Current and Emerging Therapeutic Targets for Metastatic Renal Cell Carcinoma

  • Kevin Zarrabi
  • Shenhong Wu
Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Genitourinary Cancers


Purpose of review

The treatment of advanced renal cell carcinoma has evolved dramatically over recent years. In this review, we will summarize current and emerging therapies based on molecular targets and provide insight into treatment strategy for metastatic renal cell carcinoma.

Recent findings

We have witnessed a paradigm shift in the therapeutic landscape as treatment was formerly reliant on cytokine-based agents which have now been replaced with therapies targeting angiogenesis, mammalian target of rapamycin pathways, and immune responses. These dramatic changes are primarily due to our improved understanding of the underlying mutations and molecular mechanisms leading to tumorigenesis and progression.


We now have targeted agents in the form of small-molecule tyrosine kinase inhibitors, monoclonal antibodies, and mTOR inhibitors. Moreover, immunotherapy-targeting checkpoints of T-lymphocyte activity has provided increased overall survival and a new class of agents with potential to radically change the treatment options. With these agents and their combination, durable responses are increasingly seen even though treatment resistance remains a huge challenge. New treatment strategies are rapidly developing and the therapeutic landscape is expected for further evolution.


Renal cell carcinoma Targeted therapy Immunotherapy 



renal cell carcinoma


tyrosine kinase inhibitor


metastatic renal cell carcinoma


high-dose interleukin-2




vascular endothelial growth factor


platelet-derived growth factor


mammalian target of rapamycin


progression-free survival


overall survival


National Comprehensive Cancer Network


median progression free survival




mesenchymal epithelial transition


objective response rate


monoclonal antibody


fibroblast growth factor receptor


non-small cell lung cancer


health-related quality of life


tumor-associated macrophages


tumor vaccines


activin receptor-like kinase 1


Authors’ Contributions

KZ and SW contributed to the data collection, data analysis, and writing of the manuscript.


This report required no funding.

Compliance with Ethical Standards

Conflict of Interest

Kevin Zarrabi declares that he has no conflict of interest.

Shenhong Wu has served as a speaker for Exelixis, Novartis, and Pfizer.

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.

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Vitale MG, Carteni G. Recent developments in second and third line therapy of metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2016;16(5):469–71.CrossRefPubMedGoogle Scholar
  2. 2.
    Zarrabi K, Fang C, Wu S. New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy. J Hematol Oncol. 2017;10(1):38.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ross K, Jones RJ. Immune checkpoint inhibitors in renal cell carcinoma. Clin Sci (Lond). 2017;131(21):2627–42.CrossRefGoogle Scholar
  4. 4.
    Rabinovitch RA, Zelefsky MJ, Gaynor JJ, Fuks Z. Patterns of failure following surgical resection of renal cell carcinoma: implications for adjuvant local and systemic therapy. J Clin Oncol. 1994;12(1):206–12.CrossRefPubMedGoogle Scholar
  5. 5.
    Barata PC, Ornstein MC, Garcia JA. The evolving treatment landscape of advanced renal cell carcinoma in patients progressing after VEGF inhibition. J Kidney Cancer VHL. 2017;4(2):10–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rodriguez-Vida A, Hutson TE, Bellmunt J, Strijbos MH. New treatment options for metastatic renal cell carcinoma. ESMO Open. 2017;2(2):e000185.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Gill DM, Agarwal N, Vaishampayan U. Evolving treatment paradigm in metastatic renal cell carcinoma. Am Soc Clin Oncol Educ Book. 2017;37:319–29.CrossRefPubMedGoogle Scholar
  8. 8.
    Negrier S, et al. Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. Cancer J Sci Am. 2000;6(Suppl 1):S93–8.PubMedGoogle Scholar
  9. 9.
    De Meerleer G, et al. Radiotherapy for renal-cell carcinoma. Lancet Oncol. 2014;15(4):e170–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–90.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Atkins MB, Larkin J. Immunotherapy combined or sequenced with targeted therapy in the treatment of solid tumors: current perspectives. J Natl Cancer Inst. 2016;108(6):djv414.CrossRefPubMedGoogle Scholar
  12. 12.
    Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67(5):913–24.CrossRefPubMedGoogle Scholar
  13. 13.
    NCCN Clinical Practice Guidelines in Oncology. [Webpage] 2016 2016]; Available from:
  14. 14.
    Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295(21):2516–24.CrossRefPubMedGoogle Scholar
  15. 15.
    Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49(6):1287–96.CrossRefPubMedGoogle Scholar
  17. 17.
    Motzer RJ, McCann L, Deen K. Pazopanib versus sunitinib in renal cancer. N Engl J Med. 2013;369(20):1970.CrossRefPubMedGoogle Scholar
  18. 18.
    Frampton JE. Pazopanib: a review in advanced renal cell carcinoma. Target Oncol. 2017;12(4):543–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol. 2014;32(14):1412–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Pal SK, Vogelzang NJ. A “game of thrones” in metastatic renal cell carcinoma: vascular endothelial growth factor-tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors battling for position. Clin Genitourin Cancer. 2013;11(1):1–4.CrossRefPubMedGoogle Scholar
  21. 21.
    Delea TE, et al. Cost-effectiveness of pazopanib versus sunitinib for renal cancer in the United States. J Manag Care Spec Pharm. 2015;21(1):46–54. 54a-bCrossRefPubMedGoogle Scholar
  22. 22.
    Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349(5):427–34.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103–11.CrossRefPubMedGoogle Scholar
  24. 24.
    Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28(13):2137–43.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Rini BI, Garcia JA, Cooney MM, Elson P, Tyler A, Beatty K, et al. A phase I study of sunitinib plus bevacizumab in advanced solid tumors. Clin Cancer Res. 2009;15(19):6277–83.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(9):1432–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cavaliere C, D’Aniello C, Pepa C, Pisconti S, Berretta M, Facchini G. Current and emerging treatments for metastatic renal cell carcinoma. Curr Cancer Drug Targets. 2017;17:1.CrossRefGoogle Scholar
  28. 28.
    Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Bracarda S, Iacovelli R, Boni L, Rizzo M, Derosa L, Rossi M, et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol. 2016;27(2):366.CrossRefPubMedGoogle Scholar
  30. 30.
    U.S National Library of Medicine, C.g. Study of efficacy and safety of sunitinib given on an individualized schedule, NCT01499121. 2017. Available from:
  31. 31.
    U.S National Library of Medicine, C.g., Sunitinib scheduling in metastatic renal cell carcinoma (mRCC), NCT02060370. 2017. M.D. Anderson Cancer center.Google Scholar
  32. 32.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27(20):3312–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32(8):760–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhou L, Liu XD, Sun M, Zhang X, German P, Bai S, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35(21):2687–97.CrossRefPubMedGoogle Scholar
  36. 36.
    Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014;111(37):13373–8.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    • Choueiri TK, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917–27. The METEOR trial is a landmark study which led to the approval of cabozantinib for clinical use in patients with mRCC. METEOR served as a proof-or-principle that MET and AXL are drug targets with clinical benefit. Due to the success of METEOR, multiple agents which target MET and AXL are in development. CrossRefPubMedGoogle Scholar
  38. 38.
    Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013;31(30):3791–9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin. 2017;67(6):507–24.CrossRefPubMedGoogle Scholar
  40. 40.
    Kim ES. Tivozanib: first global approval. Drugs. 2017;77(17):1917–23.CrossRefPubMedGoogle Scholar
  41. 41.
    Brivanib Metastatic Renal Cell Carcinoma, NCT01253668. 2017. Available from:
  42. 42.
    Voss MH, Bhatt RS, Plimack ER, Rini BI, Alter RS, Beck JT, et al. The DART study: results from the dose-escalation and expansion cohorts evaluating the combination of dalantercept plus axitinib in advanced renal cell carcinoma. Clin Cancer Res. 2017;23(14):3557–65.CrossRefPubMedGoogle Scholar
  43. 43.
    Bendell JC, Gordon MS, Hurwitz HI, Jones SF, Mendelson DS, Blobe GC, et al. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer. Clin Cancer Res. 2014;20(2):480–9.CrossRefPubMedGoogle Scholar
  44. 44. A randomized phase 2 trial of axitinib and TRC105 versus axitinib alone in patients with advanced or metastatic renal cell carcinoma. 2017. U.S. National Library of medicine.
  45. 45.
    Berlato C, Khan MN, Schioppa T, Thompson R, Maniati E, Montfort A, et al. A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer. J Clin Invest. 2017;127(3):801–13.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer. 2010;46(7):1260–70.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011;2(12):1117–33.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Barnes PJ. New drugs for asthma. Discov Med. 2004;4(24):421–6.PubMedGoogle Scholar
  49. 49.
    Plitas G, Wu K, Carlson J, Cimaglia N, Morrow M, Rudensky AY, Wolchok JD. Phase I/II study of mogamulizumab, an anti-CCR4 antibody targeting regulatory T cells in advanced cancer patients. J Clin Oncol. 2016;34(suppl 15):TPS3098Google Scholar
  50. 50.
    Study of pre-operative combination therapy with mogamulizumab and nivolumab against solid cancer patients. 2017. Available from:
  51. 51.
    Schoffski P, et al. Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial. Eur J Cancer. 2017;87:147–63.CrossRefPubMedGoogle Scholar
  52. 52.
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.CrossRefPubMedGoogle Scholar
  53. 53.
    Wallace EM, Rizzi JP, Han G, Wehn PM, Cao Z, du X, et al. A small-molecule antagonist of HIF2alpha is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 2016;76(18):5491–500.CrossRefPubMedGoogle Scholar
  54. 54.
    Yuan R, Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol. 2009;2:45.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    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(22):2271–81.CrossRefPubMedGoogle Scholar
  56. 56.
    Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–56.CrossRefPubMedGoogle Scholar
  57. 57.
    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(6):1339–45.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, et al. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016;27(3):441–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Mendiratta P, Rini BI, Ornstein MC. Emerging immunotherapy in advanced renal cell carcinoma. Urol Oncol. 2017;35(12):687–93.CrossRefPubMedGoogle Scholar
  60. 60.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.CrossRefPubMedGoogle Scholar
  61. 61.
    Choueiri TK, Figueroa DJ, Fay AP, Signoretti S, Liu Y, Gagnon R, et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin Cancer Res. 2015;21(5):1071–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    •• Motzer RJ, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13. The CheckMate 025 trial was the first randomized phase III trial examining immunotherapy in mRCC patients and has revolutionized the treatment landscape of this disease process. Nivolumab is the most promising of the novel treatment agents and the therapeutic potential continues to be examined in ongoing trials. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, et al. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):994–1003.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol. 2016;34(8):833–42.CrossRefPubMedGoogle Scholar
  66. 66.
    Choueiri TK, Hodi FS, Thompson JA, McDermott DF, Hwu W-J, Lawrence DP. Pembrolizumab (pembro) plus low-dose ipilimumab (ipi) for patients (pts) with advanced renal cell carcinoma (RCC): Phase 1 KEYNOTE-029 study. Proc Am Soc Clin Oncol. 2017;35:510.CrossRefGoogle Scholar
  67. 67.
    Rini BI, Stein M, Shannon P, Eddy S, Tyler A, Stephenson JJ Jr, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2011;117(4):758–67.CrossRefPubMedGoogle Scholar
  68. 68.
    Hammers HJ, Plimack ER, Infante JR, Ernstoff MS, Rini BI, McDermott DF, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). 2014 ASCO Annual Meeting. J Clin Oncol. 2014;32:5s (suppl; abstr 4504).Google Scholar
  69. 69.
    • Escudier B, Tannir NM, McDermott DF, Frontera OA, Melichar B, Plimack ER, et al. LBA5 CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. In: ESMO. 2017. Spain: Annals of Oncology. The nivolumab plus ipilimumab combination therapy in the first-line setting has the potential to alter treatment recommendations for previously untreated patients with mRCC. The prospect of combination immunotherapy is novel to the field of mRCC. Google Scholar
  70. 70.
    Santoni M, Massari F, Amantini C, Nabissi M, Maines F, Burattini L, et al. Emerging role of tumor-associated macrophages as therapeutic targets in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother. 2013;62(12):1757–68.CrossRefPubMedGoogle Scholar
  71. 71.
    Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 2012;7(12):e50946.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Amato RJ. Vaccine therapy for renal cell carcinoma. Rev Urol. 2003;5(2):65–71.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, et al. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(11):1599–611.CrossRefPubMedGoogle Scholar
  74. 74.
    Amin A, Dudek AZ, Logan TF, Lance RS, Holzbeierlein JM, Knox JJ, et al. Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J Immunother Cancer. 2015;3:14.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005;23(3):329–36.CrossRefPubMedGoogle Scholar
  76. 76.
    Boss DS, Glen H, Beijnen JH, Keesen M, Morrison R, Tait B, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer. 2012;106(10):1598–604.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    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(15):1473–82.CrossRefPubMedGoogle Scholar
  78. 78.
    Kadowaki N. Combination of targeted therapy and immunotherapy for cancer. Gan To Kagaku Ryoho. 2015;42(9):1046–9.PubMedGoogle Scholar
  79. 79.
    Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70(15):6171–80.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Ishibashi K, Haber T, Breuksch I, Gebhard S, Sugino T, Kubo H, et al. Overriding TKI resistance of renal cell carcinoma by combination therapy with IL-6 receptor blockade. Oncotarget. 2017;8(33):55230–45.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): results from a phase Ib trial. J Clin Oncol. 2017;35(suppl; abstr 4504)Google Scholar
  83. 83.
    McDermott DF, Atkins MB, Motzer RJ, Rini BI, Escudier BJ, Fong L, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). In: 2017 Genitourinary Cancers Symposium. 2017.Google Scholar
  84. 84.
    Wiecek W, Karcher H. Nivolumab versus cabozantinib: comparing overall survival in metastatic renal cell carcinoma. PLoS One. 2016;11(6):e0155389.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    George S, Motzer RJ, Hammers HJ, Redman BG, Kuzel TM, Tykodi SS, et al. Safety and efficacy of Nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol. 2016;2(9):1179–86.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Escudier B, Motzer RJ, Sharma P, Wagstaff J, Plimack ER, Hammers HJ, et al. Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025. Eur Urol. 2017;72(3):368–76.CrossRefPubMedGoogle Scholar
  87. 87.
    Beuselinck B, Oudard S, Rixe O, Wolter P, Blesius A, Ayllon J, et al. Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib. Ann Oncol. 2011;22(4):794–800.CrossRefPubMedGoogle Scholar
  88. 88.
    Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31(4):412–9.CrossRefPubMedGoogle Scholar
  89. 89.
    Bernard J, Escudier TP, Motzer RJ, Olencki T, Aren OR, Oudard S. Efficacy of cabozantinib (C) vs everolimus (E) in patients (pts) with advanced renal cell carcinoma (RCC) and bone metastases (mets) from the phase III METEOR study. In: ASCO Annual Meeting 2016. 2017. Journal of Cilnical Oncology: Chicago.Google Scholar
  90. 90.
    Ghatalia P, Yang ES, Lasseigne BN, Ramaker RC, Cooper SJ, Chen D, et al. Kinase gene expression profiling of metastatic clear cell renal cell carcinoma tissue identifies potential new therapeutic targets. PLoS One. 2016;11(8):e0160924.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Rini B, Goddard A, Knezevic D, Maddala T, Zhou M, Aydin H, et al. A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. Lancet Oncol. 2015;16(6):676–85.CrossRefPubMedGoogle Scholar
  92. 92.
    Dai J, Lu Y, Wang J, Yang L, Han Y, Wang Y, et al. A four-gene signature predicts survival in clear-cell renal-cell carcinoma. Oncotarget. 2016;7(50):82712–26.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineStony Brook University HospitalStony BrookUSA
  2. 2.Division of Hematology/Oncology, Department of MedicineNorthport VA Medical CenterNorthportUSA

Personalised recommendations