Julien Adam1,2, Yves Allory3,4,5, Mathieu Rouanne6,7, Camélia Radulescu3. 1. Département de Pathologie, Hôpital Paris Saint-Joseph, 75014, Paris, France. 2. INSERM U1186, Gustave Roussy, 94805, Villejuif, France. 3. Département de Pathologie, Hôpital Foch, UVSQ, Université Paris-Saclay, 92150, Suresnes, France. 4. Départment de Pathologie, Institut Curie, 92210, Saint-Cloud, France. 5. Centre National de la Recherche Scientifique (CNRS) UMR144, Equipe Labellisée Ligue Nationale Contre le Cancer, 75005, Paris, France. 6. Département d'Urologie, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Hôpital FOCH, 40, rue Worth, 92150, Suresnes, France. rouanne.mathieu@gmail.com. 7. Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, 94805, Villejuif, France. rouanne.mathieu@gmail.com.
Abstract
PURPOSE: While immunotherapy has become an increasingly attractive strategy in patients with urothelial bladder cancer, the need for a biomarker to identify patients whose cancer is the most likely to respond has never been more crucial. This review systematically evaluates evidence regarding PD-L1 as a predictive biomarker of response to anti-PD(L)1 monoclonal antibodies in patients with urothelial bladder carcinoma, and discusses its current limits in routine clinical practice. METHODS: We performed a critical review of PubMed/Medline according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective clinical trials evaluating anti-PD(L)1 monoclonal antibodies in urothelial bladder carcinoma together with retrospective studies evaluating PD-L1 expression in patients with bladder cancer were included. RESULTS: Evidence data related to PD-L1 as a predictive biomarker of response to immune checkpoint blockade monotherapy across clinical trials are detailed in this review. The different companion diagnostic assays, and the methods for PD-L1 scoring in urothelial bladder carcinoma are reported. Additionally, the issues related to the implementation of PD-L1 testing in clinical practice are discussed. CONCLUSIONS: PD-(L)1 monoclonal antibodies atezolizumab and pembrolizumab are restricted to patients with PD-L1 positive status in the first-line setting in patients with advanced or metastatic urothelial bladder carcinoma who are ineligible to cisplatin-based chemotherapy. Importantly, the use of anti-PD(L)1 mAb in the other clinical settings is not based on PD-L1 status, but rather on patients' clinical characteristics. Further identification of biomarkers with high negative predictive value will also be of utmost importance to identify patients who may not respond to such immunotherapies.
PURPOSE: While immunotherapy has become an increasingly attractive strategy in patients with urothelial bladder cancer, the need for a biomarker to identify patients whose cancer is the most likely to respond has never been more crucial. This review systematically evaluates evidence regarding PD-L1 as a predictive biomarker of response to anti-PD(L)1 monoclonal antibodies in patients with urothelial bladder carcinoma, and discusses its current limits in routine clinical practice. METHODS: We performed a critical review of PubMed/Medline according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective clinical trials evaluating anti-PD(L)1 monoclonal antibodies in urothelial bladder carcinoma together with retrospective studies evaluating PD-L1 expression in patients with bladder cancer were included. RESULTS: Evidence data related to PD-L1 as a predictive biomarker of response to immune checkpoint blockade monotherapy across clinical trials are detailed in this review. The different companion diagnostic assays, and the methods for PD-L1 scoring in urothelial bladder carcinoma are reported. Additionally, the issues related to the implementation of PD-L1 testing in clinical practice are discussed. CONCLUSIONS:PD-(L)1 monoclonal antibodies atezolizumab and pembrolizumab are restricted to patients with PD-L1 positive status in the first-line setting in patients with advanced or metastatic urothelial bladder carcinoma who are ineligible to cisplatin-based chemotherapy. Importantly, the use of anti-PD(L)1 mAb in the other clinical settings is not based on PD-L1 status, but rather on patients' clinical characteristics. Further identification of biomarkers with high negative predictive value will also be of utmost importance to identify patients who may not respond to such immunotherapies.
Authors: Joaquim Bellmunt; Ronald de Wit; David J Vaughn; Yves Fradet; Jae-Lyun Lee; Lawrence Fong; Nicholas J Vogelzang; Miguel A Climent; Daniel P Petrylak; Toni K Choueiri; Andrea Necchi; Winald Gerritsen; Howard Gurney; David I Quinn; Stéphane Culine; Cora N Sternberg; Yabing Mai; Christian H Poehlein; Rodolfo F Perini; Dean F Bajorin Journal: N Engl J Med Date: 2017-02-17 Impact factor: 91.245
Authors: Markus Eckstein; Philipp Erben; Maximilian C Kriegmair; Thomas S Worst; Cleo-Aron Weiß; Ralph M Wirtz; Sven Wach; Robert Stoehr; Danijel Sikic; Carol I Geppert; Veronika Weyerer; Simone Bertz; Johannes Breyer; Wolfgang Otto; Bastian Keck; Maximilian Burger; Helge Taubert; Wilko Weichert; Bernd Wullich; Christian Bolenz; Arndt Hartmann; Franziska Erlmeier Journal: Eur J Cancer Date: 2018-12-05 Impact factor: 9.162
Authors: Jonathan E Rosenberg; Jean Hoffman-Censits; Tom Powles; Michiel S van der Heijden; Arjun V Balar; Andrea Necchi; Nancy Dawson; Peter H O'Donnell; Ani Balmanoukian; Yohann Loriot; Sandy Srinivas; Margitta M Retz; Petros Grivas; Richard W Joseph; Matthew D Galsky; Mark T Fleming; Daniel P Petrylak; Jose Luis Perez-Gracia; Howard A Burris; Daniel Castellano; Christina Canil; Joaquim Bellmunt; Dean Bajorin; Dorothee Nickles; Richard Bourgon; Garrett M Frampton; Na Cui; Sanjeev Mariathasan; Oyewale Abidoye; Gregg D Fine; Robert Dreicer Journal: Lancet Date: 2016-03-04 Impact factor: 79.321
Authors: Thomas Powles; Ignacio Durán; Michiel S van der Heijden; Yohann Loriot; Nicholas J Vogelzang; Ugo De Giorgi; Stéphane Oudard; Margitta M Retz; Daniel Castellano; Aristotelis Bamias; Aude Fléchon; Gwenaëlle Gravis; Syed Hussain; Toshimi Takano; Ning Leng; Edward E Kadel; Romain Banchereau; Priti S Hegde; Sanjeev Mariathasan; Na Cui; Xiaodong Shen; Christina L Derleth; Marjorie C Green; Alain Ravaud Journal: Lancet Date: 2017-12-18 Impact factor: 79.321
Authors: Arjun V Balar; Matthew D Galsky; Jonathan E Rosenberg; Thomas Powles; Daniel P Petrylak; Joaquim Bellmunt; Yohann Loriot; Andrea Necchi; Jean Hoffman-Censits; Jose Luis Perez-Gracia; Nancy A Dawson; Michiel S van der Heijden; Robert Dreicer; Sandy Srinivas; Margitta M Retz; Richard W Joseph; Alexandra Drakaki; Ulka N Vaishampayan; Srikala S Sridhar; David I Quinn; Ignacio Durán; David R Shaffer; Bernhard J Eigl; Petros D Grivas; Evan Y Yu; Shi Li; Edward E Kadel; Zachary Boyd; Richard Bourgon; Priti S Hegde; Sanjeev Mariathasan; AnnChristine Thåström; Oyewale O Abidoye; Gregg D Fine; Dean F Bajorin Journal: Lancet Date: 2016-12-08 Impact factor: 79.321
Authors: Arjun V Balar; Daniel Castellano; Peter H O'Donnell; Petros Grivas; Jacqueline Vuky; Thomas Powles; Elizabeth R Plimack; Noah M Hahn; Ronald de Wit; Lei Pang; Mary J Savage; Rodolfo F Perini; Stephen M Keefe; Dean Bajorin; Joaquim Bellmunt Journal: Lancet Oncol Date: 2017-09-26 Impact factor: 41.316
Authors: Andrea B Apolo; Jeffrey R Infante; Ani Balmanoukian; Manish R Patel; Ding Wang; Karen Kelly; Anthony E Mega; Carolyn D Britten; Alain Ravaud; Alain C Mita; Howard Safran; Thomas E Stinchcombe; Marko Srdanov; Arnold B Gelb; Michael Schlichting; Kevin Chin; James L Gulley Journal: J Clin Oncol Date: 2017-04-04 Impact factor: 44.544
Authors: Padmanee Sharma; Margaret K Callahan; Petri Bono; Joseph Kim; Pavlina Spiliopoulou; Emiliano Calvo; Rathi N Pillai; Patrick A Ott; Filippo de Braud; Michael Morse; Dung T Le; Dirk Jaeger; Emily Chan; Chris Harbison; Chen-Sheng Lin; Marina Tschaika; Alex Azrilevich; Jonathan E Rosenberg Journal: Lancet Oncol Date: 2016-10-09 Impact factor: 41.316