PD-L1 Testing

Programmed death-ligand 1 (PD-L1) is an immune-related biomarker that can be expressed on the surface of many tissue types, including tumor cells. For certain types and stages of cancer, testing for PD-L1 expression may help to identify patients most likely to benefit from treatment with PD-L1 inhibitors. Novel immunotherapies, known as immune checkpoint inhibitors, can interrupt signals generated by immune checkpoint proteins, such as PD-L1, and enhance antitumor T-cell immunity.   Several PD-L1 inhibitors, including atezolizumab, durvalumab, nivolumab, and pembrolizumab, have been approved for a number of clinical indications and are being evaluated in multiple malignancies. The U.S. Food and Drug Administration (FDA) divides PD-L1 immunohistochemistry (IHC) tests into two groups: companion diagnostics, which provide information that is essential for the safe and effective use of a drug (test results are required for drug use), and complementary or codiagnostic tests, which may be used in treatment selection but are not considered essential for use of the corresponding therapy (test results are NOT required for drug use).  

Quick Answers for Clinicians

What is the difference between companion PD-L1 and complementary PD-L1 testing?

COMPANION PD-L1 testing is shown to be predictive of patient response to a specific immunotherapy for the type of tumor, on a specific platform. Testing is required for a specific immunotherapy to be used. COMPLEMENTARY PD-L1 testing may be predictive of patient response to a specific immunotherapy for the type of tumor, but is not required for the immunotherapy to be used. 

How do I determine the appropriate PD-L1 test to order?

This depends on the patient’s malignancy and the intended use of the PD-L1 inhibitor. Refer to the PD-L1 Testing by Sample Type and Drug table for tests that may be available for specific cancer types.

Which testing algorithms are related to this topic?

Indications for Testing

PD-L1 testing may be considered for patients with specific types of malignancies to predict response to specific immune checkpoint inhibitors.

PD-L1 Laboratory Testing

PD-L1 testing recommendations depend on the drug being considered for use, the malignancy, and the stage of cancer in question. Please refer to the specific agent package inserts in the table below for complete clinical indications.

There are also several interpretive scoring systems available, including the tumor proportion score (TPS), combined positive score (CPS), and tumor-infiltrating immune cell (IC) staining assessments. The selection of which scoring system to use, as well as the interpretive cutoffs, depends on the test, tumor, and indications. In brief, the TPS is used for non-small cell lung cancer (NSCLC) tumors tested by the PD-L1 22C3  and the PD-L1 28-8  tests and is based on the proportion of tumor cells that express PD-L1. The CPS is used to report PD-L1 22C3 test results    (in FDA-approved indications other than NSCLC) and is calculated in a manner similar to that of the TPS, but includes PD-L1 expression in tumor-associated lymphocytes and macrophages as well as tumor cells, over the overall number of tumor cells (staining and nonstaining). The SP142 assay has two different scoring systems. NSCLC tissue is scored using a stepwise approach based on tumor cell and tumor-infiltrating IC staining assessments. Urothelial carcinoma and triple-negative breast carcinoma (TNBC) tissues are scored by a tumor-infiltrating IC staining algorithm, which calculates the proportion of the tumor area represented by PD-L1-expressing immune cells. Refer to the interpretation manuals linked to from the table below for details because updates are frequently released.

PD-L1 Testing by Sample Type and Drug
Sample Type Drug Under Consideration PD-L1 Test Additional Resources
Breast carcinoma (triple negative) Atezolizumab (TECENTRIQ) PD-L1 SP142 for treatment with atezolizumab (TECENTRIQ) (COMPANION testing; not currently performed at ARUP Laboratories)

Indications for use 

Interpretation manual 

Cervical carcinoma (including cervical squamous cell carcinoma and endocervical adenocarcinoma) Pembrolizumab (KEYTRUDA) PD-L1 22C3 IHC with Combined Positive Score (CPS) Interpretation, pembrolizumab (KEYTRUDA) 3000197 (COMPANION testing)

Indications for use 

Interpretation manual 

Classical Hodgkin lymphoma Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Nivolumab (OPDIVO) PD-L1 testing NOT indicated Indications for use 
Cutaneous squamous cell carcinoma Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Endometrial carcinoma Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Esophageal squamous cell carcinoma Pembrolizumab (KEYTRUDA) PD-L1 22C3 IHC with Combined Positive Score (CPS) Interpretation, pembrolizumab (KEYTRUDA) 3000197 (COMPANION testing)

Indications for use 

Interpretation manual 

Nivolumab (OPDIVO) PD-L1 testing NOT indicated Indications for use 
Gastric/gastroesophageal junction adenocarcinoma Pembrolizumab (KEYTRUDA) PD-L1 22C3 IHC with Combined Positive Score (CPS) Interpretation, pembrolizumab (KEYTRUDA) 3000197 (COMPANION testing)

Indications for use 

Interpretation manual 

Head and neck squamous cell carcinoma

Pembrolizumab (KEYTRUDA)

PD-L1 22C3 IHC with Combined Positive Score (CPS) Interpretation, pembrolizumab (KEYTRUDA) 3000197 (COMPANION testing)

Indications for use 

Interpretation manual 

Nivolumab (OPDIVO) PD-L1 28-8 pharmDx by Immunohistochemistry with Interpretation, nivolumab (OPDIVO) 2013684 (COMPLEMENTARY testing)

Indications for use 

Interpretation manual 

Hepatocellular carcinoma Nivolumab (OPDIVO) PD-L1 testing NOT indicated Indications for use 
Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Atezolizumab (TECENTRIQ) PD-L1 testing NOT indicated Indications for use 
Melanoma Nivolumab (OPDIVO) PD-L1 testing NOT required Indications for use 
Pembrolizumab (KEYTRUDA) PD-L1 testing NOT required Indications for use 
Merkel cell carcinoma Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Microsatellite instable and mismatch repair protein-deficient malignancies Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Nivolumab (OPDIVO) PD-L1 testing NOT indicated Indications for use 
Non-small cell lung cancer Pembrolizumab (KEYTRUDA) PD-L1 22C3 IHC with Tumor Proportion Score (TPS) Interpretation, pembrolizumab (KEYTRUDA) 2013284 (COMPANION testing)

Indications for use 

Interpretation manual 

Nivolumab (OPDIVO) plus ipilibumab (YERVOY) PD-L1 28-8 pharmDx by Immunohistochemistry with Interpretation, nivolumab (OPDIVO) 2013684 COMPANION testing)

Indications for use (OPDIVO) 

Indications for use (YERVOY) 

Interpretation manual 

Nivolumab (OPDIVO) PD-L1 28-8 pharmDx by Immunohistochemistry with Interpretation, nivolumab (OPDIVO) 2013684 (nonsquamous NSCLC only) (COMPLEMENTARY testing)

Indications for use 

Interpretation manual 

Atezolizumab (TECENTRIQ) PD-L1 SP142 for treatment with atezolizumab (TECENTRIQ) (COMPLEMENTARY testing; not currently performed at ARUP Laboratories)

Indications for use 

Interpretation manual 

Atezolizumab (TECENTRIQ) and chemotherapy PD-L1 SP142 for treatment with atezolizumab (TECENTRIQ) (COMPLEMENTARY testing; not currently performed at ARUP Laboratories)

Indications for use 

Interpretation manual 

Durvalumab (IMFINZI) PD-L1 SP263 for treatment with durvalumab (IMFINZI) (COMPLEMENTARY testing; not currently performed at ARUP Laboratories)

Indications for use 

Interpretation manual 

Primary mediastinal large B-cell lymphoma Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Renal cell carcinoma Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Nivolumab (OPDIVO) PD-L1 testing NOT indicated Indications for use 
Small cell lung cancer Pembrolizumab (KEYTRUDA) PD-L1 testing NOT required Indications for use 
Nivolumab (OPDIVO) PD-L1 testing NOT required Indications for use 
Atezolizumab (TECENTRIQ) PD-L1 testing NOT required Indications for use 
Durvalumab (IMFINZI) PD-L1 testing NOT required

Indications for use 

Tumor mutational burden-high cancer Pembrolizumab (KEYTRUDA) PD-L1 testing NOT indicated Indications for use 
Urothelial carcinoma Pembrolizumab (KEYTRUDA) PD-L1 22C3 IHC with Combined Positive Score (CPS) Interpretation, pembrolizumab (KEYTRUDA) 3000197 (COMPANION testing)

Indications for use 

Interpretation manual 

Atezolizumab (TECENTRIQ) PD-L1 SP142 for treatment with atezolizumab (TECENTRIQ) (COMPANION testing; not currently performed at ARUP Laboratories)

Indications for use 

Interpretation manual 

Nivolumab (OPDIVO) PD-L1 28-8 pharmDx by Immunohistochemistry with Interpretation, nivolumab (OPDIVO) 2013684 COMPLEMENTARY testing)

Indications for use 

Interpretation manual 

Durvalumab (IMFINZI) PD-L1 SP263 for treatment with durvalumab (IMFINZI) (COMPLEMENTARY testing; not currently performed at ARUP Laboratories)

Indications for use 

Interpretation manual 

ARUP Laboratory Tests

Use for NSCLC specimens only

Companion diagnostic testing to aid in the prediction of response to pembrolizumab (KEYTRUDA) as first- or second-line monotherapy in patients with NSCLC

Use for gastric/gastroesophageal junction (GEJ), urothelial, cervical, esophageal squamous cell carcinoma (ESCC), or head and neck squamous cell carcinoma (HNSCC) specimens only to aid in prediction of response to pembrolizumab (KEYTRUDA)

FDA-approved companion diagnostic testing to aid in predicting the overall survival benefit from nivolumab (OPDIVO) in combination with ipilimumab (YERVOY) as first-line therapy for patients with NSCLC

FDA-approved complementary codiagnostic test that may aid in predicting response to nivolumab (OPDIVO) treatment for patients with nonsquamous NSCLC, urothelial carcinoma, or HNSCC

Medical Experts

Author

References

Resources from the ARUP Institute for Clinical and Experimental Pathology®