Molecular Profiling of Tisotumab Vedotin-Treated Patients Identifies Immune Pathways Associated with Clinical Activity.

PURPOSE: Tisotumab vedotin (TV) is a tissue factor (TF)-specific antibody-drug conjugate (ADC) that was evaluated in the innovaTV 204 study in patients with recurrent or metastatic cervical cancer (r/mCC). Although TF expression is required for TV binding to tumor cells, clinical responses were found to be independent of TF levels. This study aimed to evaluate whether baseline tumor gene expression signatures consistent with the proposed mechanisms of action of TV were associated with clinical outcomes.

EXPERIMENTAL

DESIGN

Pretreatment tumor samples from patients enrolled in innovaTV 204 (NCT03438396), a phase II, single-arm, multicenter trial of TV in r/mCC following chemotherapy, were profiled for molecular biomarkers. Gene expression analyses of immune-related signatures were stratified by clinical response. In vitro antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) assays were performed using tumor cell lines with variable TF expression.

RESULTS

TF expression was confirmed in most patients but did not associate with response. Higher expression of gene signatures linked to natural killer (NK) cells and myeloid cells was associated with improved clinical outcomes. In vitro, TV induced tumor cell death through myeloid-mediated ADCP and NK-mediated ADCC across various TF expression levels.

CONCLUSIONS

This work provides supportive evidence for TV mechanisms of action that involve antitumor effects through direct cytotoxic and immune effector-mediated mechanisms. The association of immune-related gene signatures with improved clinical outcomes supports a multimodal mechanism of action for TV in the clinic and provides further rationale for ADC efficacy in tumors with heterogeneous target expression.