CAP Publishes New Guideline on PD-L1 Testing of Patients with Lung Cancer

The development of immunotherapy and immunomodulatory drugs continues to evolve, driving the need for universally accepted standardized criteria for immunohistochemistry (IHC)-based testing of immune checkpoint proteins, particularly for programmed cell death ligand-1 (PD-L1).

The CAP, in collaboration with the American Society of Clinical Oncology, Association for Molecular Pathology, International Association for the Study of Lung Cancer, Pulmonary Pathology SocietyB, and the LUNGevity Foundation, recently published an evidence-based guideline for the testing of immunotherapy biomarkers, including PD-L1 and tumor mutation burden (TMB), in patients with non-small cell lung carcinoma (NSCLC).

The guideline was prompted by the proliferation of PD-L1 assays and scoring criteria, which have evolved alongside individual therapies. Some of these assays have received companion diagnostic (CDx) approvals from regulatory agencies like the FDA and Health Canada. However, due to cost and access concerns, PD-L1 antibodies and assays developed outside of randomized control trials have gained widespread use. Consequently, this has led to confusion among pathologists and clinicians regarding the optimal approach to biomarker testing for selecting patients for immune checkpoint inhibitor therapy.

The guideline aims to provide an overview of the clinical rationale for PD-L1 and TMB testing in NSCLC patients, highlighting the technical challenges of PD-L1 testing and interpretation. It also addresses the limitations of TMB testing for lung cancer patients.

Below are the guideline’s six recommendations, emphasizing the importance of validated PD-L1 IHC expression assays for selecting patients for immune checkpoint inhibitors.

Recommendations:

• In patients with advanced non-small cell lung cancer, pathologists should use a validated PD-L1 IHC expression assay, in conjunction with other targetable genomic biomarker assays where appropriate, to optimize selection for treatment with immune checkpoint inhibitors.
• Pathologists should ensure appropriate validation has been performed on all specimen types and fixatives.
  • Note: Specific validation requirements are out of scope with this guideline and laboratories should refer to the Principles of Analytic Validation of Immunohistochemical Assays Guideline for details on how to validate IHC specimens.
• When feasible, pathologists should use clinically validated PD-L1 IHC assays as intended.
• Pathologists that choose to use laboratory developed tests (LDTs) for PD-L1 expression should validate according to the requirements of their accrediting body.
• Pathologists should report PD-L1 IHC results using a percent expression score. Clinicians should not use tumor mutation burden alone to select patients with advanced NSCLC for immune checkpoint inhibitors based on insufficient evidence in this population.

As part of the expert panel, we recognize that the regulatory-approved diagnostics are clinically validated, and as such their use is recommended. However, laboratories may be relying on laboratory developed tests because of limited access to a full suite of approved clones and platforms, as well as the increased cost of running companion diagnostic-labeled assays. To ensure patient access to PD-L1 testing, particularly at the local level, we endorse the use of LDTs and validated PD-L1 IHC (LDTs) following technical validation against one or more of the approved companion diagnostic PD-L1 assays.

The new guideline for testing of immunotherapy biomarkers in patients with NSCLC will be reviewed every five years for potential updates. The expert panel may recommend earlier updates in collaboration with other organizations involved in the guideline's development.

Larissa Furtado, MD, FCAP, is a molecular pathologist and an associate member of the pathology department at St. Jude Children’s Research Hospital. Dr. Furtado is also a co-chair of the evidence-based guideline for the testing of immunotherapy biomarkers, including PD-L1 and tumor mutation burden in patients with non-small cell lung carcinoma.

Lynette Sholl, MD, FCAP, is the vice chair of anatomic pathology, interim director of the Center for Advanced Molecular Diagnostics, and chief of thoracic pathology at Brigham and Women’s Hospital. She is an associate professor of pathology at Harvard Medical School, where her research focuses on identifying pathologic, immunohistochemical, and genetic markers that will improve the classification of lung cancer, provide predictive information regarding therapy, and provide more precise prognostic information. Dr. Sholl is also a co-chair of the evidence-based guideline for the testing of immunotherapy biomarkers, including PD-L1 and tumor mutation burden in patients with non-small cell lung carcinoma.