Neoadjuvant Immunotherapy in Bladder Cancer: Ushering in a New Era of Treatment-A Systematic Review of Current Evidence.

Background and objective: Immune checkpoint inhibitors (ICIs), alone or with platinum-based chemotherapy, have increasingly been studied as neoadjuvant therapy for muscle-invasive bladder cancer (BC). We sought to evaluate the current evidence about neoadjuvant immunotherapy for BC. Methods: In this systematic review, conducted in October 2024, only prospective studies on neoadjuvant immunotherapy for BC were included. Extracted variables encompassed study design, clinical-pathological characteristics, perioperative outcomes, pathological complete response (pCR) rates, overall survival (OS), event-free survival, and immune-related (irAEs) and treatment-related (TRAEs) adverse events. Key findings and limitations: From 726 records, 35 studies met the inclusion criteria. The highest pCR rate observed was 54%, utilizing durvalumab. Perioperative chemoimmunotherapy with durvalumab plus cisplatin/gemcitabine showed greater OS than chemotherapy alone in the NIAGARA trial. The NEMIO trial achieved the highest 12-mo OS rate of 97%, using durvalumab in combination with tremelimumab and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin, followed by the AURA trial (95%) and the LCCC1520 trial (91%). At 24 mo, the NEBULA trial reported a 100% OS rate with three doses of atezolizumab, while PrECOG PrE0807 reached and OS rate of 89% with nivolumab and lirilumab. The highest rates of grade 3 and 4 irAEs were reported for nivolumab combined with ipilimumab (54%) and for durvalumab combined with tremelimumab (64%). The most common grade 3/4 irAEs were hepatitis (2-27%), kidney injury (2-100%), and skin rash (1.1-41%). Grade 3/4 TRAEs were comparable between the ICI and chemotherapy groups. Conclusions and clinical implications: Neoadjuvant immunotherapy for BC has shown promising efficacy and a manageable adverse event profile. However, financial toxicity, the absence of predictive biomarkers, and the risk of significant irAEs remain challenges. Patient summary: This study reviewed recent clinical trials that tested immunotherapy before surgery in patients with bladder cancer. The results suggest that a combination of immunotherapy and chemotherapy may improve outcomes and reduce the risk of cancer returning. These findings could help shape future treatment options for patients with muscle-invasive bladder cancer.