Neoadjuvant Immunotherapy in Bladder Cancer: Ushering in a New Era of Treatment—A Systematic Review of Current Evidence
Caio Vinícius Suartz, Richard Dobrucki de Lima, Lucas Schenk de almeida, Bruno Liebl, Roberto Iglesias Lopes, Gabriel Baêta Branquinho Reis, Pedro Vasconcelos Henry Sant’Anna, Vinícius Daniel Faris de Campos, José Maurício Mota, Bárbara Vieira Lima Aguiar Melão, William Carlos Nahas, Walid Shahrour, Walid Shabana, Leopoldo Alves Ribeiro‐Filho, Paul Toren, Vicent Fradet
Abstract
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.