PURPOSE OF REVIEW: The current treatment landscape of metastatic renal cell carcinoma has changed dramatically from the dominance of single-agent tyrosine kinase inhibitor (TKI) therapy to immune-checkpoint inhibitor (ICI)-based combinations in recent years. However, the optimal subsequent therapy remains ill-defined owing to the novelty of this approach. RECENT FINDINGS: Treatment with TKIs after failure of single or dual ICI therapies may result in robust clinical efficacy. Nonetheless, there is a trend toward lower efficacy of TKIs after previous ICI-TKI combination therapy. Currently, tivozanib is the only drug whose third- and later-line use after failure of TKI and ICI is supported by evidence, with significantly longer progression-free survival and higher objective response rates than sorafenib. Data from retrospective studies highlight the safety and clinical activity of ICI rechallenge. SUMMARY: Overall, the level of evidence remains low. Treatment after failure of dual ICI therapy is not well defined and may consist of any available TKI. Although first-line use of TKI is less common, strong evidence suggests cabozantinib or nivolumab as standard options in that setting. The recommendations after first-line TKI-ICI therapy failure mirror this recommendation, although the data are less robust.

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 King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University of Texas Southwestern Dallas Texas USA

Department of Urology Weill Cornell Medical College New York New York USA

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

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

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Updated systematic review and network meta-analysis of first-line treatments for metastatic renal cell carcinoma with extended follow-up data