Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors
Authors: Maiorano Brigida Anna , Di Maio Massimo , Cerbone Linda , Maiello Evaristo , Procopio Giuseppe , Roviello Giandomenico ,   MeetURO Group, Accettura Caterina , Aieta Michele , Alberti Martina , Aliprandi Marta , Altavilla Amelia , Antonuzzo Lorenzo , Artemi Adele , Arundine Dario , Astore Serena , Attademo Laura , Atzori Francesco , Aurilio Gaetano , Azzariti Amalia , Baciarello Giulia , Baier Susanne , Baldazzi Valentina , Banna Giuseppe L , Barile Carmen , Barra Salvina , Barraco Chiara , Basile Debora , Bassanelli Maria , Basso Umberto , Bauckneht Matteo , Bearz Alessandra , Bellia Salvatore R , Benedetti Benedetta , Berardi Rossana , Bergamini Marco , Bersanelli Melissa , Bertoni Maria , Bianchi Emanuela , Biasini Claudia , Bidin Livia , Bimbatti Davide , Bleve Sara , Boccardo Francesco , Bolzacchini Elena , Bonato Adele , Bonomi Lucia , Bordonaro Sebastiano , Borghesi Marco , Bortolus Roberto , Bortot Lucia , Bosso Davide , Bottiglieri Achille , Bozza Giovanni , Bregni Marco , Brighi Nicole , Bronte Enrico , Bruni Alessio , Bruno Michele , Buffoni Martina , Buonerba Luciana , Buonerba Carlo , Buti Sebastiano , Buttigliero Consuelo , Cadau Jessica , Caffo Orazio , Calabrò Fabio , Calvani Nicola , Campobasso Davide , Capacci Samanta , Capitanio Umberto , Caponnetto Salvatore R , Carella Claudia , Carlini Paolo , Carrozza Francesco , Cartenì Giacomo , Caruso Davide , Casadei Chiara , Catalano Fabio , Catalano Martina , Cattrini Carlo , Cavasin Nicolò , Cavo Alessia , Cecchi Luigi G , Cecere Sabrina C , Cerbone Linda , Ceresoli Giovanni L , Chiari Rita , Chiellino Silvia , Chiuri Vincenzo E , Ciccarelli Stefano , Cicero Giuseppe L , Cinausero Marika , Citarella Fabrizio , Claps Melanie , Cocorocchio Emilia , Conteduca Vincenza , Coppola Elisabetta , Cordua Nadia , Cossu Rocca Maria , Courthod Giulia , Cremante Malvina , Cullurà Daniela , Cursano Maria C , D'Ostilio Nicola , Dalla Volta Alberto , Damassi Alessandra , Daniele Bruno , De Giorgi Ugo FF , De Lisa Mariagrazia , De Lisi Delia , De Summa Simona , De Vivo Rocco , Debonis Silvia A , Del Re Marzia , Depetris Ilaria , Di Civita Mattia A , Di Costanzo Fabrizio , Di Francesco Simona , Di Girolamo Stefania , Di Lorenzo Giuseppe , Di Maio Massimo , Di Napoli Marilena , Di Rocco Roberta , Di Tullio Piergiorgio , Dinota Angelo , Dionese Michele , Donati Donatella , Doni Laura , Doronzo Antonio , Dri Arianna , Ermacora Paola , Evangelista Laura , Fanelli Martina , Farè Elena , Farnesi Azzurra , Farolfi Alberto , Febbraro Antonio , Fedele Palma , Federico Piera , Filaci Gilberto , Filippi Roberto , Filograna Alessia , Foderaro Simone , Fontana Antonella , Formisano Luigi , Fornarini Giuseppe , Francini Edoardo , Franzese Ciro , Fratino Lucia , Galanti Daniele , Galli Luca , Gamba Teresa , Gambale Elisabetta , Garattini Silvio K , Garibaldi Elisabetta , Gasparro Donatello , Gentile Anna L , Germano Domenico , Gernone Angela , Ghilardi Laura , Giannatempo Patrizia , Gianni Caterina , Gianotti Emilia , Giorgione Roberta , Giudice Giulia C , Giunta Emilio F , Gridelli Cesare , Grillone Francesco , Guadalupi Valentina , Gualtieri Simona , Guarneri Alessia S , Guglielmo Priscilla , Hamzaj Alketa , Hamzaj Afete , Iaia Maria L , Ierinò Debora , Incorvaia Lorena , Ingenito Concetta , Inzerilli Nicola , Jubran Salim , Kinspergher Stefania , La Camera Antonella , La Russa Francesca , Lai Eleonora , Lancia Federica , Landriscina Matteo , Lanfranchi Francesco , Latteri Fiorenza , Lenci Edoardo , Lipari Helga MA , Llaja Obispo Migual A , Lo Vecchio Monica , Lombardo Valentina N , Lombardo Laura , Luciani Andrea , Macerelli Marianna , Maffezzoli Michele , Maines Francesca , Maiorano Brigida A , Malgeri Andrea , Marinelli Daniele , Maruzzo Marco , Masini Cristina , Massi Daiana , Mastrorosa Alessandro , Mattana Alvise , Mencoboni Manlio , Mennitto Alessia , Mercinelli Chiara , Messina Carlo , Messina Marco , Migliaccio Fortuna , Migliari Marco , Montagna Benedetta , Montanari Daniela , Morelli Anna M , Morelli Franco , Moroso Stefano , Mosca Alessandra , Mucciarini Claudia , Hernandez Fernando M , Murgia Viviana , Murianni Veronica , Murru Maura , Muto Andrea , Naglieri Emanuele , Nasso Cecilia , Nicodemo Maurizio , Nolè Franco , Orlando Valentina , Ortega Cinzia , Paccagnella Elisabetta , Pacelli Roberto , Palazzo Antonio , Palesandro Erica , Pantano Francesco , Paolieri Federico , Pappagallo Maria N , Pappalardo Laura , Pasqualini Antonella , Passalacqua Rodolfo , Passarelli Anna , Pecoraro Giovanna , Pedrazzoli Paolo , Pelin Giulia M , Pellino Antonio , Pepe Alessio , Perna Marco , Perrino Matteo , Perrone Francesco , Perrucci Bruno , Persano Mara , Piancastelli Alessandra , Picciotto Maria , Pierantoni Francesco , Pignata Sandro , Pilato Brunella , Piras Margherita , Pireddu Annagrazia , Pisano Chiara , Pisano Carmela , Piscazzi Annamaria , Pisconti Salvatore R , Pisino Marco , Pitrè Alessandra , Poeta Maria L , Pompella Luca , Poti Giulia , Prati Veronica , Procopio Giuseppe , Puglia Livio , Razzini Giorgia , Rebuzzi Sara E , Recine Federica , Rescigno Pasquale , Ribera Dario , Ricotta Riccardo , Rizzo Alessio , Rizzo Mimma , Roberto Michela , Rollo Luisa , Rossetti Sabrina , Rossi Virginia , Rossi Ernesto , Rossi Lorena , Rosti Giovanni , Roviello Giandomenico , Russi Elvio G , Salesi Nello , Salfi Alessia , Sammarco Enrico , Sanguedolce Francesca , Sansi Camilla , Santamaria Fiorenza , Santini Daniele , Santoni Matteo , Sartori Donata , Sartragno Camilla , Sava Teodoro , Sbrana Andrea , Scagliarini Sarah , Scala Stefania , Scandurra Giuseppa , Scattolin Daniela , Schepisi Giuseppe , Schettino Clorinda , Schinzari Giovanni , Secondino Simona , Sepe Pierangela , Serra Riccardo , Signori Alessio , Silvestro Giustino , Sirotovà Zuzana , Sorarù Mariella , Soto Parra Hector , Spinelli Gian P , Stellato Marco , Stumbo Luciano , Tagliaferri Pierosandro , Tambaro Rosa , Tamberi Stefano , Testi Irene , Toma Ilaria , Tomasino Mirko , Tommasi Stefania , Tortora Vincenzo , Tortorella Anna , Toscani ilaria , Tralongo Paolo , Triolo Renza , Tucci Marcello , Urban Susanna , Urso Luca , Valsecchi Anna A , Veccia Antonello , Vela Chiara , Ventriglia Jole , Verde Antonio , Verzoni Elenza , Vignani Francesca , Vitale Maria G , Vittimberga Isabella , Zacchi Francesca , Zago Giulia , Zagonel Vittorina , Zanardi Elisa , Zara Diego , Zeppellini Annalisa , Zonno Antonia , Zucali Paola A , Zumstein Lucrezia 
Published: March 2024

ImportanceImmune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial.ObjectivesTo evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs.Data SourcesPubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023.Study SelectionTwo authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1–positive and –negative tumors.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies.Main Outcomes and MeasuresPrimary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1–positive tumors and patients with PD-L1–negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1–positive and –negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials.ResultsA total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1–positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1–positive tumors and 5.1% to 63.2% in patients with PD-L1–negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1–positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P &amp;lt; .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1–positive tumors and from 6.0 to 19.1 months in patients with PD-L1–negative tumors. The pooled HR showed a significant reduction for patients with PD-L1–positive tumors compared with those with PD-L1–negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P &amp;lt; .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response.Conclusions and RelevanceThis systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents.