CONTEXT: There have been substantial changes in the management of patients with metastatic renal cell carcinoma (mRCC) over the past decade, with upfront immunotherapy-based combinations replacing targeted therapies. A broad range of combinations have been approved, and comparisons of their efficacy and safety are needed to guide the optimal choice of first-line therapy. OBJECTIVE: To perform indirect comparisons of efficacy and safety of first-line immune checkpoint inhibitor (ICI)-based combination therapies for mRCC. EVIDENCE ACQUISITION: We searched multiple databases and abstracts of major scientific meetings up to February 2021 to identify phase III randomized controlled trials of patients receiving first-line ICI-based combination therapies for mRCC. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. The secondary endpoints included complete response rates (CRRs), objective response rates (ORRs), grade ≥3 treatment-related adverse events (TRAEs), and rates of treatment discontinuation due to adverse events (AEs). Subgroup network meta-analyses were performed based on patients' risk group categories and programmed death ligand 1 (PD-L1) expression status. EVIDENCE SYNTHESIS: Six trials were included in our network meta-analyses comprising 5121 patients. Nivolumab plus cabozantinib had the highest likelihood of providing the maximal OS (P score: 0.7573). Lenvatinib plus pembrolizumab demonstrated the highest likelihood of PFS (P score: 0.9906) and ORR (P score: 0.9564). CRRs were more likely to be associated with nivolumab plus ipilimumab (P score: 0.8682). In patients with ≥1% PD-L1 expression, the highest likelihood of better PFS was associated with lenvatinib plus pembrolizumab and nivolumab plus ipilimumab. Nivolumab plus ipilimumab was also associated with the lowest rates of grade ≥3 TRAEs; while the highest likelihood of AE-related treatment discontinuation was associated with lenvatinib plus pembrolizumab and nivolumab plus ipilimumab. CONCLUSIONS: Our network meta-analysis suggests that combinations of ICIs and tyrosine kinase inhibitors (TKIs) provide superior PFS, ORR, and OS to ICI-ICI combinations, regardless of the on International mRCC Database Consortium risk group. However, an ICI-ICI combination could be the optimal treatment for tumors with increased PD-L1 expression. The newly introduced ICI-TKI combinations, nivolumab plus cabozantinib and lenvatinib plus pembrolizumab, showed promising activity and are likely to have an important role in the mRCC treatment strategy. PATIENT SUMMARY: The use of immune checkpoint inhibitor (ICI)-based combinations (ICI plus tyrosine kinase inhibitor and ICI-ICI) improved oncological outcomes of metastatic renal cell carcinoma. Programmed death ligand 1 (PD-L1) expression status could help guide physicians and patients to select the appropriate treatment strategy.

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

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology Jikei University School of Medicine Tokyo Japan

Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology University of Jordan Amman Jordan

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

European Association of Urology Research Foundation Arnhem The Netherlands

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

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