Abstract C041: Antitumor and immunomodulatory activity of ARV-6723, a PROteoloysis TArgeting Chimera (PROTAC) hematopoietic progenitor kinase 1 (HPK1) degrader, across high- and low-immunogenic solid tumors

Abstract HPK1 (MAP4K1), a protein kinase broadly expressed across immune cells, has key immunomodulatory functions. In T cells, HPK1 negatively regulates T cell receptor–mediated signaling and contributes to T-cell exhaustion, findings that have driven the clinical development of several small-molecule HPK1 inhibitors (HPKi). Beyond its catalytic activity, HPK1 exhibits kinase-independent scaffolding and regulatory functions in myeloid and innate immune cells, supporting the rationale for targeting HPK1 through PROTAC-mediated degradation. Tumor efficacy and mechanistic studies were performed to characterize ARV-6723, as a single agent or combined with an anti-mouse programmed death-1 (PD-1) antibody, and to compare its activity with a clinical HPK1i in syngeneic tumor models. The murine colon cancer model CT26 served as a highly immunogenic model, due to its robust immune cell infiltration and sensitivity to anti-PD-1 therapy. The murine melanoma model B16F10 and murine pancreatic cancer model KPCY (KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx1-Cre;Rosa26YFP/YFP-cl.2699) were employed as low-immunogenic models, characterized by T-cell exclusion and resistance to anti-PD-1 therapy. Flow cytometry of tumor-infiltrating lymphocytes and transcriptome analyses were used to elucidate the mechanisms underlying the differential biology of ARV-6723. In the CT26 model, ARV-6723 (30 mg/kg orally [PO] once daily [QD]) showed robust tumor growth inhibition (TGI; 88%; P<0.001) vs marginal activity with the clinical HPK1i (75 mg/kg PO QD; TGI 33%). In the B16F10 model, ARV-6723 (30 mg/kg PO twice daily) achieved significant efficacy (TGI 79%; P<0.001) compared with minimal HPK1i activity (TGI 13%). In the KPCY-cl.2699 model, ARV-6723 (30 mg/kg PO QD) yielded 89% TGI (P<0.01) as a single agent and 96% TGI (P<0.01) when combined with an anti-PD-1 antibody, whereas neither the anti-PD-1 antibody nor HPK1i alone had antitumor activity (P>0.05). Flow cytometry revealed differential immunomodulatory activity with ARV-6723 not seen with the HPK1i or anti-PD-1 antibody, including increased tumor infiltration of Ly6Chi macrophages and activated natural killer cells, and decreased infiltration of neutrophils and B cells. Furthermore, whole transcriptomic analysis revealed significant gene expression pathway changes suggesting increased T-cell activation, interferon-gamma signaling, and antigen presentation with ARV-6723 treatment, and comparatively modest transcriptomic changes with HPK1i treatment. These data demonstrate the superior antitumor efficacy of ARV-6723 compared with single-agent anti-PD-1 antibody or a clinical HPK1i across a range of immunological settings. Mechanistic interrogation revealed distinct biologic activity of ARV-6723, suggesting a broader immunomodulatory role driven by HPK1 protein degradation compared with HPK1 inhibition. These findings support further investigation of ARV-6723 in multiple therapeutic settings, including where robust immunomodulation of the tumor microenvironment is needed for efficacy, eg, the setting of immunotherapy resistance. Citation Format: Anna C. Van Acker, William L. Corwin, Albert DeBerardinis, Emma Rousseau, Rebecca Conrad, Morena Scopel, Christopher Kuhlberg, Gregory Cadelina, Kim Davenport, Wendy Wu, John Corradi, Jennifer Pizzano, Keith R. Hornberger, Angela M. Cacace, Sean Landrette, XiaoZhe (Janet) Wang, Ignacio J. Juncadella. Antitumor and immunomodulatory activity of ARV-6723, a PROteoloysis TArgeting Chimera (PROTAC) hematopoietic progenitor kinase 1 (HPK1) degrader, across high- and low-immunogenic solid tumors [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C041.