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

Marina Baretti, Ludmila Danilova, Jennifer N. Durham, Courtney B. Betts, Leslie Cope, Dimitrios N. Sidiropoulos, Joseph A. Tandurella, Soren Charmsaz, Nicole Gross, Alexei Hernandez, Won Jin Ho, Chris Thoburn, Rosalind Walker, James Leatherman, Sarah Mitchell, Brian Christmas, Ali Saeed, Daria A. Gaykalova, Srinivasan Yegnasubramanian, Elana J. Fertig, Lisa M. Coussens, Mark Yarchoan, Elizabeth Jaffee and Nilofer S. Azad ()
Additional contact information
Marina Baretti: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Ludmila Danilova: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Jennifer N. Durham: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Courtney B. Betts: Oregon Health & Science University
Leslie Cope: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Dimitrios N. Sidiropoulos: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Joseph A. Tandurella: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Soren Charmsaz: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Nicole Gross: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Alexei Hernandez: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Won Jin Ho: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Chris Thoburn: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Rosalind Walker: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
James Leatherman: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Sarah Mitchell: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Brian Christmas: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Ali Saeed: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Daria A. Gaykalova: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Srinivasan Yegnasubramanian: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Elana J. Fertig: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Lisa M. Coussens: Oregon Health & Science University
Mark Yarchoan: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Elizabeth Jaffee: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Nilofer S. Azad: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52528-7

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