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Introduction <p>Cholangiocarcinoma (CCA) is an aggressive cancer characterized by high metastatic potential and poor prognosis. Recent advances in understanding the molecular biology of CCA have led to the development of novel therapeutic strategies. However, the immunosuppressive tumor microenvironment in CCA enables immune evasion, which contributes to the limited effectiveness of immune checkpoint inhibitors (ICIs) in metastatic CCA patients. Epigenetic modifications play a critical role in cancer progression. Previous preclinical and clinical work from our group and others demonstrated that the HDAC inhibitor entinostat remodeled the tumor microenvironment and sensitized cancers to immune checkpoint inhibition, resulting in durable radiological responses in a subset of patients. This raises the potential for similar therapeutic strategies in CCA.</p> Methods <p>In accordance with our previously published study involving PDAC patients from the same clinical trial, this phase II, single-center, open-label trial was conducted to assess the efficacy of entinostat in combination with nivolumab in patients with advanced CCA. Patients received oral entinostat at a dose of 5&#xa0;mg once weekly. After a 14-day lead-in with entinostat alone, treatment was expanded to combine weekly oral entinostat in addition to nivolumab 240&#xa0;mg intravenously every 2&#xa0;weeks. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Moreover, we evaluated peripheral immune profiles by high-dimensional mass cytometry by time-of-flight (CyTOF) on cryopreserved paired baseline and on treatment PBMC samples.</p> Results <p>Between November 2017 and November 2020, a total of 13 patients with unresectable or metastatic previously treated CCA were enrolled. Among them, two patients (15%) demonstrated stable disease (SD) as best response, while the remaining eleven patients (85%) demonstrated disease progression (PD). No partial response was observed per RECIST 1.1 criteria. Adverse reaction to at least one study drug occurred in12 patients (92%). Grade ≥ 3 treatment-related AE (TRAEs) were encountered in 5 patients (38%). The most common grade ≥ 3 AEs were decreased cell counts. CyTOF profiling of PBMCs revealed that the HDAC inhibitor mediated immune reprogramming seen in the PDAC was not consistently reproduced for both myeloid and T cell compartments in CCA.</p> Conclusion <p>While the combination of entinostat and nivolumab did not demonstrate clinical efficacy in CCA, the translational insights from this study underscore the complexity of this malignancy. Overcoming the unique immunosuppressive barriers in CCA will require innovative approaches that integrate novel immunomodulatory agents and precision-based strategies to optimize patient outcomes.</p> Trail registration <p>NCT03250273, Trial pre-registration: 8/14/2017, Study Start: 11/06/2017.</p>

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Entinostat in combination with nivolumab for patients with advanced cholangiocarcinoma: a phase 2 clinical trial

  • 期刊论文

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  • 发表日期：

    2025年7月8日

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  • Elsa Hallab,
  • Jennifer N. Durham,
  • Rosalind Walker,
  • Leslie Cope,
  • Soren Charmsaz,
  • Nicole E. Gross,
  • Dimitrios N. Sidiropoulos,
  • Alexei Hernandez,
  • James Leatherman,
  • Sarah Mitchell,
  • Mark Yarchoan,
  • Won Jin Ho,
  • Nilofer S. Azad,
  • Marina Baretti

摘要

Introduction

Cholangiocarcinoma (CCA) is an aggressive cancer characterized by high metastatic potential and poor prognosis. Recent advances in understanding the molecular biology of CCA have led to the development of novel therapeutic strategies. However, the immunosuppressive tumor microenvironment in CCA enables immune evasion, which contributes to the limited effectiveness of immune checkpoint inhibitors (ICIs) in metastatic CCA patients. Epigenetic modifications play a critical role in cancer progression. Previous preclinical and clinical work from our group and others demonstrated that the HDAC inhibitor entinostat remodeled the tumor microenvironment and sensitized cancers to immune checkpoint inhibition, resulting in durable radiological responses in a subset of patients. This raises the potential for similar therapeutic strategies in CCA.

Methods

In accordance with our previously published study involving PDAC patients from the same clinical trial, this phase II, single-center, open-label trial was conducted to assess the efficacy of entinostat in combination with nivolumab in patients with advanced CCA. Patients received oral entinostat at a dose of 5 mg once weekly. After a 14-day lead-in with entinostat alone, treatment was expanded to combine weekly oral entinostat in addition to nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Moreover, we evaluated peripheral immune profiles by high-dimensional mass cytometry by time-of-flight (CyTOF) on cryopreserved paired baseline and on treatment PBMC samples.

Results

Between November 2017 and November 2020, a total of 13 patients with unresectable or metastatic previously treated CCA were enrolled. Among them, two patients (15%) demonstrated stable disease (SD) as best response, while the remaining eleven patients (85%) demonstrated disease progression (PD). No partial response was observed per RECIST 1.1 criteria. Adverse reaction to at least one study drug occurred in12 patients (92%). Grade ≥ 3 treatment-related AE (TRAEs) were encountered in 5 patients (38%). The most common grade ≥ 3 AEs were decreased cell counts. CyTOF profiling of PBMCs revealed that the HDAC inhibitor mediated immune reprogramming seen in the PDAC was not consistently reproduced for both myeloid and T cell compartments in CCA.

Conclusion

While the combination of entinostat and nivolumab did not demonstrate clinical efficacy in CCA, the translational insights from this study underscore the complexity of this malignancy. Overcoming the unique immunosuppressive barriers in CCA will require innovative approaches that integrate novel immunomodulatory agents and precision-based strategies to optimize patient outcomes.

Trail registration

NCT03250273, Trial pre-registration: 8/14/2017, Study Start: 11/06/2017.