PMID- 33757737 OWN - NLM STAT- MEDLINE DCOM- 20220201 LR - 20220201 IS - 2588-9311 (Electronic) IS - 2588-9311 (Linking) VI - 4 IP - 5 DP - 2021 Oct TI - First-line Immunotherapy-based Combinations for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. PG - 755-765 LID - S2588-9311(21)00045-6 [pii] LID - 10.1016/j.euo.2021.03.001 [doi] AB - 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. CI - Copyright (c) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved. FAU - Quhal, Fahad AU - Quhal F AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia. FAU - Mori, Keiichiro AU - Mori K AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Jikei University School of Medicine, Tokyo, Japan. FAU - Bruchbacher, Andreas AU - Bruchbacher A AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. FAU - Resch, Irene AU - Resch I AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. FAU - Mostafaei, Hadi AU - Mostafaei H AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. FAU - Pradere, Benjamin AU - Pradere B AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. FAU - Schuettfort, Victor M AU - Schuettfort VM AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. FAU - Laukhtina, Ekaterina AU - Laukhtina E AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia. FAU - Egawa, Shin AU - Egawa S AD - Department of Urology, Jikei University School of Medicine, Tokyo, Japan. FAU - Fajkovic, Harun AU - Fajkovic H AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. FAU - Remzi, Mesut AU - Remzi M AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. FAU - Shariat, Shahrokh F AU - Shariat SF AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Urology, University of Jordan, Amman, Jordan; European Association of Urology Research Foundation, Arnhem, The Netherlands. FAU - Schmidinger, Manuela AU - Schmidinger M AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Electronic address: manuela.schmidinger@meduniwien.ac.at. LA - eng PT - Journal Article PT - Meta-Analysis PT - Review PT - Systematic Review DEP - 20210320 PL - Netherlands TA - Eur Urol Oncol JT - European urology oncology JID - 101724904 RN - 0 (Ipilimumab) SB - IM MH - *Carcinoma, Renal Cell/drug therapy MH - Humans MH - Immunotherapy MH - Ipilimumab MH - *Kidney Neoplasms/drug therapy MH - Network Meta-Analysis OTO - NOTNLM OT - First line OT - Immune checkpoint inhibitors OT - Network meta-analysis OT - Renal cell carcinoma EDAT- 2021/03/25 06:00 MHDA- 2022/02/02 06:00 CRDT- 2021/03/24 05:58 PHST- 2020/12/11 00:00 [received] PHST- 2021/02/17 00:00 [revised] PHST- 2021/03/01 00:00 [accepted] PHST- 2021/03/25 06:00 [pubmed] PHST- 2022/02/02 06:00 [medline] PHST- 2021/03/24 05:58 [entrez] AID - S2588-9311(21)00045-6 [pii] AID - 10.1016/j.euo.2021.03.001 [doi] PST - ppublish SO - Eur Urol Oncol. 2021 Oct;4(5):755-765. doi: 10.1016/j.euo.2021.03.001. Epub 2021 Mar 20.