Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial

Pancreatic ductal adenocarcinoma (PDA) is characterized by low cytotoxic lymphocytes, abundant immune-suppressive cells, and resistance to immune checkpoint inhibitors (ICI). Preclinical PDA models showed the HDAC inhibitor entinostat reduced myeloid cell immunosuppression, sensitizing tumors to ICI therapy. This phase II study combined entinostat with nivolumab (PD1 inhibitor) in patients with advanced PDA (NCT03250273). Patients received entinostat 5 mg orally once weekly for 14-day lead-in, followed by entinostat and nivolumab. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response, progression free-survival and overall survival. Between November 2017 and November 2020, 27 evaluable patients were enrolled. Three showed partial responses (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months. Grade ≥3 treatment-related adverse events occurred in 19 patients (63%), including decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As exploratory analysis, peripheral and tumor immune profiles changes were assessed using CyTOF, mIHC, and RNA-seq. Entinostat increased dendritic cell activation and maturation. Gene expression analysis revealed an enrichment in inflammatory response pathways with combination treatment. Although the primary endpoint was not met, entinostat and nivolumab showed durable responses in a small subset of PDA patients. Myeloid cell immunomodulation supported the preclinical hypothesis, providing a basis for future combinatorial therapies to enhance clinical benefits in PDA.

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Publication Details

Journal
Nature Communications
Published
2024-11-12
DOI
https://doi.org/10.1038/s41467-024-52528-7
Citations
30
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
8.19

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article

Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial

Soren Charmsaz, Alexei Hernandez, Jennifer N. Durham, James W. Leatherman et al.
30 citations
Nature Communications
Pancreatic and Hepatic Oncology Research
8.19
article

Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial

Soren Charmsaz, Alexei Hernandez, Jennifer N. Durham, James W. Leatherman, Leslie Cope, Lisa M. Coussens, Marina Baretti, Elana J. Fertig, Christopher J. Thoburn, Joseph A. Tandurella, Ludmila Danilova, Brian J. Christmas, Sarah Mitchell, Won Jin Ho, Nicole Groß, Elizabeth M. Jaffee, Daria A. Gaykalova, Dimitrios N. Sidiropoulos, Nilofer S. Azad, Ali Saeed, Mark Yarchoan, Rosalind Walker, Srinivasan Yegnasubramanian, Courtney B. Betts
article en
30 citations

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by low cytotoxic lymphocytes, abundant immune-suppressive cells, and resistance to immune checkpoint inhibitors (ICI). Preclinical PDA models showed the HDAC inhibitor entinostat reduced myeloid cell immunosuppression, sensitizing tumors to ICI therapy. This phase II study combined entinostat with nivolumab (PD1 inhibitor) in patients with advanced PDA (NCT03250273). Patients received entinostat 5 mg orally once weekly for 14-day lead-in, followed by entinostat and nivolumab. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response, progression free-survival and overall survival. Between November 2017 and November 2020, 27 evaluable patients were enrolled. Three showed partial responses (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months. Grade ≥3 treatment-related adverse events occurred in 19 patients (63%), including decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As exploratory analysis, peripheral and tumor immune profiles changes were assessed using CyTOF, mIHC, and RNA-seq. Entinostat increased dendritic cell activation and maturation. Gene expression analysis revealed an enrichment in inflammatory response pathways with combination treatment. Although the primary endpoint was not met, entinostat and nivolumab showed durable responses in a small subset of PDA patients. Myeloid cell immunomodulation supported the preclinical hypothesis, providing a basis for future combinatorial therapies to enhance clinical benefits in PDA.

Nature CommunicationsVol. 15(1)
University of Maryland, Baltimore (US), Bloomberg (United States) (US), University of Maryland Medical Center (US), Johns Hopkins University (US), Oregon Health & Science University (US), Convergence (US), Johns Hopkins Hospital (US), Akoya Biosciences (United States) (US), Sidney Kimmel Comprehensive Cancer Center (US)
Conquer Cancer Foundation, Johns Hopkins University, Syndax Pharmaceuticals, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, Moonshot Research and Development Program
Openalex Percentile: Top 2%
Pancreatic and Hepatic Oncology Research
8.19
DOIOpen Access PDFOpenAlex
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