Transurethral resection of bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) is the standard of care in high-risk, non-muscle-invasive bladder cancer (NMIBC). Although many patients respond, recurrence and progression are common. In addition, patients may be unable to receive induction + maintenance due to intolerance or supply issues. Therefore, alternative treatment options are urgently required. Programmed cell death (ligand) 1 (PD-[L]1) inhibitors show clinical benefit in phase 1/2 trials in BCG-unresponsive NMIBC patients. This review presents the status of PD-(L)1 inhibition in high-risk NMIBC and discusses future directions. PubMed and Google scholar were searched for articles relating to NMIBC immunotherapy and ClinicalTrials.gov for planned and ongoing clinical trials. Preclinical and early clinical studies show that BCG upregulates PD-L1 expression in bladder cancer cells and, when combined with a PD-(L)1 inhibitor, a potent antitumor response is activated. Based on this mechanism, several PD-(L)1 inhibitors are in phase 3 trials in BCG-naïve, high-risk NMIBC in combination with BCG. Whereas PD-(L)1 inhibitors are well characterized in patients with advanced malignancies, the impact of immune-related adverse events (irAE) on the benefit/risk ratio in NMIBC should be determined. Alternative routes to intravenous administration, like subcutaneous and intravesical administration, may facilitate adherence and access. The outcomes of combination of PD-(L)1 inhibitors and BCG in NMIBC are highly anticipated. There will be a need to address treatment resources, optimal management of irAEs and education and training related to use of this therapy in clinical practice.
Urologic oncology. 2023 Nov 13 [Epub ahead of print]
Jens Bedke, Peter C Black, Bernadett Szabados, Félix Guerrero-Ramos, Shahrokh François Shariat, Evanguelos Xylinas, Julia Brinkmann, John A Blake-Haskins, Rossano Cesari, Joan Palou Redorta
Department of Urology and Transplantation Surgery, Kilinikum Stuttgart, Stuttgart, Germany. Electronic address: ., Department of Urologic Sciences, University of British Columbia, Vancouver, Canada., University College London Hospital, London, UK; Bart's Cancer Institute, Queen Mary University of London, London, UK., Department of Urology, Hospital Universitario 12 de Octubre, Madrid, Spain., Department of Urology, Comprehensive Cancer Network, Medical University of Vienna, Vienna, Austria., Department of Urology, Hôpital Bichat - Claude-Bernard, Université de Paris Cité, Paris, France., Pfizer Pharma GmbH, Berlin, Germany., Pfizer Inc., San Diego, CA., Pfizer Inc., Milan, Italy., Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain.