Purpose of Review
Due to the rapidly changing field of kidney cancer therapeutics, addressing the state of the art systemic therapy regimens, and sequencing with cytoreductive nephrectomy are the primary focus of this review. We will also discuss the role of biomarkers and novel therapeutic targets in the management of renal cell carcinoma.
The management of metastatic renal cell cancer has undergone a paradigm shift with immune checkpoint inhibitors being used in the frontline setting. Over the last 4 years, programmed cell death-1 (PD-1) inhibitors as well as programmed cell death ligand-1 inhibitors have become available in various combinations with cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors and tyrosine kinase inhibitors (TKIs). These drugs have improved outcomes in patients with renal cell cancer and more work is being done to refine these targets as well as discover newer ones.
Despite the availability of several new treatment options, some questions that still need to be addressed in the management of kidney cancer include the sequencing of treatment options, treatment of patients who progress on immune checkpoint inhibitors, and role of biomarkers to ascertain the best treatment options to minimize costs and improve outcomes.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Cancer of the Kidney and Renal Pelvis - Cancer Stat Facts. SEER https://seer.cancer.gov/statfacts/html/kidrp.html.
Linehan WM. Genetic basis of kidney cancer: role of genomics for the development of disease-based therapeutics. Genome Res. 2012;22:2089–100.
Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs—part A: renal, penile, and testicular tumours. Eur Urol. 2016;70:93–105.
Chow W-H, Devesa SS. Contemporary renal cell cancer epidemiology. Cancer J. 2008;14:288–301.
Deniz B, et al. Treatment sequences for advanced renal cell carcinoma: a health economic assessment. PLoS One. 2019;14.
Rini, B. I. & Campbell, S. C. Renal cell carcinoma. (PMPH-USA, 2009).
Dhupkar, P. & Gordon, N. Interleukin-2: old and new approaches to enhance immune-therapeutic efficacy. in Immunotherapy (eds. Naing, A. & Hajjar, J.) 33–51 (Springer International Publishing, 2017). https://doi.org/10.1007/978-3-319-53156-4_2.
Clement JM, McDermott DF. The high-dose aldesleukin (IL-2) “select” trial: a trial designed to prospectively validate predictive models of response to high-dose IL-2 treatment in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2009;7:E7–9.
NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/default.aspx#kidney.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.
Bæk Møller N, et al. Drug-induced hypertension caused by multikinase inhibitors (sorafenib, sunitinib, lenvatinib and axitinib) in renal cell carcinoma treatment. Int J Mol Sci. 2019;20:4712.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81.
Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473–82.
Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016;17:378–88.
Motzer RJ, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. JCO. 2014;33:1430–7.
Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. https://www.nejm.org/doi/10.1056/NEJMoa1510665?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dwww.ncbi.nlm.nih.gov (2015) https://doi.org/10.1056/NEJMoa1510665.
Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825–30.
Hammers HJ, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. JCO. 2017;35:3851–8.
•• Motzer RJ, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018. https://doi.org/10.1056/NEJMoa1712126. This was the CheckMate 214 phase III trial, where ipilimumab 1 mg/kg and nivolumab 3 mg/kg for four cycles followed by nivolumab 3 mg/kg every 2 weeks was compared to sunitinib in the frontline setting. The checkpoint inhibitor combination improved RR, PFS and OS; leading to FDA approval for patients with poor/intermediate-risk disease in the frontline setting.
Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 2013;172:500–6.
Amin A, et al. Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study. J ImmunoTher Cancer. 2018;6:109.
Chowdhury S, et al. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). JCO. 2017;35:4506–6.
Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott D, Cho DC, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19:405–15.
•• Rini BI, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–27. This was the KEYNOTE-426 phase III trial where pembrolizumab and axitinib were compared to sunitinib in treatment naïve advanced clear-cell RCC. The combination demonstrated improved PFS, OS across all IMDC risk categories; led to FDA approval of the combination.
•• Motzer RJ, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103–15. This was the phase III JAVELIN Renal 101 study comparing avelumab and axitinib to sunitinib in treatment naïve RCC; leading to FDA approval.
Rini BI, Powles T, Atkins MB, Escudier B, McDermott D, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393:2404–15.
Tykodi SS, et al. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated results for KEYNOTE-427 cohort a. JCO. 2019;37:4570–0.
Thomas LJ, Vitale L, O'Neill T, Dolnick RY, Wallace PK, Minderman H, et al. Development of a novel antibody–drug conjugate for the potential treatment of ovarian, lung, and renal cell carcinoma expressing TIM-1. Mol Cancer Ther. 2016;15:2946–54.
Safety and Efficacy of CDX-014, an Antibody-Drug Conjugate against T Cell immunoglobulin mucin-1 (TIM-1), in advanced Renal Cell Carcinoma | OncologyPRO. https://oncologypro.esmo.org/Meeting-Resources/ESMO-2019-Congress/Safety-and-Efficacy-of-CDX-014-an-Antibody-Drug-Conjugate-against-T-Cell-immunoglobulin-mucin-1-TIM-1-in-advanced-Renal-Cell-Carcinoma.
Pal SK, Forero-Torres A, Thompson JA, Morris JC, Chhabra S, Hoimes CJ, et al. A phase 1 trial of SGN-CD70A in patients with CD70-positive, metastatic renal cell carcinoma. Cancer. 2019;125:1124–32.
Massard C, et al. First-in-human study to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory renal cell carcinoma. Cancer Chemother Pharmacol. 2019;83:1057–63.
Thompson JA, Motzer RJ, Molina AM, Choueiri TK, Heath EI, Redman BG, et al. Phase I trials of anti-ENPP3 antibody–drug conjugates in advanced refractory renal cell carcinomas. Clin Cancer Res. 2018;24:4399–406.
A Phase I Study of HERV-E TCR Transduced Autologous T Cells (HERV-E TCR T Cells) in Patients (pts) with Metastatic Clear Cell Renal Cell Carcinoma... | OncologyPRO. https://oncologypro.esmo.org/Meeting-Resources/ESMO-2018-Congress/A-Phase-I-Study-of-HERV-E-TCR-Transduced-Autologous-T-Cells-HERV-E-TCR-T-Cells-in-Patients-pts-with-Metastatic-Clear-Cell-Renal-Cell-Carcinoma-mccRCC.
Iacovelli, R. et al. Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis Targ Oncol 11, 143–148 (2016).
The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–9.
Molecular Characteristics of Clinical Response to Atezolizumab plus Bevacizumab Differ from Sunitinib in IMmotion151 Study | ESMO. https://www.esmo.org/Oncology-News/IMmotion151-molecular-correlates-atezolizumab-plus-bevacizumab-vs-sunitinib-mRCC-Rini.
•• McDermott DF, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24:749–57. This study described the clinical activity of the combination of atezolizumab and bevacizumab in metastatic RCC. Importantly, in addition, exploratory biomarker analyses was reported (including tumor mutation and neoantigen burden, angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures) and were correlated with response.
•• Choueiri TK, et al. Biomarker analyses from JAVELIN Renal 101: avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). JCO. 2019;37:101–1. Similar to IMMOTION150/151, JAVELIN Renal 101 investigators have also presented their take on biomarkers associated with response to the checkpoint inhibitor/TKI combination including the identification of a gene signature.
Jeyakumar G, et al. Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy. J ImmunoTher Cancer. 2017;5:82.
Kim HL, Mayerson E, Lara PN, Messing E, Tangen C, Shuch BM, et al. Considerations for the next clinical trial evaluating the role of cytoreductive nephrectomy for metastatic renal cell carcinoma. Eur Urol Focus. 2019;5:927–9.
Bex A, Mulders P, Jewett M, Wagstaff J, van Thienen J, Blank CU, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5:164–70.
Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379:417–27.
•• Mejean A, et al. Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): update on Carmena trial with focus on intermediate IMDC-risk population. JCO. 2019;37:4508–8. These two papers (44,45) describe results from the CARMENA trial, which concluded that sunitinib alone was not inferior for OS to the option of CN followed by sunitinib in patients with metastatic RCC (MSKCC intermediate-risk or poor-risk disease), which were confirmed after a long term follow up of 61.5 months as well.
•• Ulka Vaishampayan MD, George J, Vigneau F. Predictors of cytoreductive nephrectomy for metastatic kidney cancer in SEER and Metropolitan Detroit Databases. J Kidney Cancer VHL. 2019;6:13–25. The role of cytoreductive nephrectomy is still not absolutely clear in patients who receive immunotherapy treatments in the frontline setting. This paper discusses the SWOG trial S1931, a phase III trial designed to address this question.
Choueiri TK, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. JCO. 2008;26:127–31.
Tannir NM, Plimack E, Ng C, Tamboli P, Bekele NB, Xiao L, et al. A phase 2 trial of sunitinib in patients with advanced non–clear cell renal cell carcinoma. Eur Urol. 2012;62:1013–9.
Ravaud A, Oudard S, de Fromont M, Chevreau C, Gravis G, Zanetta S, et al. First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French genitourinary group (GETUG). Ann Oncol. 2015;26:1123–8.
Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, et al. Everolimus versus sunitinib prospective evaluation in metastatic non–clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016;69:866–74.
Knox JJ, Barrios CH, Kim TM, Cosgriff T, Srimuninnimit V, Pittman K, et al. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Ann Oncol. 2017;28:1339–45.
Choueiri TK, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol. 2013;31:181–6.
Choueiri TK, Plimack E, Arkenau HT, Jonasch E, Heng DYC, Powles T, et al. Biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer. J Clin Oncol. 2017;35:2993–3001.
Martínez Chanzá N, Xie W, Asim Bilen M, Dzimitrowicz H, Burkart J, Geynisman DM, et al. Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. Lancet Oncol. 2019;20:581–90.
Cabozantinib S-Malate, Crizotinib, savolitinib, or sunitinib malate in treating patients with locally advanced or metastatic kidney cancer—full text view—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02761057.
McKay RR, et al. The clinical activity of PD-1/PD-L1 inhibitors in metastatic non-clear cell renal cell carcinoma. Cancer Immunol Res. 2018;6:758–65.
Vogelzang NJ, et al. Efficacy and safety of nivolumab in patients with non-clear cell renal cell carcinoma (RCC): results from the phase IIIb/IV CheckMate 374 study. JCO. 2019;37:562–2.
McDermott DF, et al. First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): results from KEYNOTE-427 cohort B. JCO. 2019;37:546–6.
Powles T, et al. A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). JCO. 2019;37:545–5.
• Flippot R, et al. Atezolizumab plus bevacizumab in non-clear cell renal cell carcinoma (NccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (ccRCCsd): updated results of activity and predictive biomarkers from a phase II study. JCO. 2019;37:4583–3. Papers 57–-60 are important trials addressing the role of immunotherapy drugs in non-clear cell RCC.
Conflict of Interest
Shuchi Gulati declares that she has no conflict of interest.
Ulka Vaishampayan has received research funding from Bristol-Myers Squibb and Exelixis, and has received compensation from Bristol-Myers Squibb, Exelixis, and Pfizer for service as a consultant.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Genitourinary Cancers
About this article
Cite this article
Gulati, S., Vaishampayan, U. Current State of Systemic Therapies for Advanced Renal Cell Carcinoma. Curr Oncol Rep 22, 26 (2020). https://doi.org/10.1007/s11912-020-0892-1
- Kidney cancer
- Clear cell
- Non-clear cell