Mathieu Rouanne1,2, Mathieu Roumiguié3,4, Nadine Houédé3,5,6, Alexandra Masson-Lecomte3,7, Pierre Colin3,8, Géraldine Pignot3,9, Stéphane Larré3,10, Evanguelos Xylinas3,11, Morgan Rouprêt3,12, Yann Neuzillet13,3. 1. Department of Urology, Hôpital Foch, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, 40 Rue Worth, 92150, Suresnes, France. rouanne.mathieu@gmail.com. 2. INSERM U1015, Gustave Roussy, Université Paris-Saclay, Villejuif, France. rouanne.mathieu@gmail.com. 3. Comité de Cancérologie de l'Association Française d'Urologie (ccAFU), Bladder Cancer Group, Maison de l'Urologie, Paris, France. 4. Department of Urology, Institut Universitaire du Cancer, Oncopole, Toulouse, France. 5. Department of Medical Oncology, CHU de Nîmes, Nimes, France. 6. INSERM U1194, Montpellier Cancer Research Institute, Université de Montpellier, Montpellier, France. 7. Department of Urology, Hôpital Saint-Louis, Université Paris-Diderot, Paris, France. 8. Department of Urology, Hôpital privé de la Louvière, Lille, France. 9. Department of Urology, Institut Paoli-Calmettes, Marseille, France. 10. Department of Urology, CHU de Reims, Reims, France. 11. Department of Urology, CHU Bichat, Paris, France. 12. Department of Urology, Hôpital La Pitié-Salpétrière, AP-HP, GRC n°5, ONCOTYPE-URO, Paris, France. 13. Department of Urology, Hôpital Foch, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, 40 Rue Worth, 92150, Suresnes, France.
Abstract
PURPOSE: Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings. METHODS: A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included. RESULTS: Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed. CONCLUSIONS: Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.
PURPOSE: Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings. METHODS: A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included. RESULTS: Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed. CONCLUSIONS: Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.
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