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Review
. 2017 Feb;35(2):179-188.
doi: 10.1007/s00345-016-1868-5. Epub 2016 Jun 9.

Systemic therapy in metastatic renal cell carcinoma

Jens Bedke  1 , Thomas Gauler  2 , Viktor Grünwald  3 , Axel Hegele  4 , Edwin Herrmann  5 , Stefan Hinz  6 , Jan Janssen  7 , Stephan Schmitz  8 , Martin Schostak  9 , Hans Tesch  10 , Stefan Zastrow  11 , Kurt Miller  6
Affiliations
Review

Systemic therapy in metastatic renal cell carcinoma

Jens Bedke et al. World J Urol. 2017 Feb.

Abstract

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-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.

Keywords: Checkpoint inhibitor; Renal cell carcinoma; Sequence; Systemic treatment; Targeted therapy; Tyrosine kinase inhibitor mTOR inhibition.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Histological subtypes of renal cell carcinoma. a Clear cell RCC (×20). b Papillary RCC Type I (×20). c Papillary RCC Type II (×20). d Chromophobe RCC (×40)
Fig. 2
Fig. 2
a–c Flow charts of the potential therapeutic options for the first-, second- and third-line treatment of mRCC (levels of evidence in brackets). BEV bevacizumab, IFN-α Interferon alfa, EVE everolimus, PAZ pazopanib, SUN sunitinib, TEM temsirolimus, AXI axitinib, SOR sorafenib, VEGFR vascular endothelial growth factor receptor, mTOR mammalian target of rapamycin, NIV nivolumab, CAB cabozantinib. *Level of evidence for pazopanib and sorafenib in poor risk patients is 2a as data are based on a subgroup analysis. Level of evidence for the entire cohort is 1b. #Sorafenib was inferior to axitinib in a RCT in terms of PFS, but not different in OS [28]
See this image and copyright information in PMC

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