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Poster Discussion session - Breast cancer, metastatic

4464 - Post-treatment biopsies show evidence of cell cycle arrest and immune cell infiltration into tumors of ladiratuzumab vedotin-treated advanced breast cancer patients

Date

21 Oct 2018

Session

Poster Discussion session - Breast cancer, metastatic

Topics

Tumour Immunology

Tumour Site

Breast Cancer

Presenters

Jennifer Specht

Citation

Annals of Oncology (2018) 29 (suppl_8): viii90-viii121. 10.1093/annonc/mdy272

Authors

J. Specht1, L. Pusztai2, A. Forero-Torres3, M. Mita4, A. Weise5, I. Krop6, A. Grosse-Wilde7, Z. Wang8, M. Li7, S. Hengel9, P. Garfin10, G. Means7, M. Onsum7, S. Modi11

Author affiliations

  • 1 Seattle Cancer Care Alliance, University of Washington, 98019 - Seattle/US
  • 2 Yale Cancer Cener, Yale School of Medicine, 05620 - New Haven/US
  • 3 Division Of Hematology And Oncology, University of Alabama at Birmingham, 35294 - Birmingham/US
  • 4 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 90048 - Los Angeles/US
  • 5 Medical Oncology, Karmonas Cancer Institute, 48201 - Detroit/US
  • 6 Breast Oncology Center, Dana Farber Cancer Institute, 02215 - Boston/US
  • 7 Diagnostics And Biomarkers, Seattle Genetics, 98021 - Bothell/US
  • 8 Bioinformatics, Seattle Genetics, 98021 - Bothell/US
  • 9 Quantitative Pharmacology And Disposition, Seattle Genetics, 98021 - Bothell/US
  • 10 Clinical research, Seattle Genetics, 98021 - Bothell/US
  • 11 Division Of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, New York City/US
More

Resources

Abstract 4464

Background

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).

Methods

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).

Results

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.

Conclusions

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

Seattle Genetics.

Funding

Seattle Genetics.

Editorial Acknowledgement

Not applicable.

Disclosure

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.

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