Immune checkpoint inhibitor (ICI)-based combination therapies are the recommended first-line treatment for metastatic renal cell carcinoma (mRCC). However, no head-to-head phase-3 randomized controlled trials (RCTs) have compared the efficacy of different ICI-based combination therapies. Here, we compared the efficacy of various first-line ICI-based combination therapies in patients with mRCC using updated survival data from phase-3 RCTs. Three databases were searched in June 2023 for RCTs that analyzed oncologic outcomes in mRCC patients treated with ICI-based combination therapies as first-line treatment. A network meta-analysis compared outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. Subgroup analyses were based on the International mRCC Database Consortium risk classification. The treatment ranking analysis of the entire cohort showed that nivolumab + cabozantinib (81%) had the highest likelihood of improving OS, followed by nivolumab + ipilimumab (75%); pembrolizumab + lenvatinib had the highest likelihood of improving PFS (99%), ORR (97%), and CR (86%). These results remained valid even when the analysis was limited to patients with intermediate/poor risk, except that nivolumab + ipilimumab had the highest likelihood of achieving CR (100%). Further, OS benefits of ICI doublets were not inferior to those of ICI + tyrosine kinase inhibitor combinations. Recommendation of combination therapies with ICIs and/or tyrosine kinase inhibitors based on survival benefits and patient pretreatment risk classification will help advance personalized medicine for mRCC.

Clinic for Medical Oncology and Clinic for Urology West German Cancer Center Essen University Hospital Essen Essen Germany

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Wahringer Gurtel 18 20 1090 Vienna Austria

Department of Urology Dentistry and Pharmaceutical Sciences Okayama University Graduate School of Medicine Okayama Japan

Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology La Croix Du Sud Hospital Quint Fonsegrives France

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University of Rennes Rennes France

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

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