Abstract 3093: Molecular profiling of tisotumab vedotin-treated patients identified immune pathways associated with clinical activity, supporting the multimodal mechanism of action

Abstract Introduction: Tisotumab vedotin (TV) is an antibody drug conjugate comprised of a human tissue factor (TF)-specific IgG1κ monoclonal antibody chemically conjugated via a protease-cleavable valine-citrulline linker to the microtubule-disrupting agent monomethyl auristatin E. TV is approved in the US based on the pivotal single arm innovaTV 204 study and the randomized phase 3 innovaTV 301 study for patients with recurrent/metastatic cervical cancer who have progressed on/after chemotherapy. The purpose of this study was to explore the tumor microenvironment of patients with cervical cancer for characteristics associated with immune-mediated mechanisms of action (MoA) of TV. Methods: RNA sequencing was performed on available pre-treatment biopsies from 41 patients enrolled in the innovaTV 204 study. Differentially expressed genes and gene signatures were identified by comparing responders (per RECIST v1.1, complete or partial response) and non-responders (stable or progressive disease) using a linear model adjusting for clinical factors, where mean fold differences and nominal p-values between groups were determined. Associations with overall survival (OS) were determined using a Cox proportional hazards model. To further explore signatures involved in TV MoA, Fc-mediated effector functions of TV were analyzed using tumor cell lines with varying TF expression levels co-cultured with variations of TV/tisotumab antibodies and immune cells. Results: Mean levels of a natural killer (NK) cell signature were higher in TV responders vs. non-responders. The NK cell signature, as well as an M1 macrophage and monocyte signatures were also associated with better OS among patients from innovaTV 204. Levels of these signatures in untreated patients with cervical cancer from TCGA were not associated with better OS, suggesting that their link with this outcome was specific to TV treatment. Immune cell effector mechanisms were confirmed in vitro by assessing viability of tumor cell with various TF expression levels co-cultured with immune cells. Tumor cell viability analysis suggested TV may contribute to immune cell-mediated clearance of target tumor cells via Fc-mediated effector mechanisms, which was reduced with an Fc-inert variant of TV. Conclusions: Immune gene signatures associated with the Fc-mediated effector mechanisms of antibody-dependent cellular cytotoxicity (NK cells) and antibody-dependent cellular phagocytosis (macrophages/monocytes) were associated with improved OS and overall response rate in innovaTV204 patients. Preclinical results demonstrate Fc-dependent immune cell engagement as a MoA of TV. Together, these results provide additional evidence of TV’s multimodal MoA in patients with advanced cervical cancer. Citation Format: Sriram Sridhar, Guy Roukens, Christina Yu, Han Si, Steven Xu, Lauren Brady, Merzu Belete, Mark Bieda, Khyati N. Shah, Regina Aquino, Denise Gallagher, Brandon Higgs, Mark Fereshteh, Maria Jure-Kunkel, Jeffrey R. Harris. Molecular profiling of tisotumab vedotin-treated patients identified immune pathways associated with clinical activity, supporting the multimodal mechanism of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3093.