PD-L1

  • Programmed cell death ligand protein 1 (PD-L1)
  • Gene location: chromosome 9 (9p24.1)

Biology

  • PD-L1, also known as B7-H1 or CD274, is a 33 kDa B7 family protein commonly expressed on macrophages, activated T cells, and B cells in response to inflammatory conditions.1-3
  • The CD274/PD-L1 gene is located on chromosome 9p24.1; it is highly conserved across species.1,3
  • PD-L1, a transmembrane protein critical to the checkpoint inhibitory immune response,facilitates organismal self-recognition and immune system mediation.2
  • PD-L1 interacts with PD-1 as a major immune system checkpoint that induces immune tolerance; when PD-1-expressing immune cells encounter PD-L1, T-cell functions are diminished.4,5

Etiology and Epidemiology

  • Elevated PD-L1 expression is present in approximately 40% to 65% of gastric cancer tumors and is reported with the combined positive score (CPS), which measures the ratio of PD-L1 stained cells to normal cells.6,7
  • PD-L1 is generally considered an indicator of poor prognosis, resulting in significantly shorter overall survival (OS) and relapse-free survival (RFS).4
  • Gastric tumors upregulate PD-L1 expression via various pathways (eg, JAK/STAT3, Wnt, and MAPK) ­and through modulation of multiple signaling molecules, thereby facilitating hypoxia-mediated escape from adaptive immunity.1,2
  • Increased PD-L1 expression is associated with increased immune escape, metastatic potential, and proliferation.1

PD-L1 Testing

When to Test:

  • PD-L1 testing by immunohistochemistry (IHC) is recommended in all patients with newly diagnosed gastric or gastroesophageal junction (GEJ) adenocarcinoma (including those with locally advanced, recurrent, or metastatic gastric cancers) who are candidates for immunotherapy.7

Available Testing Methods:

  • PD-L1 testing should be conducted via qualitative IHC using anti–PD-L1 antibodies on preserved gastric adenocarcinoma tissue.7
  • The Agilent PD-L1 IHC 22C3 pharmDx assay is an FDA-approved companion diagnostic device to select patients with gastric or GEJ adenocarcinoma whose tumors express PD-L1 (combined positive score [CPS] ≥ 1) and for whom treatment with pembrolizumab may be appropriate.8

PD-L1 CPS

  • PD-L1 CPS is a scoring system to assess PD-L1 expression in gastric and GEJ cancers and to help determine eligibility for immune checkpoint inhibitors.8,9
  • PD-L1 expression is considered positive when the CPS is 1 or more. A minimum of 100 tumor cells must be on the stained slide for the specimen to be valid.8,9
  • CPS is calculated as the number of PD-L1-staining cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, with the product then multiplied by 100.8,9

Testing Guideline Recommendations:

  • The NCCN recommends PD-L1 testing for patients with locally advanced, recurrent, or metastatic gastric cancers who are candidates for immunotherapy.7
  • Specifically, a companion diagnostic test should be used to help identify patients eligible for treatment with PD-L1 inhibitors.7
Figure

PD-L1 Targeted Therapies

Approved Agent(s):

  • Two agents have been approved in combination with platinum- and fluoropyrimidine-based chemotherapy in adults for the first-line treatment of unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors express PD-L1.10-12
  • Initially approved in this setting in 2017, pembrolizumab received an updated indication in 2023 for use in patients whose tumors express PD-L1 (CPS ≥ 1).10,11
  • In December 2024, tislelizumab was approved for use in patients whose tumors express PD-L1 (≥ 1).12

Mechanism of Action:

  • Both agents bind to PD-1 and prevent interaction with ligands PD-L1 and PD-L2, releasing the inhibition of the immune response and thereby bolstering the immune response to tumor cells.13,14

Tislelizumab

  • FDA-Approved indication:
    • In combination with platinum- and fluoropyrimidine-based chemotherapy in adults for the first-line treatment of unresectable or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (≥ 1).13
  • Drug Information:
  • Patient Resources:

Pembrolizumab

  • FDA-Approved Indication:
    • In combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic, HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-approved test.14
  • Drug Information:
    • Learn more about pembrolizumab
  • Patient Resources:

References

  1. Zhang Y, Yang Y, Chen Y, et al. PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer. Front Immunol. 2022;13:1060497. doi:10.3389/fimmu.2022.1060497
  2. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742.
  3. Fabrizio FP, Trombetta D, Rossi A, Sparaneo A, Castellana S, Muscarella LA. Gene code CD274/PD-L1: from molecular basis toward cancer immunotherapy. Ther Adv Med Oncol. 2018;10:1758835918815598. doi:10.1177/1758835918815598
  4. Yamashita K, Iwatsuki M, Harada K, et al. Prognostic impacts of the combined positive score and the tumor proportion score for programmed death ligand-1 expression by double immunohistochemical staining in patients with advanced gastric cancer. Gastric Cancer. 2020;23(1):95-104. doi:10.1007/s10120-019-00999-9
  5. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti–PD-1 therapy. Clin Cancer Res. 2014;20(19):5064-5074. doi:10.1158/1078-0432.CCR-13-3271
  6. Fiocco C, Spencer K. Defining PD-L1 Expression in gastric cancer: how positive is cps for finding and treating the right patients? ASCO Daily News. June 28, 2023. Accessed March 3, 2025. https://dailynews.ascopubs.org/do/defining-pd-l1-expression-gastric-cancer-positive-cps-finding-and-treating-right
  7. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version5.2024. Accessed March 3, 2025. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  8. FDA amends pembrolizumab's gastic cancer indication. FDA. November 8, 2023. Accessed March 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-amends-pembrolizumabs-gastric-cancer-indication
  9. Klempner SJ, Cowden ES, Cytryn SL, et al. PD-L1 immunohistochemistry in gastric cancer: comparison of combined positive score and tumor area positivity across 28-8, 22C3, and SP263 assays. JCO Precis Oncol. 2024;8:e2400230. doi:10.1200/PO.24.00230
  10. FDA grants accelerated approval to pembrolizumab for advanced gastric cancer. FDA. September 22, 2017. Accessed March 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-advanced-gastric-cancer
  11. FDA amends pembrolizumab's gastric cancer indication. FDA. November 8, 2023. Accessed March 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-amends-pembrolizumabs-gastric-cancer-indication
  12. TEVIMBRA approved in U.S. for first-line treatment of gastric and gastroesophageal junction cancers in combination with chemotherapy. Press release. BeiGene. December 27, 2024. Accessed March 18, 2025. https://ir.beigene.com/news/tevimbra-approved-in-u-s-for-first-line-treatment-of-gastric-and-gastroesophageal-junction-cancers-in-combination/cedb475b-fcfe-47a4-8afe-8a501d9cf849/
  13. Tevimbra (tislelizumab). Prescribing information. BeiGene USA; 2025. Accessed March 3, 2025. https://www.beigene.com/PDF/TEVIMBRAUSPI.pdf
  14. Keytruda (pembrolizumab). Prescribing information. Merck & Co; 2025. Accessed March 3, 2025. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf