Limited predictive value of PD-L1 TPS for pathological response in NSCLC is not attributable to interobserver variability

Background PD-L1 tumor proportion score (TPS) is used to guide immunotherapy in non-small cell lung cancer (NSCLC), yet its ability to predict pathological response in the neoadjuvant setting remains limited. Methods Thirty pathologists from 11 countries independently assessed PD-L1 TPS in pre-treatment biopsies and residual viable tumor (RVT) in matched resection specimens after neoadjuvant chemoimmunotherapy in 30 digitized cases from the ReGraDE (regression grading in Germany) study. Interobserver agreement was evaluated using intraclass correlation coefficients (ICC) and Fleiss' kappa. Associations between TPS and RVT were analyzed using Pearson correlation, and correlations derived from single-rater and averaged TPS were compared using the Williams test. Results Interobserver agreement was moderate for both TPS and RVT (ICC = 0.74, 95% CI 0.60–0.87, and ICC = 0.74, 95% CI 0.62–0.85, respectively) and became near-perfect when mean scores per case were calculated across observers (ICC = 0.99, for both). However, TPS remained poorly correlated with RVT for both single-rater assessment (r = –0.17, p = 0.38) and averaged TPS (r = –0.16, p = 0.39) with no significant difference between these approaches (p = 0.96). Differences in interpretation thresholds were observed particularly in borderline cases around the 1% TPS cut-off and in distinguishing 0% from minimal RVT, but did not account for the lack of association between TPS and RVT. Systematic differences were observed depending on individual professional experience, particularly in borderline cases. Conclusion Interobserver variability does not explain the limited predictive value of PD-L1 TPS in the neoadjuvant setting, suggesting an intrinsic limitation of the biomarker.

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Journal
Lung Cancer
Published
2026-06-26
DOI
https://doi.org/10.1016/j.lungcan.2026.109510
Primary Topic
Cancer Immunotherapy and Biomarkers
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article
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article

Limited predictive value of PD-L1 TPS for pathological response in NSCLC is not attributable to interobserver variability

Felix Elsner, Kristijan Skok, Alessandro Gambella, Gerardo Cazzato et al.
Lung Cancer
Cancer Immunotherapy and Biomarkers
article

Limited predictive value of PD-L1 TPS for pathological response in NSCLC is not attributable to interobserver variability

Felix Elsner, Kristijan Skok, Alessandro Gambella, Gerardo Cazzato, Konrad Steinestel, Hanibal Bohnenberger, Jan‐Olof Dahlberg, Gheorghe‐Emilian Olteanu, Anja C. Roden, Konstantin Bräutigam, Helmut Popper, Anne‐Sophie Becker, Christian Matek, Menelaos G. Samaras, João Martins Gama, Esther Conde, Fernando López‐Ríos, Francesca Lunardi, Annikka Weissferdt, Jozef Zustin, David Suster, Georg Hutarew, Francesca Ambrosi, Daniel Curto, Andreea-Raluca Cozac-Szőke, Lena-Maria Löwer-Kiem, Christian Meyer, Stefano Lucà, Christiane Kümpers
article en

Abstract

Background PD-L1 tumor proportion score (TPS) is used to guide immunotherapy in non-small cell lung cancer (NSCLC), yet its ability to predict pathological response in the neoadjuvant setting remains limited. Methods Thirty pathologists from 11 countries independently assessed PD-L1 TPS in pre-treatment biopsies and residual viable tumor (RVT) in matched resection specimens after neoadjuvant chemoimmunotherapy in 30 digitized cases from the ReGraDE (regression grading in Germany) study. Interobserver agreement was evaluated using intraclass correlation coefficients (ICC) and Fleiss' kappa. Associations between TPS and RVT were analyzed using Pearson correlation, and correlations derived from single-rater and averaged TPS were compared using the Williams test. Results Interobserver agreement was moderate for both TPS and RVT (ICC = 0.74, 95% CI 0.60–0.87, and ICC = 0.74, 95% CI 0.62–0.85, respectively) and became near-perfect when mean scores per case were calculated across observers (ICC = 0.99, for both). However, TPS remained poorly correlated with RVT for both single-rater assessment (r = –0.17, p = 0.38) and averaged TPS (r = –0.16, p = 0.39) with no significant difference between these approaches (p = 0.96). Differences in interpretation thresholds were observed particularly in borderline cases around the 1% TPS cut-off and in distinguishing 0% from minimal RVT, but did not account for the lack of association between TPS and RVT. Systematic differences were observed depending on individual professional experience, particularly in borderline cases. Conclusion Interobserver variability does not explain the limited predictive value of PD-L1 TPS in the neoadjuvant setting, suggesting an intrinsic limitation of the biomarker.

Lung CancerVol. 218
Rutgers, The State University of New Jersey (US), The University of Texas MD Anderson Cancer Center (US), Institute of Cancer Research (GB), National and Kapodistrian University of Athens (GR), Medical University of Graz (AT), University of Pavia (IT), Paracelsus Medical University (AT), University Hospital of Basel (CH), Universitatea de Medicină, Farmacie, Științe și Tehnologie „George Emil Palade” din Târgu Mureș (RO), University of Maribor (SI), Research Institute Hospital 12 de Octubre (ES), Universitätsklinikum Erlangen (DE), Victor Babeș University of Medicine and Pharmacy Timișoara (RO), Royal Brompton Hospital (GB), Ospedale Maggiore Carlo Alberto Pizzardi (IT), Nuremberg Hospital (DE), Hospital Universitario 12 De Octubre (ES), Instituto Português de Oncologia Francisco Gentil (PT), NIHR Royal Brompton Cardiovascular Biomedical Research Unit (GB), University Hospital Schleswig-Holstein (DE), Universitätsmedizin Göttingen (DE), Mayo Clinic in Arizona (US), University of Campania "Luigi Vanvitelli" (IT), Praxis für Humangenetik (DE), Comprehensive Cancer Center Erlangen (DE), Policlinico San Matteo Fondazione (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Växjö Kommun (SE), Bundeswehrkrankenhaus Ulm (DE), Rutgers New Jersey Medical School (US), University of Rostock (DE), University of Bari Aldo Moro (IT), University of Regensburg (DE), University of Genoa (IT), University of Lübeck (DE), University of Bologna (IT)
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