A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer

Cesar Augusto Santa-Maria*, Taigo Kato, Jae Hyun Park, Kazuma Kiyotani, Alfred Rademaker, Ami N. Shah, Leeaht Gross, Luis Z. Blanco, Sarika Jain, Lisa Flaum, Claudia Tellez, Regina Stein, Regina Uthe, William J. Gradishar, Massimo Cristofanilli, Yusuke Nakamura, Francis J. Giles

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune-gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline. Eighteen evaluable patients were accrued (11 ER-positive; seven TNBC). Only three patients had a response (ORR = 17%), thus the study did not proceed to the second stage. Responses were only observed in patients with TNBC (ORR = 43%). Responders versus non-responders had upregulation of CD8, granzyme A, and perforin 1 gene expression, and higher mutational and neoantigen burden. Patients with TNBC had an oligoclonal shift of the most abundant TCR-beta clonotypes compared to those with ER-positive disease, p = 0.004. We conclude responses are low in unselected metastatic breast cancer, however, higher rates of clinical benefit were observed in TNBC. Immunogenomic dynamics may help identify phenotypes most likely to respond to immunotherapy.

Original languageEnglish (US)
Pages (from-to)18985-18996
Number of pages12
JournalOncotarget
Volume9
Issue number27
DOIs
StatePublished - Apr 10 2018

Keywords

  • Immune checkpoint
  • Immunogenomics
  • Metastatic breast cancer
  • T cell receptor sequencing

ASJC Scopus subject areas

  • Oncology

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    Santa-Maria, C. A., Kato, T., Park, J. H., Kiyotani, K., Rademaker, A., Shah, A. N., Gross, L., Blanco, L. Z., Jain, S., Flaum, L., Tellez, C., Stein, R., Uthe, R., Gradishar, W. J., Cristofanilli, M., Nakamura, Y., & Giles, F. J. (2018). A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer. Oncotarget, 9(27), 18985-18996. https://doi.org/10.18632/oncotarget.24867