Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors
Brigida Anna Maiorano, Massimo Di Maïo, Linda Cerbone, Evaristo Maiello, Giuseppe Procopio, Giandomenico Roviello, MeetURO Group, Caterina Accettura, Michele Aieta, Martina Alberti, Marta Aliprandi, Amelia Altavilla, Lorenzo Antonuzzo, Adele Artemi, Dario Arundine, Serena Astore, Laura Attademo, Francesco Atzori, Gaetano Aurilio, Amalia Azzariti, Giulia Baciarello, Susanne Baier, Valentina Baldazzi, Giuseppe Luigi Banna, Carmen Barile, Salvina Barra, Chiara Barraco, Debora Basile, Maria Bassanelli, Umberto Basso, Matteo Bauckneht, Alessandra Bearz, S.R. Bellia, Benedetta Benedetti, Rossana Berardi, Marco Bergamini, Melissa Bersanelli, Maria Bertoni, Emanuela Bianchi, Claudia Biasini, L. Bidin, Davide Bimbatti, Sara Bleve, Francesco Boccardo, Elena Bolzacchini, Adele Bonato, Lucia Bonomi, Sebastiano Bordonaro, Marco Borghesi, Roberto Bortolus, L. Bortot, Davide Bosso, Achille Bottiglieri, Giovanni Bozza, Marco Bregni, Nicole Brighi, Enrico Bronte, Alessio Bruni, Michele Bruno, M. Buffoni, Luciana Buonerba, Carlo Buonerba, Sebastiano Buti, Consuelo Buttigliero, Jessica Cadau, Orazio Caffo, Fabio Calabrò, Nicola Calvani, Davide Campobasso, Samanta Capacci, Umberto Capitanio, S Caponnetto, Claudia Carella, Paolo Carlini, Francesco Carrozza, Giacomo Cartenì, Davide Caruso, Chiara Casadei, Fabio Catalano, Martina Catalano, Carlo Cattrini, Nicolò Cavasin, Alessia Cavo, Luigi Cecchi, Sabrina Chiara Cecere, Linda Cerbone, Giovanni Luca Ceresoli, Rita Chiari, Silvia Chiellino, Vincenzo Emanuele Chiurì, Stefano Ciccarelli, Giuseppe Cicero, M. Cinausero, Fabrizio Citarella, Mélanie Claps, Emilia Cocorocchio, Vincenza Conteduca, Elisabetta Coppola, Nadia Cordua, Maria Cossu Rocca
Abstract
Importance: Immune 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. Objectives: To evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs. Data Sources: PubMed, 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 Selection: Two 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 Synthesis: The 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 Measures: Primary 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. Results: A 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 < .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 < .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response. Conclusions and Relevance: This 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.