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Recent progress and current challenges of immunotherapy in advanced/metastatic esophagogastric adenocarcinoma

  • Author Footnotes
    1 Markus Moehler and Anica Högner share the first co-authorship and contributed equally.
    Markus Moehler
    Correspondence
    Corresponding author:
    Footnotes
    1 Markus Moehler and Anica Högner share the first co-authorship and contributed equally.
    Affiliations
    Universitätsmedizin Mainz, Johannes Gutenberg Universität Mainz, 55131 Mainz, Germany
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  • Author Footnotes
    1 Markus Moehler and Anica Högner share the first co-authorship and contributed equally.
    Anica Högner
    Footnotes
    1 Markus Moehler and Anica Högner share the first co-authorship and contributed equally.
    Affiliations
    Charité – University Medicine Berlin, Department of Haematology, Oncology and Cancer Immunology, Campus Virchow-Klinikum, Berlin, Germany
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  • Anna D. Wagner
    Affiliations
    Department of Oncology, Division of Medical Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
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  • Radka Obermannova
    Affiliations
    Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute and Faculty of Medicine, Masaryk University, Brno, Czech Republic
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  • Maria Alsina
    Affiliations
    Vall D'Hebron University Hospital, Department of Medical Oncology, and Vall D'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Passeig de La Vall D'Hebron, Barcelona, Spain
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  • Peter Thuss-Patience
    Affiliations
    Charité – University Medicine Berlin, Department of Haematology, Oncology and Cancer Immunology, Campus Virchow-Klinikum, Berlin, Germany
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  • Hanneke van Laarhoven
    Affiliations
    Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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  • Elizabeth Smyth
    Affiliations
    Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
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  • Author Footnotes
    1 Markus Moehler and Anica Högner share the first co-authorship and contributed equally.
Published:September 29, 2022DOI:https://doi.org/10.1016/j.ejca.2022.08.023

      Highlights

      • Newly approved immune checkpoint inhibitors (ICI) enrich options for GEJ/GC therapies.
      • Relevant phase II/III trials focus on important biomarkers including PD-L1 assessment.
      • Next research may clarify ICI resistance mechanisms and varied gender responses.

      Abstract

      The new era of immunotherapy is successfully implemented in the treatment of metastatic/locally advanced esophagogastric adenocarcinoma (EGAC), as it has been investigated in combinations with/without chemotherapy in human epidermal growth factor receptor 2 (Her2)-positive and Her2-negative tumors. Recent approvals of immune checkpoint inhibitors (ICI) enrich the therapeutic landscape in nearly every therapeutic line. Based on CHECKMATE-649, the combination of nivolumab and chemotherapy in first-line therapy of programmed cell death protein 1 (PD-L1)-positive patients with advanced gastroesophageal junction cancer (GEJC), esophageal cancer (EC), and gastric cancer (GC) was approved in Europe for PD-L1 combined positivity score (CPS) ≥ 5 patients and independently from PD-L1 score in the USA and Asia. Based on KEYNOTE-590, patients with advanced GEJC and EC qualify for the combination of pembrolizumab plus chemotherapy in Europe (CPS ≥ 10) and the USA. For Her2-positive patients, trastuzumab with first-line chemotherapy plus pembrolizumab has beneficial response rates and resulted in approval in the USA (KEYNOTE-811). In third-line therapy, superior overall survival (OS) was achieved by the administration of nivolumab (approval in Japan, ATTRACTION-02), and pembrolizumab shows a positive effect on the duration of response (KEYNOTE-059). Questions of resistance to immunotherapy or the role of gender in response to ICI need to be clarified. This review provides an overview of the current approvals of ICI in advanced EGAC and reflects results of relevant phase II/III trials with focus on possible biomarkers, including PD-L1 CPS and microsatellite-instability (MSI) status.

      Keywords

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