Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in Non–Small-Cell Lung Cancer

Abstract

Purpose Three programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of non-small-cell lung cancer (NSCLC). Treatment with pembrolizumab in NSCLC requires PD-L1 immunohistochemistry (IHC) testing. Nivolumab and atezolizumab are approved without PD-L1 testing, though US Food and Drug Administration-cleared complementary PD-L1 tests are available for both. PD-L1 IHC assays used to assess PD-L1 expression in patients treated with programmed death-1/PD-L1 inhibitors in clinical trials include PD-L1 IHC 28-8 pharmDx (28-8), PD-L1 IHC 22C3 pharmDx (22C3), Ventana PD-L1 SP142 (SP142), and Ventana PD-L1 SP263 (SP263). Differences in antibodies and IHC platforms have raised questions about comparability among these assays and their diagnostic use. This review provides practical information to help physicians and pathologists understand analytical features and comparability of various PD-L1 IHC assays and their diagnostic use. Methods We reviewed and summarized published or otherwise reported studies (January 2016 to January 2017) on clinical trial and laboratory-developed PD-L1 IHC assays (LDAs). Studies assessing the effect of diagnostic methods on PD-L1 expression levels were analyzed to address practical issues related to tissue samples used for testing. Results High concordance and interobserver reproducibility were observed with the 28-8, 22C3, and SP263 clinical trial assays for PD-L1 expression on tumor cell membranes, whereas lower PD-L1 expression was detected with SP142. Immune-cell PD-L1 expression was variable and interobserver concordance was poor. Inter- and intratumoral heterogeneity had variable effects on PD-L1 expression. Concordance among LDAs was variable. Conclusion High concordance among 28-8, 22C3, and SP263 when assessing PD-L1 expression on tumor cell membranes suggests possible interchangeability of their clinical use for NSCLC but not for assessment of PD-L1 expression on immune cells. Development of LDAs requires stringent standardization before their recommendation for routine clinical use.

Patient Selection for Anti-PD-1/PD-L1 Therapy in Advanced Non-Small-Cell Lung Cancer: Implications for Clinical Practice

“…Irrespective of the assay used, atezolizumab was shown to improve survival in patients with PD-L1-negative tumors, confirming the original findings of the trial [15]. Other studies have demonstrated high concordance between most PD-L1 IHC assays, but have not correlated these data with clinical results [16][17][18]. Efforts are underway by the pharmaceutical industry and regulators to harmonize these diagnostic tests.…”

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

“…KEYNOTE‐028 only included patients who were screened as positive for the PD‐L1 biomarker (also defined as >1% PD‐L1 expression in both tumour and immune cells). Second, the two trials analysed PD‐L1 as a binary rather than continuous variable, despite the impact of the latter on clinical outcomes . Whether the benefit of nivolumab or pembrolizumab dissipated with lower levels of PD‐L1 expression is unclear.…”

Inter‐ and intraobserver agreement of programmed death ligand 1 scoring in head and neck squamous cell carcinoma, urothelial carcinoma and breast carcinoma

“…Programmed death ligand 1 (PD‐L1) is a transmembrane protein expressed on immune cells (IC) and tumour cells (TC), whereas programmed cell death (PD)‐1 is expressed on IC and its expression can be induced following T cell activation. Upon binding to the receptor PD‐1 in IC, the overexpressed PD‐L1 in TC leads to functional inactivation of T cells and down‐regulation of T cell antitumoral activity, resulting in immune evasion . In recent years, PD‐L1 and PD‐1 have emerged as a key check‐point that can be manipulated with inhibitory monoclonal antibodies in various cancer types.…”