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CAP Releases Testing Guidelines for Immunotherapy Biomarkers in NSCLC

NEW YORK – The College of American Pathologists (CAP) in collaboration with the International Association for the Study of Lung Cancer (IASLC), Pulmonary Pathology Society (PPS), Association for Molecular Pathology (AMP), and the LUNGevity Foundation on Tuesday released guidelines for the testing of immunotherapy biomarkers such as PD-L1 and tumor mutation burden (TMB) in lung cancer.

The guidelines were released in the Archives of Pathology & Laboratory Medicine. The recommendations aimed to address the uncertainty around selecting and implementing tests for PD-L1 and TMB in practice due to the variability in available methods. The expert panel creating the guidelines found that laboratories may be using laboratory-developed tests (LDTs) rather than approved platforms and companion diagnostics due to limited access and the cost of the approved assays.

"In contrast to most genomic biomarkers, which tend to represent relatively stable and binary data points in a patient's tumor profile in treatment-naive patients, PD-L1 expression is dynamic and heterogeneous, complicating the choice of sample for testing," the panel wrote in the published guidelines.

To help unify how PD-L1 expression is tested for and reported in results, CAP issued six guidelines focused on ensuring pathologists validate the test they use, even if it's an LDT; test the correct subset of patients; and report results in a uniform way.

The first guideline recommends that pathologists use a validated PD-L1 immunohistochemistry expression assay, together with genomic biomarker assays, to optimize selection for treatment with immune checkpoint inhibitors for patients with advanced non-small cell lung cancer. The panel found across more than 30 studies that greater benefit from immunotherapy was correlated with PD-L1 expression status in advanced disease NSCLC patients without EGFR and ALK mutations.

The CAP guidelines also recommended that pathologists ensure appropriate validation has been performed on all specimen types and fixatives. The expert panel acknowledged there have been few studies exploring associations between the tumor specimen used to test for PD-L1 expression and clinical outcomes on immunotherapy. The guideline cautioned that certain types of tumor samples may lead to discordant results due to the heterogeneity of PD-L1 expression, such as samples from metastatic lesions, as well as small biopsy samples.

When it came to using either clinically validated PD-L1 immunohistochemistry assays or LDTs for PD-L1 expression, CAP recommended pathologists use the approved diagnostics as intended and, if using an LDT, that they validate the LDTs against the approved CDx before use. The panel recognized that some labs use LDTs due to cost and access issues, but previous studies have found that only between 50 percent and 60 percent of LDTs were analytically compatible to CDx assays.

To report PD-L1 results, the guidelines said pathologists should report PD-L1 immunohistochemistry results using a percentage expression score due to studies showing that the levels of PD-L1 tumor proportion score (TPS) have shown a correlation with patient response and survival on immunotherapy. NSCLC patients with high PD-L1 expression, greater than 50 percent of cells, largely have higher response rates and improved outcomes, the panel found. They recognized that reporting an exact percentage may be difficult at times and recommended reporting a range of PD-L1 TPS expression in those cases.

Finally, the CAP guidelines recommended that clinicians not use TMB alone to select patients with advanced NSCLC for immunotherapy. The panel found there was insufficient evidence to show that TMB alone could be used to select these patients and that it had an effect on response and survival on immunotherapy.