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Current and Emerging Therapeutic Targets for Metastatic Renal Cell Carcinoma

  • Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)
  • Published:
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Abstract

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.

Summary

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.

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Abbreviations

RCC:

renal cell carcinoma

TKI:

tyrosine kinase inhibitor

mRCC:

metastatic renal cell carcinoma

HDIL-2:

high-dose interleukin-2

IFN-α:

interferon-alpha

VEGF:

vascular endothelial growth factor

PDGF:

platelet-derived growth factor

mTOR:

mammalian target of rapamycin

PFS:

progression-free survival

OS:

overall survival

NCCN:

National Comprehensive Cancer Network

mPFS:

median progression free survival

AXL:

anexelekto

MET:

mesenchymal epithelial transition

ORR:

objective response rate

mAB:

monoclonal antibody

FGFR:

fibroblast growth factor receptor

NSCLC:

non-small cell lung cancer

HRQoL:

health-related quality of life

TAMs:

tumor-associated macrophages

TVs:

tumor vaccines

ALK:

activin receptor-like kinase 1

References

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

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ross K, Jones RJ. Immune checkpoint inhibitors in renal cell carcinoma. Clin Sci (Lond). 2017;131(21):2627–42.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rodriguez-Vida A, Hutson TE, Bellmunt J, Strijbos MH. New treatment options for metastatic renal cell carcinoma. ESMO Open. 2017;2(2):e000185.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  9. De Meerleer G, et al. Radiotherapy for renal-cell carcinoma. Lancet Oncol. 2014;15(4):e170–7.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  13. NCCN Clinical Practice Guidelines in Oncology. [Webpage] 2016 2016]; Available from: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  17. Motzer RJ, McCann L, Deen K. Pazopanib versus sunitinib in renal cancer. N Engl J Med. 2013;369(20):1970.

    Article  CAS  PubMed  Google Scholar 

  18. Frampton JE. Pazopanib: a review in advanced renal cell carcinoma. Target Oncol. 2017;12(4):543–54.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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-b

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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: https://clinicaltrials.gov/ct2/show/NCT01499121.

  31. U.S National Library of Medicine, C.g., Sunitinib scheduling in metastatic renal cell carcinoma (mRCC), NCT02060370. 2017. M.D. Anderson Cancer center.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin. 2017;67(6):507–24.

    Article  PubMed  Google Scholar 

  40. Kim ES. Tivozanib: first global approval. Drugs. 2017;77(17):1917–23.

    Article  CAS  PubMed  Google Scholar 

  41. Brivanib Metastatic Renal Cell Carcinoma, NCT01253668. 2017. Available from: https://www.clinicaltrials.gov/show/NCT01253668.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  44. ClinicalTrials.gov. 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. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer. 2010;46(7):1260–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011;2(12):1117–33.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Barnes PJ. New drugs for asthma. Discov Med. 2004;4(24):421–6.

    PubMed  Google Scholar 

  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):TPS3098

  50. Study of pre-operative combination therapy with mogamulizumab and nivolumab against solid cancer patients. 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT02946671.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  59. Mendiratta P, Rini BI, Ornstein MC. Emerging immunotherapy in advanced renal cell carcinoma. Urol Oncol. 2017;35(12):687–93.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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).

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Amato RJ. Vaccine therapy for renal cell carcinoma. Rev Urol. 2003;5(2):65–71.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  78. Kadowaki N. Combination of targeted therapy and immunotherapy for cancer. Gan To Kagaku Ryoho. 2015;42(9):1046–9.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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)

  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.

  84. Wiecek W, Karcher H. Nivolumab versus cabozantinib: comparing overall survival in metastatic renal cell carcinoma. PLoS One. 2016;11(6):e0155389.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Stony Brook University Hospital, Stony Brook, NY, USA

    Kevin Zarrabi & Shenhong Wu

  2. Division of Hematology/Oncology, Department of Medicine, Northport VA Medical Center, Northport, NY, USA

    Shenhong Wu

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

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Correspondence to Shenhong Wu.

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Kevin Zarrabi declares that he has no conflict of interest.

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

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Zarrabi, K., Wu, S. Current and Emerging Therapeutic Targets for Metastatic Renal Cell Carcinoma. Curr Oncol Rep 20, 41 (2018). https://doi.org/10.1007/s11912-018-0684-z

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