PMID- 27277600 OWN - NLM STAT- MEDLINE DCOM- 20170418 LR - 20231112 IS - 1433-8726 (Electronic) IS - 0724-4983 (Print) IS - 0724-4983 (Linking) VI - 35 IP - 2 DP - 2017 Feb TI - Systemic therapy in metastatic renal cell carcinoma. PG - 179-188 LID - 10.1007/s00345-016-1868-5 [doi] AB - PURPOSE: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC). METHODS: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing. RESULTS: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-alpha) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited. CONCLUSIONS: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy. FAU - Bedke, Jens AU - Bedke J AD - Department of Urology, Eberhard Karls University Tubingen, Hoppe-Seyler-Strasse 3, 72076, Tubingen, Germany. bedke@live.com. FAU - Gauler, Thomas AU - Gauler T AD - Department of Radiation Oncology, University of Essen, Essen, Germany. FAU - Grunwald, Viktor AU - Grunwald V AD - Department of Hematology and Oncology, Medical School Hannover, Hannover, Germany. FAU - Hegele, Axel AU - Hegele A AD - Department of Urology and Pediatric Urology, University of Marburg, Marburg, Germany. FAU - Herrmann, Edwin AU - Herrmann E AD - Department of Urology, University of Munster, Munster, Germany. FAU - Hinz, Stefan AU - Hinz S AD - Department of Urology, Charite Universitaetsmedizin Berlin, Berlin, Germany. FAU - Janssen, Jan AU - Janssen J AD - Onkologie Westerstede, Westerstede, Germany. FAU - Schmitz, Stephan AU - Schmitz S AD - Gemeinschaftspraxis fur Onkologie und Hamatologie, Koln, Germany. FAU - Schostak, Martin AU - Schostak M AD - Department of Urology, University of Magdeburg, Magdeburg, Germany. FAU - Tesch, Hans AU - Tesch H AD - Onkologie Bethanien, Frankfurt am Main, Germany. FAU - Zastrow, Stefan AU - Zastrow S AD - Department of Urology, Technical University of Dresden, Dresden, Germany. FAU - Miller, Kurt AU - Miller K AD - Department of Urology, Charite Universitaetsmedizin Berlin, Berlin, Germany. LA - eng PT - Journal Article PT - Review DEP - 20160609 PL - Germany TA - World J Urol JT - World journal of urology JID - 8307716 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Imidazoles) RN - 0 (Indazoles) RN - 0 (Indoles) RN - 0 (Phenylurea Compounds) RN - 0 (Pyrimidines) RN - 0 (Pyrroles) RN - 0 (Sulfonamides) RN - 25X51I8RD4 (Niacinamide) RN - 31YO63LBSN (Nivolumab) RN - 624KN6GM2T (temsirolimus) RN - 7RN5DR86CK (pazopanib) RN - 9HW64Q8G6G (Everolimus) RN - 9ZOQ3TZI87 (Sorafenib) RN - C9LVQ0YUXG (Axitinib) RN - V99T50803M (Sunitinib) RN - W36ZG6FT64 (Sirolimus) RN - Clear-cell metastatic renal cell carcinoma SB - IM MH - Antibodies, Monoclonal/therapeutic use MH - Antineoplastic Agents/*therapeutic use MH - Axitinib MH - Carcinoma, Renal Cell/*drug therapy MH - Decision Trees MH - Everolimus/therapeutic use MH - Humans MH - Imidazoles/therapeutic use MH - Indazoles/therapeutic use MH - Indoles/therapeutic use MH - Niacinamide/analogs & derivatives/therapeutic use MH - Nivolumab MH - Phenylurea Compounds/therapeutic use MH - Pyrimidines/therapeutic use MH - Pyrroles/therapeutic use MH - Sirolimus/analogs & derivatives/therapeutic use MH - Sorafenib MH - Sulfonamides/therapeutic use MH - Sunitinib PMC - PMC5272893 OTO - NOTNLM OT - Checkpoint inhibitor OT - Renal cell carcinoma OT - Sequence OT - Systemic treatment OT - Targeted therapy OT - Tyrosine kinase inhibitor mTOR inhibition COIS- AH: consultancies, honoraria or study participation from Pierre Fabre, BMS, GSK and Novartis. JB: consultancies, honoraria or study participation from Bayer, BMS, GSK, Immatics, Novartis, Pfizer and Roche. EH: consultancies, honoraria or study participation from Bayer, BMS, GSK, Novartis and Pfizer. JJ: Consultancies and honoraria of study participation from: Roche, Pfizer, GSK, Bayer, Lilly, Janssen-Cilag, Amgen, Celgene, Sanofi, Pharma Mar, Puma, Teva, Merck Sereno, Novartis. MS: consultancies, honoraria or study participation from Bayer, BMS, Novartis and Roche. SH: consultancies, honoraria from Novartis. SS: consultancies, honoraria or study participation from Amgen, Janssen-Cilag, Celgene, Novartis und MSD Sharp & Dohme. TG: consultancies or honoraria: Bayer, BMS, GSK, Novartis, Roche. VG: consultancies, honoraria or travel support: Bayer, BMS; Novartis, Pfizer. EDAT- 2016/06/10 06:00 MHDA- 2017/04/19 06:00 PMCR- 2016/06/09 CRDT- 2016/06/10 06:00 PHST- 2016/02/17 00:00 [received] PHST- 2016/05/24 00:00 [accepted] PHST- 2016/06/10 06:00 [pubmed] PHST- 2017/04/19 06:00 [medline] PHST- 2016/06/10 06:00 [entrez] PHST- 2016/06/09 00:00 [pmc-release] AID - 10.1007/s00345-016-1868-5 [pii] AID - 1868 [pii] AID - 10.1007/s00345-016-1868-5 [doi] PST - ppublish SO - World J Urol. 2017 Feb;35(2):179-188. doi: 10.1007/s00345-016-1868-5. Epub 2016 Jun 9.