Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in
Reinhard Büttner1, John R Gosney1, Birgit Guldhammer Skov1
1Reinhard Büttner, University Hospital Cologne, Cologne; Manfred Dietel, Charité Universitätsmedizin Berlin, Berlin, Germany; John R. Gosney, Royal Liverpool University Hospital, Liverpool; Andrew C. Wotherspoon, Royal Marsden Hospital, London; Keith M. Kerr, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom; Birgit Guldhammer Skov, Copenhagen University Hospital, Copenhagen, Denmark; Julien Adam, Gustave Roussy Cancer Center, Villejuif; Frédérique Penault-Llorca, Jean Perrin Comprehensive Cancer Center, Clermont-Ferrand, France; Noriko Motoi, National Cancer Center Hospital, Tokyo, Japan; Kenneth J. Bloom, Human Longevity, San Diego, CA; John W. Longshore, Carolinas Pathology Group, Charlotte, NC; Fernando López-Ríos, Hospital Universitario HM Sanchinarro, Madrid, Spain; Giuseppe Viale, University of Milan, Milan, Italy; and Ming-Sound Tsao, University Health Network, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
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.
Insights
Programmed death-1/programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays show high concordance for tumor cell membrane expression in non-small-cell lung cancer, suggesting potential interchangeability. However, immune cell expression is variable and requires further standardization.
Area of Science:
- Oncology
- Immunotherapy
- Diagnostic Pathology
Background:
- Three programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are approved for non-small-cell lung cancer (NSCLC).
- PD-L1 immunohistochemistry (IHC) testing is required for pembrolizumab, while nivolumab and atezolizumab have available complementary tests.
- Four PD-L1 IHC assays (28-8, 22C3, SP142, SP263) are used in clinical trials, raising questions about their comparability and diagnostic utility due to differences in antibodies and platforms.
Purpose of the Study:
- To provide practical information for physicians and pathologists on the analytical features and comparability of various PD-L1 IHC assays.
- To address practical issues related to tissue samples used for testing PD-L1 expression.
- To evaluate the diagnostic use of different PD-L1 IHC assays in NSCLC treatment.
Main Methods:
- A review and summary of published studies (January 2016 to January 2017) on clinical trial and laboratory-developed PD-L1 IHC assays (LDAs).
- Analysis of studies assessing the effect of diagnostic methods on PD-L1 expression levels.
- Evaluation of interobserver reproducibility and concordance among different assays.
Main Results:
- High concordance and interobserver reproducibility were observed for the 28-8, 22C3, and SP263 assays when assessing PD-L1 on tumor cell membranes.
- The SP142 assay detected lower PD-L1 expression compared to the other three assays.
- PD-L1 expression on immune cells showed variability and poor interobserver concordance; inter- and intratumoral heterogeneity also impacted expression.
- Concordance among laboratory-developed assays (LDAs) was variable.
Conclusions:
- The 28-8, 22C3, and SP263 assays demonstrate high concordance for tumor cell membrane PD-L1 expression, suggesting potential interchangeability in clinical use for NSCLC.
- These assays are not interchangeable for assessing PD-L1 expression on immune cells.
- Laboratory-developed assays require stringent standardization before routine clinical use.
