Cancer Immunology, Immunotherapy (Feb 2025)

Novel combination therapy for platinum-eligible patients with locally advanced or metastatic urothelial carcinoma: a systematic review and network meta-analysis

  • 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)

DOI
https://doi.org/10.1007/s00262-024-03910-3
Journal volume & issue
Vol. 74, no. 3
pp. 1 – 14

Abstract

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Abstract 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.

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