Ladiratuzumab vedotin (LV) is a monomethyl auristatin E (MMAE)-conjugated IgG1 humanized antibody-drug conjugate (ADC) against LIV-1, a highly expressed transmembrane protein in breast cancer. A previously reported mechanism of action for LV is MMAE-driven microtubule inhibition, which results in mitotic arrest and cell death. We present data from an ongoing phase 1 study of LV monotherapy in women with unresectable, locally advanced, or metastatic breast cancer (NCT01969643), exploring the relationship between biomarkers of tumor cytotoxicity and the activation of the immune system in the tumor microenvironment (TME) of longitudinal biopsies. LV monotherapy was well tolerated in this study and showed encouraging clinical activity (Modi 2017).
We evaluated tumor biopsies pre- and ∼4 days post-tx. Up to 40 pairs of matched samples from hormone receptor-positive (HR+) and triple negative breast cancer (TNBC) pts were analyzed by both immunohistochemistry (IHC) and RNAseq, or by mass-spectroscopy (MS).
The presence of macrophages and dendritic cells in baseline biopsies correlated with antitumor activity. Four days post-tx, MMAE levels were higher in tumor biopsies (∼10-fold increase) as measured by MS, compared to plasma. In post-tx biopsies, G2/M arrest and substantial acute changes within the TME were observed by IHC, including increased numbers of tumor infiltrating lymphocytes (TILs) in the stroma of HR+ and TNBC tumors and CD68+ macrophages in TNBC pts (∼2-fold; p < 0.06). Next generation sequencing identified increased expression of genes associated with cell cycle regulation (e.g., Cyclin B), immune response (e.g., CXCL10 and IFN-induced proteins), and confirmed signatures associated with macrophages and dendritic cells.
These data expand upon preclinical observations that MMAE-linked ADCs can induce mitotic arrest, immunomodulation, and immunogenic cell death. These translational data strongly support further clinical investigation of LV monotherapy and LV in combination with immuno-oncology agents, e.g. checkpoint inhibitors, as in the SGNLVA-002 study (NCT03310957).
Clinical trial identification
NCT01969643, first posted 25 October 2013.
Legal entity responsible for the study
J. Specht: Research funding grants: Abbvie, Cascadian Therapeutics, Celgene, Celldex, Genentech, Juno Therapeutics, Merck & Co, Nektar, Novartis, Pfizer, Seattle Genetics, Myriad Pharmaceuticals. L. Pusztai: Advisoray board membership, honoraria: Seattle Genetics (SGEN), Merck, AstraZeneca; Consultancy: Syndax, Almac, Immunogenics; Grant info: NCI, Susan Komen Foundation, Breast Cancer Research Foundation; Research Grants: SGEN, Roche, Merck; Travel expenses: SGEN, Merck, AstraZeneca, Syndax. A. Forero-Torres: Research funding grants: Seattle Genetics; Speaker's bureau: Seattle Genetics. M. Mita, I. Krop: Research funding grants: Seattle Genetics. A. Weise: Research funding: Seattle Genetics. A. Grosse-Wilde, Z. Wang, M. Li, S. Hengel, P. Garfin, G. Means, M. Onsum: Employee and stakeholder: Seattle Genetics. S. Modi: Research funding grants: Daiichi Sankyo, Genentech, Novartis, Seattle Genetics; Speaker's Bureau: Genentech.