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