Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Drug Insight: advances in renal cell carcinoma and the role of targeted therapies

Abstract

In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.

Key Points

  • Immunotherapy can be effective in patients with metastatic RCC

  • Interferon alfa confers a small but significant overall survival advantage in metastatic RCC, but only in a group of patients with good prognostic features

  • A small subset of patients (5%) obtained durable complete remission from treatment with intravenous high-dose bolus interleukin 2

  • Recent developments in the molecular biology of RCC have led to identification of multiple pathways associated with the development of this cancer

  • Sunitinib, sorafenib, axitinib, temsirolimus and bevacizumab have all shown significant activity with manageable toxicity in metastatic RCC

  • Future studies are needed to optimally utilize these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Landis SH et al. (1999) Cancer statistics, 1999. CA Cancer J Clin 49: 8–31

    Article  CAS  Google Scholar 

  2. Motzer RJ et al. (2004) Prognostic factors for survival of patients with stage IV renal cell carcinoma: Memorial Sloan–Kettering Cancer Center experience. Clin Cancer Res 10: 6302S–6303S

    Article  CAS  Google Scholar 

  3. Motzer RJ et al. (2002) Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 20: 2376–2381

    Article  Google Scholar 

  4. Cheville JC et al. (2003) Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 27: 612–624

    Article  Google Scholar 

  5. Beck SD et al. (2004) Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 11: 71–77

    Article  Google Scholar 

  6. Yao M et al. (2002) VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 94: 1569–1575

    Article  CAS  Google Scholar 

  7. Kim WY and Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22: 4991–5004

    Article  CAS  Google Scholar 

  8. Ohh M et al. (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2: 423–427

    Article  CAS  Google Scholar 

  9. Ferrara N et al. (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3: 391–400

    Article  CAS  Google Scholar 

  10. Yang JC et al. (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349: 427–434

    Article  CAS  Google Scholar 

  11. Yagoda A and Bander NH (1989) Failure of cytotoxic chemotherapy, 1983-1988, and the emerging role of monoclonal antibodies for renal cancer. Urol Int 44: 338–345

    Article  CAS  Google Scholar 

  12. Harris DT (1983) Hormonal therapy and chemotherapy of renal-cell carcinoma. Semin Oncol 10: 422–430

    CAS  PubMed  Google Scholar 

  13. Horoszewicz JS and Murphy GP (1989) An assessment of the current use of human interferons in therapy of urological cancers. J Urol 142: 1173–1180

    Article  CAS  Google Scholar 

  14. [No authors listed] (1999) Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 353: 14–17

  15. Pyrhonen S et al. (1999) Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 17: 2859–2867

    Article  CAS  Google Scholar 

  16. Fossa S et al. (1995) Interferon-alpha and survival in renal cell cancer. Br J Urol 76: 286–290

    Article  CAS  Google Scholar 

  17. Rosenberg SA et al. (1998) Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg 228: 307–319

    Article  CAS  Google Scholar 

  18. Negrier S et al. (2005) Do cytokines improve survival in patients with metastatic renal cell carcinoma (MRCC) of intermediate prognosis? Results of the prospective randomized PERCY Quattro trial [abstract #4511]. J Clin Oncol 23 (Suppl 16S)

  19. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103: 211–225

    Article  CAS  Google Scholar 

  20. Gunningham SP et al. (2001) Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia. Cancer Res 61: 3206–3211

    CAS  PubMed  Google Scholar 

  21. Sulzbacher I et al. (2003) Expression of platelet-derived growth factor-alpha alpha receptor is associated with tumor progression in clear cell renal cell carcinoma. Am J Clin Pathol 120: 107–112

    Article  CAS  Google Scholar 

  22. Uhlman DL et al. (1995) Epidermal growth factor receptor and transforming growth factor alpha expression in papillary and nonpapillary renal cell carcinoma: correlation with metastatic behavior and prognosis. Clin Cancer Res 1: 913–920

    CAS  PubMed  Google Scholar 

  23. Druker BJ et al. (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1031–1037

    Article  CAS  Google Scholar 

  24. van Oosterom AT et al. (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358: 1421–1423

    Article  CAS  Google Scholar 

  25. Giaccone G et al. (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 22: 777–784

    Article  CAS  Google Scholar 

  26. Herbst RS et al. (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 22: 785–794

    Article  CAS  Google Scholar 

  27. Kris MG et al. (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290: 2149–2158

    Article  CAS  Google Scholar 

  28. Shepherd FA et al. (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123–132

    Article  CAS  Google Scholar 

  29. Lynch TJ et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139

    Article  CAS  Google Scholar 

  30. Paez JG et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500

    Article  CAS  Google Scholar 

  31. Pao W et al. (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101: 13306–13311

    Article  CAS  Google Scholar 

  32. Heinrich MC et al. (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21: 4342–4349

    Article  CAS  Google Scholar 

  33. Debiec-Rychter M et al. (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42: 1093–1103

    Article  CAS  Google Scholar 

  34. Corless CL et al. (2005) PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23: 5357–5364

    Article  CAS  Google Scholar 

  35. Prenen H et al. (2006) Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 12: 2622–2627

    Article  CAS  Google Scholar 

  36. Antonescu CR et al. (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11: 4182–4190

    Article  CAS  Google Scholar 

  37. Wardelmann E et al. (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12: 1743–1749

    Article  CAS  Google Scholar 

  38. Rugo HS et al. (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23: 5474–5483

    Article  CAS  Google Scholar 

  39. Rini B et al. (2005) AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC) [abstract #4509]. J Clin Oncol 23 (Suppl 16S)

  40. Wilhelm SM et al. (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64: 7099–7109

    Article  CAS  Google Scholar 

  41. Sridhar SS et al. (2005) Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther 4: 677–685

    Article  CAS  Google Scholar 

  42. Strumberg D et al. (2005) Phase I clinical and pharmacokinetic study of the novel raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 23: 965–972

    Article  CAS  Google Scholar 

  43. Strumberg D et al. (2002) Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43-9006 in patients with solid tumors. Int J Clin Pharmacol Ther 40: 580–581

    Article  CAS  Google Scholar 

  44. Moore M et al. (2005) Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 16: 1688–1694

    Article  CAS  Google Scholar 

  45. Awada A et al. (2005) Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 92: 1855–1861

    Article  CAS  Google Scholar 

  46. Ratain MJ et al. (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24: 2505–2512

    Article  CAS  Google Scholar 

  47. Escudier B et al. (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356: 125–134

    Article  CAS  Google Scholar 

  48. Therasse P et al. (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205–216

    Article  CAS  Google Scholar 

  49. Eisen T et al. (2006) Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): impact of crossover on survival [abstract #4524]. J Clin Oncol 24 (Suppl 18S)

  50. Escudier B et al. (2006) Randomized phase II trial of the multi-kinase inhibitor sorafenib versus interferon (IFN) in treatment-naïve patients with metastatic renal cell carcinoma (mRCC) [abstract #4501]. J Clin Oncol 24 (Suppl 18S)

  51. Mendel DB et al. (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9: 327–337

    CAS  PubMed  Google Scholar 

  52. O'Farrell AM et al. (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101: 3597–3605

    Article  CAS  Google Scholar 

  53. Fiedler W et al. (2005) A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105: 986–993

    Article  CAS  Google Scholar 

  54. O'Farrell AM et al. (2003) An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 9: 5465–5476

    CAS  PubMed  Google Scholar 

  55. Faivre S et al. (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24: 25–35

    Article  CAS  Google Scholar 

  56. Motzer RJ et al. (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24: 16–24

    Article  CAS  Google Scholar 

  57. Motzer RJ et al. (2006) Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295: 2516–2524

    Article  CAS  Google Scholar 

  58. Rini BI et al. (2007) Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99: 81–83

    Article  CAS  Google Scholar 

  59. Motzer RJ et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356: 115–124

    Article  CAS  Google Scholar 

  60. Hudson CC et al. (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22: 7004–7014

    Article  CAS  Google Scholar 

  61. Shin Lee J et al. (2003) Expression of PTEN in renal cell carcinoma and its relation to tumor behavior and growth. J Surg Oncol 84: 166–172

    Article  Google Scholar 

  62. Hara S et al. (2005) Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor. Ann Oncol 16: 928–933

    Article  CAS  Google Scholar 

  63. Vignot S et al. (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16: 525–537

    Article  CAS  Google Scholar 

  64. Raymond E et al. (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22: 2336–2347

    Article  CAS  Google Scholar 

  65. Atkins MB et al. (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22: 909–918

    Article  CAS  Google Scholar 

  66. Hudes G et al. (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356: 2271–2281

    Article  CAS  Google Scholar 

  67. Amato RJ et al. (2006) A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC) [abstract #4530]. J Clin Oncol 24 (Suppl 18S)

  68. Atkins M et al. (2005) Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 11: 3714–3721

    Article  CAS  Google Scholar 

  69. Hainsworth JD et al. (2005) Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 23: 7889–7896

    Article  CAS  Google Scholar 

  70. Bukowski RM et al. (2006) Bevacizumab with or without erlotinib in metastatic renal cell carcinoma (RCC) [abstract #4523]. J Clin Oncol 24 (Suppl 18S)

  71. Azad NS et al. (2006) Increased efficacy and toxicity with combination anti-VEGF therapy using sorafenib and bevacizumab [abstract #3004]. J Clin Oncol 24 (Suppl 18S)

  72. Sosman JA et al. (2006) A phase I/II trial of sorafenib (S) with bevacizumab (B) in metastatic renal cell cancer (mRCC) patients (Pts) [abstract #3031]. J Clin Oncol 24 (Suppl 18S)

  73. Gollob J et al. (2006) Phase II trial of sorafenib plus interferon-alpha 2b (IFN-α2b) as first- or second-line therapy in patients (pts) with metastatic renal cell cancer (RCC) [abstract #4538]. J Clin Oncol 24(Suppl 18S)

  74. Ryan CW et al. (2006) Sorafenib plus interferon-α2b (IFN) as first-line therapy for advanced renal cell carcinoma (RCC): SWOG 0412 [abstract #4525]. J Clin Oncol 24 (Suppl 18S)

  75. Tamaskar I et al. (2006) Antitumor effects of sorafenib and sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC) who had prior therapy with anti-angiogenic agents [abstract #4597]. J Clin Oncol 24 (Suppl 18S)

  76. Rini BI et al. (2006) Efficacy and safety of sunitinib malate (SU11248) in bevacizumab-refractory metastatic renal cell carcinoma (mRCC) [abstract #4522]. J Clin Oncol 24 (Suppl 18S)

  77. Clark JI et al. (2003) Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol 21: 3133–3140

    Article  CAS  Google Scholar 

  78. Messing EM et al. (2003) Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol 21: 1214–1222

    Article  CAS  Google Scholar 

  79. Pizzocaro G et al. (2001) Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study. J Clin Oncol 19: 425–431

    Article  CAS  Google Scholar 

  80. Atzpodien J et al. (2005) Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer 92: 843–846

    Article  CAS  Google Scholar 

  81. Zalcberg JR et al. (2005) Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800mg after progression on 400mg. Eur J Cancer 41: 1751–1757

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin E Gore.

Ethics declarations

Competing interests

Martin Gore has received speaker's bureau honoraria and grant support from Bayer, Centocor, Pfizer and ScheringPlough. The other authors declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Larkin, J., Chowdhury, S. & Gore, M. Drug Insight: advances in renal cell carcinoma and the role of targeted therapies. Nat Rev Clin Oncol 4, 470–479 (2007). https://doi.org/10.1038/ncponc0901

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncponc0901

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing