Advertisement

Targeting the VEGF Pathway in Renal Cell Carcinoma

  • Cristina Suarez
  • Brian I. Rini
Chapter

Abstract

Renal cell carcinoma (RCC) has been classically characterized by its resistance to traditional chemotherapy, radiotherapy, and hormonal therapy treatments. Cytokine therapy has showed therapeutic benefit in a small percentage of RCC patients. The discovery of key molecular pathways involved in the tumorigenesis of RCC has favored the development of new and more effective therapies. The most successful molecular target identified so far is the von Hippel–Lindau (VHL)/hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway, which is known to be altered in most patients with sporadic clear-cell RCC. In the past 6 years, the use of targeted therapies has significantly increased the treatment options for patients with mRCC and improved their perspectives. Sorafenib, the first new generation targeted treatment, received Food and Drug Administration (FDA) approval in 2005 for patients with cytokine-refractory disease. Following sorafenib approval, three other VEGF-targeted agents—sunitinib, bevacizumab, and pazopanib—have been approved for the treatment of metastatic RCC. Currently, these targeted therapies have replaced the use of immunotherapy in the vast majority of mRCC patients.

Keywords

Vascular Endothelial Growth Factor Overall Survival Renal Cell Carcinoma Maximum Tolerate Dose Overall Response Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Coppin C, Porzsolt F, Awa A et al (2005) Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev (1):CD001425Google Scholar
  2. 2.
    Knudson AG Jr (1986) Genetics of human cancer. Annu Rev Genet 20:231–251PubMedCrossRefGoogle Scholar
  3. 3.
    Shuin T, Kondo K, Torigoe S et al (1994) Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res 54(11):2852–2855PubMedGoogle Scholar
  4. 4.
    Herman JG, Latif F, Weng Y et al (1994) Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA 91(21):9700–9704PubMedCrossRefGoogle Scholar
  5. 5.
    Nickerson ML, Jaeger E, Shi Y, Durocher JA et al (2008) Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 14(15):4726–4734PubMedCrossRefGoogle Scholar
  6. 6.
    Maher ER (2004) Von Hippel-Lindau disease. Curr Mol Med 4(8):833–842PubMedCrossRefGoogle Scholar
  7. 7.
    Brauch H, Weirich G, Brieger J et al (2000) VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res 60(7):1942–1948PubMedGoogle Scholar
  8. 8.
    Schraml P, Struckmann K, Hatz F et al (2002) VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma. J Pathol 196(2):186–193PubMedCrossRefGoogle Scholar
  9. 9.
    Kiselyov A, Balakin KV, Tkachenko SE (2007) VEGF/VEGFR signalling as a target for inhibiting angiogenesis. Expert Opin Investig Drugs 16(1):83–107PubMedCrossRefGoogle Scholar
  10. 10.
    Dvorak HF, Detmar M, Claffey KP et al (1995) Vascular permeability factor/vascular endothelial growth factor: an important mediator of angiogenesis in malignancy and inflammation. Int Arch Allergy Immunol 107(1–3):233–235PubMedCrossRefGoogle Scholar
  11. 11.
    Takahashi A, Sasaki H, Kim SJ et al (1994) Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 54(15):4233–4237PubMedGoogle Scholar
  12. 12.
    Nicol D, Hii SI, Walsh M, Teh B et al (1997) Vascular endothelial growth factor expression is increased in renal cell carcinoma. J Urol 157(4):1482–1486PubMedCrossRefGoogle Scholar
  13. 13.
    Ferrara N, Hillan KJ, Gerber HP et al (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3(5):391–400PubMedCrossRefGoogle Scholar
  14. 14.
    Yang JC, Haworth L, Sherry RM et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349(5):427–434PubMedCrossRefGoogle Scholar
  15. 15.
    Escudier B, Pluzanska A, Koralewski P et al (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111PubMedCrossRefGoogle Scholar
  16. 16.
    Escudier B, Bellmunt J, Négrier S et al (2010) Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 28(13):2144–2150PubMedCrossRefGoogle Scholar
  17. 17.
    Motzer RJ, Bacik J, Murphy BA et al (2002) Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289–296PubMedCrossRefGoogle Scholar
  18. 18.
    Rini BI, Halabi S, Rosenberg JE et al (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–5428PubMedCrossRefGoogle Scholar
  19. 19.
    Rini BI, Halabi S, Rosenberg JE et al (2010) 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 28(13):2137–2143PubMedCrossRefGoogle Scholar
  20. 20.
    Melichar B, Koralewski P, Ravaud A et al (2008) First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma. Ann Oncol 19(8):1470–1476PubMedCrossRefGoogle Scholar
  21. 21.
    Melichar B, Bracarda S, Matveev V et al (2011) BEVLiN: prospective study of the safety and efficacy of first-line bevacizumab (BEV) plus low-dose interferon-α2a (IFN) in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol 29(suppl): abstract 4546Google Scholar
  22. 22.
    Hainsworth JD, Sosman JA, Spigel DR et al (2005) Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 23(31):7889–7896PubMedCrossRefGoogle Scholar
  23. 23.
    Bukowski RM, Kabbinavar FF, Figlin RA et al (2007) Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol 25(29):4536–4541PubMedCrossRefGoogle Scholar
  24. 24.
    Hainsworth JD, Spigel DR, Sosman JA et al (2007) Treatment of advanced renal cell carcinoma with the combination bevacizumab/erlotinib/imatinib: a phase I/II trial. Clin Genitourin Cancer 5(7):427–432PubMedCrossRefGoogle Scholar
  25. 25.
    Hainsworth JD, Spigel DR, Burris HA 3rd et al (2010) Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol 28(13):2131–2136PubMedCrossRefGoogle Scholar
  26. 26.
    Merchan JR, Pitot HC, Qin R et al (2009) Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): safety and activity in RTKI refractory RCC patients. J Clin Oncol 27(15s):244s, abstract 5039Google Scholar
  27. 27.
    Escudier B, Negrier S, Gravis G et al (2010) Can the combination of temsirolimus and bevacizumab improve the treatment of metastatic renal cell carcinoma (mRCC)? Results of the randomized TORAVA phase II trial. J Clin Oncol 28(suppl):15s, abstract 4516Google Scholar
  28. 28.
    Feldman DR, Baum MS, Ginsberg MS et al (2009) Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27(9):1432–1439PubMedCrossRefGoogle Scholar
  29. 29.
    Rini BI, Garcia JA, Cooney MM et al (2009) A phase I study of sunitinib plus bevacizumab in advanced solid tumors. Clin Cancer Res 15(19):6277–6283PubMedCrossRefGoogle Scholar
  30. 30.
    Azad NS, Posadas EM, Kwitkowski VE et al (2008) Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26(22):3709–3714PubMedCrossRefGoogle Scholar
  31. 31.
    Sosman JA, Flaherty KT, Atkins MB (2008) Updated results of phase I trial of sorafenib (S) and bevacizumab (B) in patients with metastatic renal cell cancer (mRCC). J Clin Oncol 26(suppl):252s, abstract 5011Google Scholar
  32. 32.
    Tamaskar I, Rini B, Mekhail T et al (2008) A phase II trial of low-dose interleukin-2 (IL-2) and bevacizumab for patients (pts) with metastatic renal cell carcinoma (mRCC). Genitourinary Cancers Symposium, San Francisco, California, February 14–16. Abstract 363Google Scholar
  33. 33.
    Dandamudi UB, Ghebremichael MS, Sosman JA (2010) A phase II study of bevacizumab (B) and high-dose aldesleukin (IL-2) in patients (p) with metastatic renal cell carcinoma (mRCC): a Cytokine Working Group Study (CWGS). J Clin Oncol 28(suppl):15s, abstract 4530Google Scholar
  34. 34.
    Garcia JA, Mekhail T, Elson P et al (2011) Clinical and immunomodulatory effects of bevacizumab and low-dose interleukin-2 in patients with metastatic renal cell carcinoma: results from a phase II trial. BJU Int 107(4):562–570PubMedCrossRefGoogle Scholar
  35. 35.
    Mendel DB, Laird AD, Xin X 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 9:327–337PubMedGoogle Scholar
  36. 36.
    Rosen L, Mulay M, Long J et al (2003) Phase I trial of SU011248, a novel tyrosine kinase inhibitor in advanced solid tumors. Proc Am Soc Clin Oncol 22: abstract 765Google Scholar
  37. 37.
    Faivre S, Delbaldo C, Vera K 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(1):25–35PubMedCrossRefGoogle Scholar
  38. 38.
    Motzer RJ, Michaelson MD, Redman BG 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(1):16–24PubMedCrossRefGoogle Scholar
  39. 39.
    Motzer RJ, Rini BI, Bukowski RM et al (2006) Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295(21):2516–2524PubMedCrossRefGoogle Scholar
  40. 40.
    Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115–124PubMedCrossRefGoogle Scholar
  41. 41.
    Motzer RJ, Hutson TE, Tomczak P et al (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27(22):3584–3590PubMedCrossRefGoogle Scholar
  42. 42.
    Gore ME, Szczylik C, Porta C et al (2009) Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 10(8):757–763PubMedCrossRefGoogle Scholar
  43. 43.
    Motzer RJ, Hutson TE, Olsen MR et al (2011) Randomized phase II multicenter study of the efficacy and safety of sunitinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma: renal EFFECT trial. J Clin Oncol 29(suppl 7): abstract LBA308Google Scholar
  44. 44.
    Rini BI, Cohen DP, Lu DR et al (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103(9):763–773PubMedCrossRefGoogle Scholar
  45. 45.
    Wilhelm SM, Carter C, Tang L et al (2004) BAY43-9006 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 64:7099–7109PubMedCrossRefGoogle Scholar
  46. 46.
    Strumberg D, Richly H, Hilger RA 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(5):965–972PubMedCrossRefGoogle Scholar
  47. 47.
    Clark JW, Eder JP, Ryan D et al (2005) Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43–9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11(15):5472–5480PubMedCrossRefGoogle Scholar
  48. 48.
    Moore M, Hirte HW, Siu L 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(10):1688–1694PubMedCrossRefGoogle Scholar
  49. 49.
    Awada A, Hendlisz A, Gil T 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 tumors. Br J Cancer 92(10):1855–1861PubMedCrossRefGoogle Scholar
  50. 50.
    Ratain MJ, Eisen T, Stadler WM et al (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24(16):2505–2512PubMedCrossRefGoogle Scholar
  51. 51.
    Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134PubMedCrossRefGoogle Scholar
  52. 52.
    Escudier B, Eisen T, Stadler WM et al (2009) 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 27:3312–3318PubMedCrossRefGoogle Scholar
  53. 53.
    Sonpavde G, Hutson TE (2007) Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 9:115–119PubMedCrossRefGoogle Scholar
  54. 54.
    Hurwitz HI, Dowlati A, Saini S et al (2009) Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 15(12):4220–4227PubMedCrossRefGoogle Scholar
  55. 55.
    Hutson TE, Davis ID, Machiels JP et al (2010) Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol 28(3):475–480PubMedCrossRefGoogle Scholar
  56. 56.
    Sternberg CN, Davis ID, Mardiak J et al (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28(6):1061–1068PubMedCrossRefGoogle Scholar
  57. 57.
    Stenberg C, Hawkins R, Szczylk C et al. (2010) Randomized, double blind phase III study of pazopanib in patients with advanced/metastatic renal cell carcinoma (MRCC): final overall survival (OS) results. Paper presented at the 2010 European Society for Medical Oncology (ESMO) annual meeting, Milan, 8–10.Google Scholar
  58. 58.
    Pazopanib versus sunitinib in the treatment of locally advanced and/or metastatic renal cell carcinoma (NCT00720941) June 2011. http://www.clinicaltrials.gov
  59. 59.
    Patient preference study of pazopanib versus sunitinib in advanced or metastatic kidney cancer (NCT01064310). June 2011. http://www.clinicaltrials.gov
  60. 60.
    Escudier B, Cella D, Gschwend J et al (2010) A randomized double-blind cross-over patient preference study of pazopanib versus sunitinib in treatment-naive locally advanced or metastatic renal cell carcinoma (mRCC). J Clin Oncol 28(suppl):15s, abstract TPS237Google Scholar
  61. 61.
    Rugo HS, Herbst RS, Liu G 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 23:5474–5783PubMedCrossRefGoogle Scholar
  62. 62.
    Rixe O, Bukowski RM, Michaelson MD et al (2007) Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 8:975–984PubMedCrossRefGoogle Scholar
  63. 63.
    Rini B, Wilding GT, Hudes G et al (2009) Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 27:4462–4468PubMedCrossRefGoogle Scholar
  64. 64.
    Rixe O, Dutcher J, Motzer R et al (2009) Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC). J Clin Oncol 27(suppl):15s, abstract 5045Google Scholar
  65. 65.
    Rini BI, Escudier B, Tomczak P et al (2011) Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC): results of phase III AXIS trial. J Clin Oncol 29(suppl):15s, abstract 4503Google Scholar
  66. 66.
    Axitinib (AG-013736) with or without dose titration (Increase) in patients with kidney cancer (NCT00835978). June 2011. http://www.clinicaltrials.gov
  67. 67.
    Axitinib (AG-013736) for the treatment of metastatic renal cell cancer (NCT00920816). June 2011. http://www.clinicaltrials.gov
  68. 68.
    Nakamura K, Taguchi E, Miura T et al (2006) KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res 66(18):9134–9142PubMedCrossRefGoogle Scholar
  69. 69.
    Eskens F, de Jorge M, Esteves B et al (2008) Updated results from a phase I study of AV-951 (KRN951), a potent and selective VEGFR-1, -2 and −3 tyrosine kinase inhibitor, in patients with advanced solid tumors. AACR Meeting Abstracts, Apr 2008: LB-201Google Scholar
  70. 70.
    Bhargava P, Esteves B, Al-Adhami M et al. Effect of hypertension, nephrectomy, and prior treatment on the efficacy of tivozanib (AV-951) in a phase II randomized discontinuation trial (RDT) in patients with renal cell carcinoma (RCC). Genitourinary Cancers Symposium, San Francisco, California, March 5–7. Abstract 342Google Scholar
  71. 71.
    Bhargava P, Esteves B, Al-Adhami M et al (2010) Activity of tivozanib (AV-951) in patients with renal cell carcinoma (RCC): subgroup analysis from a phase II randomized discontinuation trial (RDT). J Clin Oncol 28(suppl):15s, abstract 4599Google Scholar
  72. 72.
    Motzer R, Bhargava P, Esteves B et al (2011) A phase III, randomized, controlled study to compare tivozanib with sorafenib in patients (pts) with advanced renal cell carcinoma (RCC). J Clin Oncol 29(suppl 7): abstract 310Google Scholar
  73. 73.
    Lindsay CR, MacPherson IR, Cassidy J (2009) Current status of cediranib: the rapid development of a novel anti-angiogenic therapy. Future Oncol 5(4):421–432PubMedCrossRefGoogle Scholar
  74. 74.
    Drevs J, Siegert P, Medinger M et al (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25(21):3045–3054PubMedCrossRefGoogle Scholar
  75. 75.
    Sridhar S, Mackenzie M, Hotte S et al (2008) Activity of cediranib (AZD2171) in patients (pts) with previously untreated metastatic renal cell cancer (RCC). A phase II trial of the PMH Consortium. J Clin Oncol 26(suppl): abstract 5047Google Scholar
  76. 76.
    Lee SH, de Lopes MD, Vora J et al (2005) In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res 11:3633–3641PubMedCrossRefGoogle Scholar
  77. 77.
    Korc M, Friesel RE (2009) The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets 9(5):639–651PubMedCrossRefGoogle Scholar
  78. 78.
    Angevin E, Lin C, Pande A et al (2010) A phase I/II study of dovitinib (TKI258), a FGFR and VEGFR inhibitor, in patients (pts) with advanced or metastatic renal cell cancer: phase I results. J Clin Oncol 28(suppl):15s, abstract 3057Google Scholar
  79. 79.
    Motzer RJ, Hudes G, Wilding G et al (2009) Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 7(1):28–33PubMedCrossRefGoogle Scholar
  80. 80.
    Patel PH, Senico PL, Curiel RE, Motzer RJ (2009) Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 7(1):24–27PubMedCrossRefGoogle Scholar
  81. 81.
    Kroog G, Feldman D, Kondagunta G et al (2009) Phase I trial of RAD001 (everolimus) plus sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27(suppl):15s, abstract 5037Google Scholar
  82. 82.
    Molina A, Feldman D, Ginsberg M et al (2011) Phase I trial sunitinib plus everolimus in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 29(suppl 7): abstract 311Google Scholar
  83. 83.
    Rini BI, Stein M, Shannon P et al (2011) Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 117(4):758–767PubMedCrossRefGoogle Scholar
  84. 84.
    Escudier B, Lassau N, Angevin E et al (2007) Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma. Clin Cancer Res 13(6):1801–1809PubMedCrossRefGoogle Scholar
  85. 85.
    Gollob JA, Rathmell WK, Richmond TM et al (2007) Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol 25(22):3288–3295PubMedCrossRefGoogle Scholar
  86. 86.
    Procopio G, Verzoni E, Bracarda S et al (2009) A randomized, open label, prospective study comparing the association between sorafenib (So) and interleukin-2 (IL-2) versus So alone in advanced untreated renal cell cancer (RCC): Rosorc Trial. J Clin Oncol 27(suppl):15s, abstract 5099Google Scholar
  87. 87.
    Lam E, Lesinski G, Mortazavi A et al (2011) Phase I study of high-dose interleukin (HD-IL2) and sorafenib in patients with metastatic clear cell renal cell carcinoma (RCC) and melanoma. J Clin Oncol 29(suppl 7): abstract 337Google Scholar
  88. 88.
    Patnaik A, Ricart A, Cooper J et al (2007) A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies. J Clin Oncol 25(suppl): abstract 3512Google Scholar
  89. 89.
    Cen P, Daleiden A, Doshi G et al (2009) A phase I study of everolimus plus sorafenib in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 27(suppl): abstract e16056Google Scholar
  90. 90.
    Harzstark A, Rosenberg J, Weinberg V et al (2009) A phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma. J Clin Oncol 27(suppl):15s, abstract 5104Google Scholar
  91. 91.
    Rini B, Szczylik C, Tannir N et al (2011) AMG 386 in combination with sorafenib in patients (pts) with metastatic renal cell cancer (mRCC): a randomized, double-blind, placebo-controlled, phase II study. J Clin Oncol 29(suppl 7): abstract 309Google Scholar
  92. 92.
    Kabbinavar F, Srinivas S, Hauke R et al (2011) A phase I trial of combined tivozanib (AV-951) and temsirolimus therapy in patients (pts) with renal cell carcinoma (RCC). J Clin Oncol 29(suppl 7): abstract 330Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Medical OncologyHospital General Vall d”HebronBarcelonaSpain
  2. 2.Department of Solid Tumor OncologyCleveland Clinic Taussig Cancer Institute, Glickman Urological and Kidney InstituteClevelandUSA

Personalised recommendations