Recent phase 3 randomized controlled trials (RCTs) demonstrate the promising impact of immune checkpoint inhibitor (ICI)-based combination therapies on locally advanced or metastatic urothelial carcinoma (UC). However, comparative data on the efficacy and toxicity of different ICI-based combinations are lacking. This study aims to compare the efficacy of first-line ICI-based combination therapies for locally advanced or metastatic UC using phase 3 RCT data. In November 2023, three databases were searched for RCTs evaluating oncological outcomes in patients with locally advanced or metastatic UC who were treated with first-line ICI-based combination therapies. Network meta-analysis (NMA) was conducted to compare outcomes, including overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), and treatment-related adverse events (TRAEs). Subgroup analyses were based on PD-L1 status and cisplatin eligibility. The NMA included five RCTs. Enfortumab vedotin (EV) + pembrolizumab ranked the highest for improving OS (100%), PFS (100%), ORR (96%), and CRR (96%), followed by nivolumab + chemotherapy. EV + pembrolizumab combination superiority held across PD-L1 status and cisplatin eligibility. In patients who are cisplatin-eligible, EV + pembrolizumab significantly improved OS (HR: 0.68, 95%CI 0.47-0.99) and PFS (HR: 0.67, 95%CI 0.49-0.92) compared to nivolumab + chemotherapy. Durvalumab + tremelimumab was the safest combination for severe TRAEs, and EV + pembrolizumab ranked second. Our analyses support EV + pembrolizumab combination as a first-line treatment for locally advanced or metastatic UC. Thus, EV + pembrolizumab may become a guideline-changing standard treatment.
Cancer immunology, immunotherapy : CII. 2025 Feb 01*** epublish ***
Takafumi Yanagisawa, Keiichiro Mori, Akihiro Matsukawa, Tatsushi Kawada, Satoshi Katayama, Ekaterina Laukhtina, Pawel Rajwa, Fahad Quhal, Benjamin Pradere, Wataru Fukuokaya, Kosuke Iwatani, Renate Pichler, Jeremy Yuen-Chun Teoh, Marco Moschini, Wojciech Krajewski, Jun Miki, Shahrokh F Shariat, Takahiro Kimura, European Association of Urology–Young Academic Urologists Urothelial Carcinoma Working Group (EAU-YAU)
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria. ., Department of Urology, The Jikei University School of Medicine, Tokyo, Japan., Department of Urology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria., S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China., Department of Urology, San Raffaele Hospital and Scientific Institute, Milan, Italy., Department of Minimally Invasive and Robotic Urology, Wrocław Medical University, Wrocław, Poland.