cancer patients of part II. The y axis shows individual patients, x axis time in days from the first bexmarilimab dose. C, cycle number; FU, follow-up visit; SURV, survival visit. Green circle, SD response; red star, PD response; blue asterisk, PD reported as AE; X: death of subject. (B) Kaplan-Meier analysis for PFS (red) and OS (blue). (C) Landmark Kaplan-Meier analysis for OS from cycle four according to PR/SD (red) or PD (blue). (D) Kaplan-Meier analysis for previous therapy line treatment duration (prior entering the trial) according to PR/SD (red) or PD (blue). Circles indicate censored events. y axis, time in days. (E) Baseline levels of IFNγ and TNFα according to DC status. (F) Change of IFNγ levels during the first cycle of treatment according to DC. Error bars represent SE. Blue, non-DC patients; red, DC patients; SE, standard error; ^∗∗p = 0.0056 for difference between DC and non-DC in the change from day 1, repeated measures ANOVA. See also Figures S2, S4, and S6, and Table S4.

Figure 2

GeoMx spatial profiling reveals pro-inflammatory conversion of TAMs in DC patients (A) Schematic for GeoMx spatial transcriptomics profiling of pre- and post-treatment biopsies from non-DC (n = 3 patients, 30 ROIs) and DC (n = 3 patients, 33 ROIs) patients. Representative images of morphology marker staining and corresponding segmentation are displayed for a single ROI. (B) Volcano plot showing differentially expressed genes in DC patient CD68⁺ areas after bexmarilimab therapy. (C) Bubble plots of top up- and downregulated pathways in CD68⁺ tumor areas of DC patients after bexmarilimab therapy (gene set enrichment analysis). (D) Volcano plot showing differentially expressed genes in non-DC patient CD68⁺ areas after bexmarilimab therapy. (E) Bubble plots of top up- and downregulated pathways in CD68⁺ tumor areas of non-DC patients after bexmarilimab therapy (gene set enrichment analysis). (F) Heatmap of M1 and M2 macrophage gene scores on CD68⁺ area. Red color indicates higher M1 or M2 gene expression than overall gene expression, blue color lower. Each tile represents median of patient’s ROIs. (G) Bar graph of M2/M1 score ratios corresponding to scores shown in (F). Each point represents patient median across ROIs and each bar patient group median. (H) Volcano plot showing differentially activated pathways between CD68⁺ areas of non-DC and DC patients’ pre-treatment biopsies (gene set enrichment analysis, n = 16 ROIs [non-DC], n = 10 ROIs [DC]). Pre, pre-treatment biopsy; Post, post-treatment biopsy; ROI, region of interest; P_adj, Benjamini-Hochberg-adjusted p value; ^∗∗P_adj < 0.01; ^∗P_adj < 0.05; ns, not significant. In (C) and (E), red color denotes pathway activation and blue downregulation. See also Figures S7–S9, and Supplementary Data S1 and S2.

Figure 3

Tumor-infiltrating leukocyte infiltration and activation following bexmarilimab therapy in DC patients (A) Volcano plot showing differentially expressed genes in DC patient CD68⁻CD31⁻ areas (n = 3 patients, n = 10 ROIs [Pre] and 23 ROIs [Post]) after bexmarilimab therapy. (B) Bubble plots of top up- and downregulated pathways in CD68⁻CD31⁻ areas of DC patients after bexmarilimab therapy (gene set enrichment analysis). Red color denotes pathway activation and blue downregulation. (C) Bar plots of cell abundancy scores calculated for the indicated immune cell types based on gene expression on CD68⁻CD31⁻ area. Median ± interquartile range, points represent individual ROIs, n = 3 patients per group. (D) Enrichment map of significantly altered pathways (P_adj < 0.05) in CD68⁺ areas of DC patients after bexmarilimab therapy. The map illustrates how these pathways altered upon bexmarilimab therapy on CD68⁺, CD31⁺, and CD68⁻CD31⁻ areas. Red indicates significant upregulation, blue significant downregulation and gray non-significant changes. Circle size represents pathway size and connecting line width represents the proportion of shared dataset genes between two pathways (n = 3 patients). (E) Principal component analysis of pre-treatment biopsy ROIs based on CD68⁻CD31⁻ area gene expression (n = 11,591 genes). (F) Volcano plot showing differentially activated pathways between CD68⁻CD31⁻ areas of non-DC and DC patients’ pre-treatment biopsies (gene set enrichment analysis, n = 16 ROIs [non-DC], n = 10 ROIs [DC]). Top five pathways (lowest P_adj) were annotated. BTC, biliary tract cancer; ER⁺ BRCA, estrogen receptor-positive breast cancer; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; Treg, regulatory T cell; Pre, pre-treatment biopsy; Post, post-treatment biopsy; ROI, region of interest; P_adj, Benjamini-Hochberg-adjusted p value; ^∗∗P_adj < 0.01; ^∗P_adj <0.05; ns, not significant. See also Figure S10, and Supplementary Data S1 and S2.