Abstract LB401: Bemcentinib and pembrolizumab may overcome exhaustive immune phenotypes in patients with treatment refractory lung adenocarcinoma and reveals a potential STAT3 bypass mechanism
Authors: Chia-Nung Hung, Daniel T. DeArmond, Jason M. Gauthier, Michael J. McGinity, Catherine Limboy, Meizhen Chen, Yajaira Esmeralda Mendoza-Plata, Jordy Urbina, Jacobo Louis Garza, Joel E. Michalek, David Micklem, Akil Jackson, Michael Chisamore, Tim H.M. Huang, Josephine A. Taverna
Journal: Cancer Research (2025)

Abstract Background: AXL expression in metastatic lung adenocarcinoma (LAC) promotes cancer cell survival, metastasis and engenders immune-suppressive tumor microenvironments. Immune cells (CD4+/CD8+ T cells, NK and NKT cells) become dysfunctional with reduced expression of granzyme B, resulting in impaired cytotoxicity. Bemcentinib (BEM), a selective oral AXL inhibitor, may enhance pembrolizumab (PEM) to restore cytotoxic T cell function in mouse models of LAC. We hypothesize that AXL-PD1 targeting may overcome immune exhaustion in LAC patients who previously failed chemoimmunotherapy. Methods: Peripheral blood monocytes (PBMC; n = 4,439,600 live cells) from 29 LAC patients enrolled in BGBC008 phase 2 open-label, single-arm study of BEM+PEM (NCT03184571) were collected at different treatment time points, analyzed by CyTOF using the Phenograph algorithm and visualized by tSNE plots. Immune cell type proportions and immune cell activation were calculated before and after treatment. Separately, we tested whether adding targeting of the JAK2/STAT3 pathway (an AXL bypass mechanism) with pacritinib, a selective JAK2 inhibitor with no JAK1 activity, can further inhibit tumor growth compared with targeting AXL-PD1 alone, in a C57BL/6 syngeneic mouse D19.1 LAC model. Results: BEM + PEM led to immune cell responses following cycle 1 treatment in LAC patients previously treated with chemo-immunotherapy. Specifically, we observed a reduction in monocytes/macrophages (p=0.0134), CD123+ plasmacytoid dendritic cells (DC; p=0.0009), cDC1 (p=0.0009), and myeloid dendritic cell populations (p = 0.0073). Combination treatment led to a reduction in M2-polarized macrophages (reduced CD206 &amp; CD163 levels), re-activation of cDC1 (high CD40 expression) and reduction in CD8+ T cell exhaustion (high granzyme B levels). Fold-change of granzyme B in CD8+ NKT cell populations positively correlated with progression free survival (PFS) (n = 29, Cor = 0.295). Additionally, high phospho-STAT3 expression in macrophages may correlate with poor PFS, supporting our previous research suggesting that pSTAT3 is a bypass mechanism of AXL signaling. In a syngeneic LAC mouse model, triple combination therapy targeting the JAK2/STAT3 pathway in addition to AXL and PD-1 resulted in 55% and 90% tumor size reduction and two-fold increase in CD8+ T cell infiltration when compared with AXL/PD-1 dual combination treatment and untreated control groups, respectively. Conclusion: CyTOF data suggest that AXL-PD1 drug targeting may overcome immune cell exhaustion and re-activate CD8+ T cell, cDC1 and NKT cells in treatment refractory LAC patients treated with BEM+PEM. Granzyme B expression in PBMCs may serve as a biomarker of treatment response. Furthermore, in vivo drug targeting of AXL-PD1-STAT3 axis demonstrates significant synergy in a syngeneic LAC mouse model, showing a strong potential for future clinical trials. Citation Format: Chia-Nung Hung, Daniel T. DeArmond, Jason M. Gauthier, Michael J. McGinity, Catherine Limboy, Meizhen Chen, Yajaira Esmeralda Mendoza-Plata, Jordy Urbina, Jacobo Louis Garza, Joel E. Michalek, David Micklem, Akil Jackson, Michael Chisamore, Tim H.M. Huang, Josephine A. Taverna. Bemcentinib and pembrolizumab may overcome exhaustive immune phenotypes in patients with treatment refractory lung adenocarcinoma and reveals a potential STAT3 bypass mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB401.