PD-L1

  • Programmed death ligand 1 (PD-L1)
  • Gene Location: chromosome 9 (9p24)

PD-L1 Biology

  • Programmed Cell Death Protein 1 (PD-1) is an immunosuppressive checkpoint expressed in immune cells, including in tumor-specific activated T cells, under conditions of chronic antigen exposure.1,2
  • Programmed Death Ligand 1 (PD-L1) is a PD-1 ligand expressed by various immune cells, including activated T cells, B cells, and epithelial cells under inflammatory conditions.3
  • Under normal circumstances, this system of proteins modulates the innate tumor response.3
  • The advent of immune checkpoint inhibitors (ICI) that target the PD-1/PD-L1 pathway in patients with advanced NSCLC represents a significant improvement over traditional chemotherapy, especially in patients with high PD-L1 expression.
  • However, challenges remain; these include the occurrence of hyper-progressive disease in some patients treated with these inhibitors, which points to a need for better patient selection and understanding of resistance mechanisms.1

Etiology and Epidemiology

  • PD-L1 is expressed in tumor cells, tumor-infiltrating cells, and antigen-presenting cells in many cancers, including NSCLC.1,2
  • Higher levels of PD-L1 expression are associated with increased tumor proliferation, aggressiveness, and poorer survival.2
  • The expression of PD-L1 by tumor cells suppresses T-cell function, enabling tumors to evade immune detection.1,2
  • PD-L1 levels have shown promise as prognostic biomarkers and therapeutic targets for immunotherapies that block the PD-1/PD-L1 pathway, but their clinical significance varies across cancer types.1

PD-L1 Testing

When to Test:

  • All patients with advanced or metastatic lung adenocarcinoma should undergo broad molecular profiling at diagnosis.4
  • Broad molecular profiling should also be considered for those with advanced or metastatic lung squamous cell carcinoma at diagnosis. In early-stage disease, testing at diagnosis should include assessment of PD-L1, EGFR, and ALK.4

Available Testing Methods:

  • Immunohistochemistry (IHC) testing is used to assess PD-L1 status.4
  • An FDA-approved immunohistochemistry (IHC) test should be used to determine the proportion of tumor cells expressing membranous staining for PD-L1; clinicians should avoid using multiple IHC assays.4

Tumor Proportion Score:

  • In NSCLC, the tumor proportion score (TPS) is used to assess the level of PD-L1 expression.
  • TPS, is calculated by the number of PD-L1 positive tumor cells divided by the total number of all tumor cells multiplied by 100. In other tumor types, such as gastric cancers, combine positive scoring (CPS) is used to quantify PD-L1 expression.5

Guideline Recommendations for Testing:

  • Based on clinical trial data and FDA approval of fam-trastuzumab deruxtecan-nxki (T-DXd), the NCCN NSCLC Panel advises testing for HER2 mutations in all patients with metastatic nonsquamous NSCLC or NSCLC not otherwise specified (NOS).4
  • Testing for HER2 mutations may also be considered for patients with metastatic squamous cell carcinoma.4

Treatment Options

Approved Agents:

  • Multiple FDA-approved ICI options are available for treating advanced NSCLC in patients with high PD-L1 expression (≥50%).5–12
  • ICIs are approved in combination with or without traditional chemotherapy and include atezolizumab, cemiplimab, durvalumab with tremelimumab, pembrolizumab, and nivolumab with ipilimumab.5–12

Mechanism of Action:

  • Atezolizumab, cemiplimab, durvalumab, pembrolizumab, and nivolumab are monoclonal antibodies that attach to PD-1 and interrupt the PD-L1 interaction. Disrupting this process obviates tumor cells’ ability to utilize this system to avoid immune system attacks.5,6,9,11,12
  • Ipilimumab and tremelimumab work via the complementary mechanism of attaching to and disrupting CTLA-4, which is a down-regulator of T cell activation; blocking it increases T cell and tumor lysis activity.8,10

Learn more about Atezolizumab

Learn more about Cemiplimab

Learn more about Durvalumab and Tremelimumab

Learn more about Nivolumab and Ipilimumab

Learn more about Pembrolizumab

References

  1. Tang Q, Chen Y, Li X, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. 2022;13:964442. doi:10.3389/fimmu.2022.964442
  2. Pawelczyk K, Piotrowska A, Ciesielska U, et al. Role of PD-L1 Expression in Non-Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers. IJMS. 2019;20(4):824. doi:10.3390/ijms20040824
  3. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742.
  4. National Comprehensive Cancer Network. NCCN guidelines version 4.2024: Non-Small Cell Lung Cancer. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  5. PD-L1 testing and scoring. Accessed October 2, 2024. https://www.keytrudahcp.com/biomarker-testing/pd-l1/
  6. KEYTRUDA (pembrolizumab) Prescribing information. Merck; 2024.
  7. OPDIVO (Nivolumab) Prescribing information. Bristol Myers Squibb; 2024.
  8. YERVOY (ipilimumab) Prescribing information. Bristol Myers Squibb; 2023.
  9. LIBTAYO (cemiplimab) Prescribing information. Bristol Myers Squibb; 2024.
  10. IMJUDO (tremelimumab). Prescribing information. AstraZeneca Pharmaceuticals; 2024.
  11. IMFINZI (durvalumab). Prescribing information. AstraZeneca Pharmaceuticals; 2024.
  12. TECENTRIQ (atezolizumab). Preceribing information. Genentech, Inc.; 2024.