The current and future role of systemic therapy in non–muscle-invasive bladder cancer

Non–muscle-invasive bladder cancer (NMIBC) categorizes early-stage urothelial carcinoma that has not invaded the bladder's muscle layer. Although it is initially treatable with transurethral resection, NMIBC has a high risk of recurrence and progression, which necessitates prolonged surveillance and intravesical therapies. Intravesical bacillus Calmette–Guérin (BCG), originally developed as a tuberculosis vaccine, has proven effective in reducing recurrence and delaying progression in NMIBC. Notably, BCG immunotherapy was among the first treatments to demonstrate that activating the immune system could control localized urothelial cancer. Although there has been recent growth in novel intravesical therapies for patients with BCG-unresponsive disease, options remain limited, and radical cystectomy is still frequently performed. Recent advances in systemic therapies, especially immunotherapies targeting the programmed cell death protein 1/programmed death ligand 1 pathway, have now affected NMIBC, with pembrolizumab receiving regulatory approval. This development has spurred numerous clinical trials investigating systemic therapeutic agents in NMIBC alone or in combination with other modalities such as intravesical therapy or radiation to improve outcomes. To understand the current landscape in this clinical space, a systematic review of systemic therapy in NMIBC was performed. Current data and ongoing studies that use systemic agents to treat this disease are presented. Despite recent progress in this domain, there remains a substantial need for more effective treatments with fewer toxicities for NMIBC. Future trials will be essential for optimizing these therapies and improving patient outcomes.