Systemic therapy in metastatic renal cell carcinoma.
OBJECTIVE
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-α) 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.
Department of Urology, Eberhard Karls University Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany. bedke@live.com.
Jens
J
Bedke
Department of Radiation Oncology, University of Essen, Essen, Germany.
Thomas
T
Gauler
Department of Hematology and Oncology, Medical School Hannover, Hannover, Germany.
Viktor
V
Grünwald
Department of Urology and Pediatric Urology, University of Marburg, Marburg, Germany.
Axel
A
Hegele
Department of Urology, University of Münster, Münster, Germany.
Edwin
E
Herrmann
Department of Urology, Charité Universitaetsmedizin Berlin, Berlin, Germany.
Stefan
S
Hinz
Onkologie Westerstede, Westerstede, Germany.
Jan
J
Janssen
Gemeinschaftspraxis für Onkologie und Hämatologie, Köln, Germany.
Stephan
S
Schmitz
Department of Urology, University of Magdeburg, Magdeburg, Germany.
Martin
M
Schostak
Onkologie Bethanien, Frankfurt am Main, Germany.
Hans
H
Tesch
Department of Urology, Technical University of Dresden, Dresden, Germany.
Stefan
S
Zastrow
Department of Urology, Charité Universitaetsmedizin Berlin, Berlin, Germany.
Kurt
K
Miller
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D003663:Decision Trees; D000068338:Everolimus / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007191:Indazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077594:Nivolumab; D010671:Phenylurea Compounds / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077157:Sorafenib; D013449:Sulfonamides / Q000627:therapeutic use; D000077210:Sunitinib
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D009536:Niacinamide; D000077594:Nivolumab; C401859:temsirolimus; C516667:pazopanib; D000068338:Everolimus; D000077157:Sorafenib; D000077784:Axitinib; D000077210:Sunitinib; D020123:Sirolimus
Checkpoint inhibitor; Renal cell carcinoma; Sequence; Systemic treatment; Targeted therapy; Tyrosine kinase inhibitor mTOR inhibition