Abstract P5-05-30: Unlocking the Therapeutic Potential of T DXd Enhertu Mechanisms of Action in HER2 Low Cancers and Immunomodulatory Effects

Abstract T-Dxd (Enhertu) is a novel antibody-drug-conjugate (ADC) targeting HER2, which has demonstrated profound clinical efficacy across breast cancers (BC) and other cancers exhibiting varying degrees of HER2 expression. However, the precise mechanism underlying its efficacy in HER2-low cancers and the role of Fc-mediated immune activation in its efficacy remain unclear. Using bystander killing studies and pharmacokinetic assessment of its payload, Deruxtecan (Dxd), we found that T-Dxd efficacy in HER2-low and HER2-negative cancers was mediated by extracellular cathepsin L proteases within the tumor microenvironment (TME). This unique mechanism enables broader Dxd cytotoxicity, bypassing traditional ADC-resistance mechanisms like HER2 downregulation and resistance to ADC-internalization. Significantly, our studies revealed that the Dxd cytotoxic payload induces immunogenic cell death (ICD) with the secretion of specific Damage-Associated Molecular Patterns that activate myeloid cells through TLR4 and STING pathways. Additionally, the T-Dxd antibody backbone retains the capability to engage with Fcγ-receptors to stimulate Antibody-Dependent Cellular Phagocytosis (ADCP) that enhances tumor antigen uptake, which in concert with ICD responses, leads to augmented antigen presentation and expansion of tumor antigen-specific CD8+ T cells. Counteracting ADCP, we also found that T-Dxd stimulates tumor CD47 expression, which we subsequently blocked using an anti-CD47 antibody in combination with T-Dxd. This combination yielded a potent therapeutic synergy that enhanced anti-tumor adaptive immune responses, both systemically and within the TME. Critically, we found that combination therapy induces CD8+ T cell immune memory, preventing tumor recurrence post therapy discontinuation and suggests a critical therapeutic role for T-Dxd-mediated stimulation of adaptive immunity. Citation Format: Li-Chung Tsao, John S. Wang, Xingru Ma, Siraj Sodhi, Joey V. Ragusa, Bushangqing Liu, Jason McBane, Tao Wang, Junping Wei, Cong-Xiao Liu, Xiao Yang, Gangjun Liu, Ivan Spasojevic, Ping Fan, Timothy N. Trotter, Michael Morse, H. Kim Lyerly, Zachary C. Hartman. Unlocking the Therapeutic Potential of T DXd Enhertu Mechanisms of Action in HER2 Low Cancers and Immunomodulatory Effects [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-05-30.