The value of programmed cell death ligand-1 (PD-L1) to predict durable responses to immune checkpoint inhibitors (ICIs) in metastatic urothelial carcinoma (mUC) is inconsistent. We hypothesize that the use of archived primary tumor material (PRIM) for PD-L1 testing in clinical trials not properly reflecting the metastatic disease status (MET) contributes to this clinical issue.
To analyze the predictive and prognostic value of PD-L1, spatial immunephenotypes, and major histocompatibility complex class I (MHC-I) determined in patient-matched PRIM/MET.
PD-L1, spatial immunephenotypes, and MHC-I were examined in 154 mUC patients with at least one available pretreatment MET (138 patient-matched PRIM/MET pairs).
PD-L1, spatial immunephenotype, and MHC-I status of (patient-matched PRIM and) pretreatment MET were correlated with chemotherapy and ICI response and outcomes.
Discordance rates in patient-matched PRIM/MET were 25/30%, 36%, and 49% for PD-L1 (CPS10/IC5%), immunephenotypes, and MHC-I (loss vs preserved), respectively. Correlations with chemotherapy and ICI responses were observed for immunephenotypes and MHC-I status determined in MET (not for PD-L1 alone), but not in PRIM. In case of ICIs, patients with cytotoxic tumor immune microenvironment (TIME) showed durable responses with disease control rates of 90% and a hazard ratio for disease progression/death of 0.05 (95% confidence interval: 0.01-0.65) versus patients with immunedepleted MET (disease control rate 29%). MET MHC-I status added an incremental value to predict durable ICI responses. Limitations include the partly retrospective design and the lack of MET multisampling on individual patient level.
The TIME is subject to substantial dynamics during metastatic evolution. MET immunephenotypes and MHC-I statuses show promising potential to predict chemotherapy and durable ICI responses, while the PRIM TIME does not. Thus, future clinical trials should rather rely on pretreatment MET biopsies reflecting the current immunological disease state than on PRIM.
Prediction of chemotherapy and responses to immune checkpoint inhibitors might be possible using representative pretreatment metastatic biopsies.
European urology. 2022 Nov 10 [Epub]
Franziska Erlmeier, Niklas Klümper, Laura Landgraf, Pamela L Strissel, Reiner Strick, Danijel Sikic, Helge Taubert, Sven Wach, Carol I Geppert, Veronika Bahlinger, Johannes Breyer, Manuel Ritter, Christian Bolenz, Florian Roghmann, Philipp Erben, Kristina Schwamborn, Ralph M Wirtz, Thomas Horn, Bernd Wullich, Michael Hölzel, Arndt Hartmann, Jürgen E Gschwend, Wilko Weichert, Markus Eckstein
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center EMN, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; BRIDGE-Consortium Germany e.V, Mannheim, Germany; Institute of Pathology, Technical University Munich, Munich, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany., Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany; Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany; Center for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Germany., Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center EMN, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany., Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center EMN, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; BRIDGE-Consortium Germany e.V, Mannheim, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany; Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Comprehensive Cancer Center EMN, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; BRIDGE-Consortium Germany e.V, Mannheim, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany; Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Comprehensive Cancer Center EMN, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; BRIDGE-Consortium Germany e.V, Mannheim, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany; Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center EMN, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; BRIDGE-Consortium Germany e.V, Mannheim, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany., BRIDGE-Consortium Germany e.V, Mannheim, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany; Department of Urology, University of Regensburg, Caritas St. Josef, Regensburg, Germany., BRIDGE-Consortium Germany e.V, Mannheim, Germany; Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany; Center for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Germany., BRIDGE-Consortium Germany e.V, Mannheim, Germany; Department of Urology and Pediatric Urology, University Hospital Ulm, University of Ulm, Ulm, Germany., BRIDGE-Consortium Germany e.V, Mannheim, Germany; Department of Urology, Marien Hospital, Ruhr-University Bochum, Herne, Germany., BRIDGE-Consortium Germany e.V, Mannheim, Germany; Department of Urology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany., Institute of Pathology, Technical University Munich, Munich, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany., BRIDGE-Consortium Germany e.V, Mannheim, Germany; STRATIFYER Molecular Pathology, Cologne, Germany., Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany; Department of Urology, Technical University Munich, Munich, Germany., Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany; Center for Integrated Oncology, Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Germany., Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center EMN, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; BRIDGE-Consortium Germany e.V, Mannheim, Germany; Bayerisches Zentrum für Krebsforschung (BZKF), Bavaria, Germany. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/36372626