PD-1 and PD-L1 as emerging therapeutic targets in gastric cancer: current evidence

Abstract:

Gastric adenocarcinoma is a leading cause of global cancer-related morbidity and mortality, and new therapeutic approaches are needed. Despite the improved outcomes with monoclonal antibodies targeting human epidermal growth factor receptor 2 and vascular endothelial growth factor receptor 2, durable responses are uncommon. Targeting immune checkpoints including PD-1, PD-L1 and CTLA-4 have led to improved survival across several tumor types, frequently characterized by prolonged benefit in responding patients. Tumoral and lymphocyte-derived immunohistochemical staining for PD-1, PD-L1, and tumor mutational burden have shown potential as predictive response biomarkers in several tumor types. Optimal incorporation of immune-mediated therapies into gastric cancer (GC) is an area of intense ongoing investigation and benefit has been demonstrated in smaller studies of advanced patients. Important questions of biomarker selection, roles for molecular characterization, optimal combinatorial approaches, and therapeutic sequencing remain. In this study, current data are reviewed for immune checkpoint inhibitors in GC, and putative biomarkers, ongoing trials, and future considerations are discussed.

Keywords::

• immunotherapy
• stomach cancer
• checkpoint inhibitor
• nivolumab
• pembrolizumab
• tumor mutational burden

Acknowledgments

The authors would like to acknowledge important contributions from authors whose works could not be cited due to space constraints. Efforts in manuscript preparation for Dr Joseph Chao were supported by National Institutes of Health grant 5K12CA001727-22. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Disclosure

Joseph Chao has received research funding from Merck in support of an investigator-initiated clinical trial (NCT02830594). The authors report no other conflicts of interest in this work.