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Targeted therapies for treatment of renal cell carcinoma: recent advances and future perspectives

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  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

A wide variety of targeted therapies are available for the treatment of renal cancer that has progressed beyond the point at which surgery is a viable option. In addition, there are many more that are in the different stages of clinical trials. Here, we provide a methodical discussion of the efficacy and safety of targeted therapies for the treatment of advanced renal cell carcinoma.

Methods

We conducted a systematic literature employing the search terms: renal cell carcinoma targets, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and each of the drugs discussed within these papers.

Results

The identified targeted therapies work by disrupting specific signalling pathways involved in tumour progression, such as those responsible for angiogenesis and cell proliferation. Tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are now established classes of drugs used in the treatment of renal cancer, with a total of six having received regulatory approval to date (sorafenib, sunitinib, pazopanib, axitinib, temsirolimus, and everolimus). Ongoing trials are likely to result in addition to these in the near future, for example, tivozanib, dovitinib, and cediranib. Furthermore, in addition to these small molecule drugs, immunotherapies involving monoclonal antibodies against signalling molecules such as vascular endothelial growth factor (bevacizumab) or programmed death-1 (nivolumab) are receiving increasing attention.

Conclusions

Targeted therapies have great potential for disrupting tumour progression by inhibiting certain signalling pathways. As our understanding of the biochemical pathways involved in cancer progresses, additional targets are certain to become apparent, expanding treatment options even further.

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Abbreviations

CSF:

Colony-stimulating factor

EMA:

European Medicines Agency

FDA:

US Food and Drug Administration

FGF:

Fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

Flt-3:

FMS-like tyrosine kinase-3

IFN-α:

Interferon-α

IL-2:

Interleukin-2

mTOR:

Mammalian target of rapamycin

PD-1:

Programmed death-1

PDGF:

Platelet-derived growth factor

PDGFR:

Platelet-derived growth factor receptor

PI3K:

Phosphatidylinositol-3-kinase

RCC:

Renal cell carcinoma

TKI:

Tyrosine kinase inhibitor

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

References

  1. IARC (2012) GLOBOCAN estimated cancer incidence, mortality and prevalence worldwide. WHO. http://globocan.iarc.fr/. Accessed Dec 2014

  2. Cohen HT, McGovern FJ (2005) Renal-cell carcinoma. N Engl J Med 353(23):2477–2490. doi:10.1056/NEJMra043172

    Article  CAS  PubMed  Google Scholar 

  3. Amato RJ (2000) Chemotherapy for renal cell carcinoma. Semin Oncol 27(2):177–186

    CAS  PubMed  Google Scholar 

  4. Mattei J, da Silva RD, Sehrt D, Molina WR, Kim FJ (2014) Targeted therapy in metastatic renal carcinoma. Cancer Lett 343(2):156–160. doi:10.1016/j.canlet.2013.09.038

    Article  CAS  PubMed  Google Scholar 

  5. Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T (1998) Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med 338(18):1272–1278. doi:10.1056/nejm199804303381805

    Article  CAS  PubMed  Google Scholar 

  6. Rohrmann K, Staehler M, Haseke N, Bachmann A, Stief CG, Siebels M (2005) Immunotherapy in metastatic renal cell carcinoma. World J Urol 23(3):196–201. doi:10.1007/s00345-004-0470-4

    Article  CAS  PubMed  Google Scholar 

  7. Voss MH, Hsieh JJ, Motzer RJ (2013) Novel approaches targeting the vascular endothelial growth factor axis in renal cell carcinoma. Cancer J (Sudbury, Mass) 19(4):299–306. doi:10.1097/PPO.0b013e31829d5cff

    Article  CAS  Google Scholar 

  8. Cortes-Funes H (2009) The role of antiangiogenesis therapy: bevacizumab and beyond. Clin Transl Oncol 11(6):349–355

    Article  CAS  PubMed  Google Scholar 

  9. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671–688. doi:10.1038/nrd2062

    Article  CAS  PubMed  Google Scholar 

  10. Vignot S, Faivre S, Aguirre D, Raymond E (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16(4):525–537. doi:10.1093/annonc/mdi113

    Article  CAS  PubMed  Google Scholar 

  11. Drake CG, Jaffee E, Pardoll DM (2006) Mechanisms of immune evasion by tumors. Adv Immunol 90:51–81. doi:10.1016/s0065-2776(06)90002-9

    Article  CAS  PubMed  Google Scholar 

  12. Topalian SL, Weiner GJ, Pardoll DM (2011) Cancer immunotherapy comes of age. J Clin Oncol 29(36):4828–4836. doi:10.1200/jco.2011.38.0899

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Bukowski RM (2012) Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma. Front Oncol 2:13. doi:10.3389/fonc.2012.00013

    Article  PubMed Central  PubMed  Google Scholar 

  14. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (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(19):7099–7109. doi:10.1158/0008-5472.can-04-1443

    Article  CAS  PubMed  Google Scholar 

  15. Awada A, Hendlisz A, Gil T, Bartholomeus S, Mano M, de Valeriola D, Strumberg D, Brendel E, Haase CG, Schwartz B, Piccart M (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(10):1855–1861. doi:10.1038/sj.bjc.6602584

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, Gore M, Desai AA, Patnaik A, Xiong HQ, Rowinsky E, Abbruzzese JL, Xia C, Simantov R, Schwartz B, O’Dwyer PJ (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24(16):2505–2512. doi:10.1200/jco.2005.03.6723

    Article  CAS  PubMed  Google Scholar 

  17. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM (2009) Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 27(8):1280–1289. doi:10.1200/jco.2008.19.3342

    Article  CAS  PubMed  Google Scholar 

  18. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134. doi:10.1056/NEJMoa060655

    Article  CAS  PubMed  Google Scholar 

  19. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM (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(20):3312–3318. doi:10.1200/jco.2008.19.5511

    Article  CAS  PubMed  Google Scholar 

  20. Bhargava P (2009) VEGF kinase inhibitors: How do they cause hypertension? Am J Physiol Regul Integr Comp Physiol 297(1):R1–R5. doi:10.1152/ajpregu.90502.2008

    Article  CAS  PubMed  Google Scholar 

  21. Li Y, Li S, Zhu Y, Liang X, Meng H, Chen J, Zhang D, Guo H, Shi B (2014) Incidence and risk of sorafenib-induced hypertension: a systematic review and meta-analysis. J Clin Hypertens (Greenwich, Conn) 16(3):177–185. doi:10.1111/jch.12273

    Article  CAS  Google Scholar 

  22. Santoni M, Conti A, De Giorgi U, Iacovelli R, Pantano F, Burattini L, Muzzonigro G, Berardi R, Santini D, Cascinu S (2014) Risk of gastrointestinal events with sorafenib, sunitinib and pazopanib in patients with solid tumors: a systematic review and meta-analysis of clinical trials. Int J Cancer J int du Cancer 135(4):763–773. doi:10.1002/ijc.28544

    Article  CAS  Google Scholar 

  23. Mulder SF, Bertens D, Desar IM, Vissers KC, Mulders PF, Punt CJ, van Spronsen DJ, Langenhuijsen JF, Kessels RP, van Herpen CM (2014) Impairment of cognitive functioning during sunitinib or sorafenib treatment in cancer patients: a cross sectional study. BMC Cancer 14:219. doi:10.1186/1471-2407-14-219

    Article  PubMed Central  PubMed  Google Scholar 

  24. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (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(1):327–337

    CAS  PubMed  Google Scholar 

  25. Raymond E, Faivre S, Vera C (2003) Final results of a phase I and pharmacokinetic study of SU11248, a novel multi-target tyrosine kinase inhibitor, in patients with advanced cancers. In: Proceedings of the American Society for Clinical Oncology 22 (192):abstr 769

  26. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (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):16–24. doi:10.1200/jco.2005.02.2574

    Article  CAS  PubMed  Google Scholar 

  27. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115–124. doi:10.1056/NEJMoa065044

    Article  CAS  PubMed  Google Scholar 

  28. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27(22):3584–3590. doi:10.1200/jco.2008.20.1293

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Molina AM, Jia X, Feldman DR, Hsieh JJ, Ginsberg MS, Velasco S, Patil S, Motzer RJ (2013) Long-term response to sunitinib therapy for metastatic renal cell carcinoma. Clin Genitourin Cancer 11(3):297–302. doi:10.1016/j.clgc.2013.04.001

    Article  PubMed Central  PubMed  Google Scholar 

  30. Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, Figlin RA, Baum MS, Motzer RJ (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103(9):763–773. doi:10.1093/jnci/djr128

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Park SJ, Lee JL, Park I, Park K, Ahn Y, Ahn JH, Lee DH, Ahn S, Song C, Hong JH, Kim CS, Ahn H (2012) Comparative efficacy of sunitinib versus sorafenib as first-line treatment for patients with metastatic renal cell carcinoma. Chemotherapy 58(6):468–474. doi:10.1159/000346484

    Article  CAS  PubMed  Google Scholar 

  32. Poprach A, Pavlik T, Melichar B, Puzanov I, Dusek L, Bortlicek Z, Vyzula R, Abrahamova J, Buchler T (2012) Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study. Ann Oncol 23(12):3137–3143. doi:10.1093/annonc/mds145

    Article  CAS  PubMed  Google Scholar 

  33. Keisner SV, Shah SR (2011) Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs 71(4):443–454. doi:10.2165/11588960-000000000-00000

    CAS  PubMed  Google Scholar 

  34. Ward JE, Stadler WM (2010) Pazopanib in renal cell carcinoma. Clin Cancer Res 16(24):5923–5927. doi:10.1158/1078-0432.ccr-10-0728

    Article  CAS  PubMed  Google Scholar 

  35. Lang JM, Harrison MR (2010) Pazopanib for the treatment of patients with advanced renal cell carcinoma. Clin Med Insights Oncol 4:95–105. doi:10.4137/cmo.s4088

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Bukowski RM (2011) Critical appraisal of pazopanib as treatment for patients with advanced metastatic renal cell carcinoma. Cancer Manag Res 3:273–285. doi:10.2147/cmr.s15557

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6(7):2012–2021. doi:10.1158/1535-7163.mct-07-0193

    Article  CAS  PubMed  Google Scholar 

  38. Hurwitz HI, Dowlati A, Saini S, Savage S, Suttle AB, Gibson DM, Hodge JP, Merkle EM, Pandite L (2009) Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 15(12):4220–4227. doi:10.1158/1078-0432.ccr-08-2740

    Article  CAS  PubMed  Google Scholar 

  39. Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA (2010) Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol 28(3):475–480. doi:10.1200/jco.2008.21.6994

    Article  CAS  PubMed  Google Scholar 

  40. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28(6):1061–1068. doi:10.1200/jco.2009.23.9764

    Article  CAS  PubMed  Google Scholar 

  41. Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID (2013) 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 (Oxford, England : 1990) 49(6):1287–1296. doi:10.1016/j.ejca.2012.12.010

    Article  CAS  Google Scholar 

  42. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK (2013) Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369(8):722–731. doi:10.1056/NEJMoa1303989

    Article  CAS  PubMed  Google Scholar 

  43. Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Negrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D (2014) 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 32(14):1412–1418. doi:10.1200/jco.2013.50.8267

    Article  CAS  PubMed  Google Scholar 

  44. Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, Wu EY, McTigue MA, Murray BW, Kania RS, O’Connor P, Shalinsky DR, Bender SL (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14(22):7272–7283. doi:10.1158/1078-0432.ccr-08-0652

    Article  CAS  PubMed  Google Scholar 

  45. Escudier B, Gore M (2011) Axitinib for the management of metastatic renal cell carcinoma. Drugs R&D 11(2):113–126. doi:10.2165/11591240-000000000-00000

    Article  Google Scholar 

  46. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G (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(24):5474–5483. doi:10.1200/jco.2005.04.192

    Article  CAS  PubMed  Google Scholar 

  47. Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J, Trask PC, Kim S, Rini BI (2007) Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 8(11):975–984. doi:10.1016/s1470-2045(07)70285-1

    Article  PubMed  Google Scholar 

  48. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378(9807):1931–1939. doi:10.1016/s0140-6736(11)61613-9

    Article  CAS  PubMed  Google Scholar 

  49. Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI (2013) Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 14(6):552–562. doi:10.1016/s1470-2045(13)70093-7

    Article  CAS  PubMed  Google Scholar 

  50. Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ (2013) Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol 14(13):1287–1294. doi:10.1016/s1470-2045(13)70465-0

    Article  CAS  PubMed  Google Scholar 

  51. Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP (2009) Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 27(27):4462–4468. doi:10.1200/jco.2008.21.7034

    Article  CAS  PubMed  Google Scholar 

  52. Fischer A, Wu S, Ho AL, Lacouture ME (2013) The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis. Invest New Drugs 31(3):787–797. doi:10.1007/s10637-013-9927-x

    Article  CAS  PubMed  Google Scholar 

  53. Qi WX, He AN, Shen Z, Yao Y (2013) Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis. Br J Clin Pharmacol 76(3):348–357. doi:10.1111/bcp.12149

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Rini BI, Quinn DI, Baum M, Wood LS, Tarazi J, Rosbrook B, Arruda LS, Cisar L, Roberts WG, Kim S, Motzer RJ (2014) Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial. Target Oncol. doi:10.1007/s11523-014-0307-z

    PubMed Central  PubMed  Google Scholar 

  55. Cowey CL (2013) Profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma. Drug Des Dev Ther 7:519–527. doi:10.2147/dddt.s31442

    Article  CAS  Google Scholar 

  56. Nakamura K, Taguchi E, Miura T, Yamamoto A, Takahashi K, Bichat F, Guilbaud N, Hasegawa K, Kubo K, Fujiwara Y, Suzuki R, Kubo K, Shibuya M, Isae T (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):9134–9142. doi:10.1158/0008-5472.can-05-4290

    Article  CAS  PubMed  Google Scholar 

  57. Taguchi E, Nakamura K, Miura T, Shibuya M, Isoe T (2008) Anti-tumor activity and tumor vessel normalization by the vascular endothelial growth factor receptor tyrosine kinase inhibitor KRN951 in a rat peritoneal disseminated tumor model. Cancer Sci 99(3):623–630. doi:10.1111/j.1349-7006.2007.00724.x

    Article  CAS  PubMed  Google Scholar 

  58. Eskens FA, de Jonge MJ, Bhargava P, Isoe T, Cotreau MM, Esteves B, Hayashi K, Burger H, Thomeer M, van Doorn L, Verweij J (2011) Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin Cancer Res 17(22):7156–7163. doi:10.1158/1078-0432.ccr-11-0411

    Article  CAS  PubMed  Google Scholar 

  59. Nosov DA, Esteves B, Lipatov ON, Lyulko AA, Anischenko AA, Chacko RT, Doval DC, Strahs A, Slichenmyer WJ, Bhargava P (2012) Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J Clin Oncol 30(14):1678–1685. doi:10.1200/jco.2011.35.3524

    Article  CAS  PubMed  Google Scholar 

  60. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE (2013) Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol 31(30):3791–3799. doi:10.1200/jco.2012.47.4940

    Article  CAS  PubMed  Google Scholar 

  61. Lee SH, Lopes de Menezes D, Vora J, Harris A, Ye H, Nordahl L, Garrett E, Samara E, Aukerman SL, Gelb AB, Heise C (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(10):3633–3641. doi:10.1158/1078-0432.ccr-04-2129

    Article  CAS  PubMed  Google Scholar 

  62. Taeger J, Moser C, Hellerbrand C, Mycielska ME, Glockzin G, Schlitt HJ, Geissler EK, Stoeltzing O, Lang SA (2011) Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in pancreatic cancer. Mol Cancer Ther 10(11):2157–2167. doi:10.1158/1535-7163.mct-11-0312

    Article  CAS  PubMed  Google Scholar 

  63. Angevin E, Lopez-Martin JA, Lin CC, Gschwend JE, Harzstark A, Castellano D, Soria JC, Sen P, Chang J, Shi M, Kay A, Escudier B (2013) Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin Cancer Res 19(5):1257–1268. doi:10.1158/1078-0432.ccr-12-2885

    Article  CAS  PubMed  Google Scholar 

  64. Escudier B, Grunwald V, Ravaud A, Ou YC, Castellano D, Lin CC, Gschwend JE, Harzstark A, Beall S, Pirotta N, Squires M, Shi M, Angevin E (2014) Phase II results of Dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res 20(11):3012–3022. doi:10.1158/1078-0432.ccr-13-3006

    Article  CAS  PubMed  Google Scholar 

  65. Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grunwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B (2014) Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol 15(3):286–296. doi:10.1016/s1470-2045(14)70030-0

    Article  CAS  PubMed  Google Scholar 

  66. Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, Thierauch KH, Zopf D (2011) Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer J int du Cancer 129(1):245–255. doi:10.1002/ijc.25864

    Article  CAS  Google Scholar 

  67. Mross K, Frost A, Steinbild S, Hedbom S, Buchert M, Fasol U, Unger C, Kratzschmar J, Heinig R, Boix O, Christensen O (2012) A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res 18(9):2658–2667. doi:10.1158/1078-0432.ccr-11-1900

    Article  CAS  PubMed  Google Scholar 

  68. Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, Tomczak P, Pyrhonen S, Fife K, Bono P, Boxall J, Wagner A, Jeffers M, Lin T, Quinn DI (2012) Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol 13(10):1055–1062. doi:10.1016/s1470-2045(12)70364-9

    Article  CAS  PubMed  Google Scholar 

  69. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jurgensmeier JM, Ogilvie DJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65(10):4389–4400. doi:10.1158/0008-5472.can-04-4409

    Article  CAS  PubMed  Google Scholar 

  70. Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, Harder J, Blum H, Robertson J, Jurgensmeier JM, Puchalski TA, Young H, Saunders O, Unger C (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):3045–3054. doi:10.1200/jco.2006.07.2066

    Article  CAS  PubMed  Google Scholar 

  71. Mulders P, Hawkins R, Nathan P, de Jong I, Osanto S, Porfiri E, Protheroe A, van Herpen CM, Mookerjee B, Pike L, Jurgensmeier JM, Gore ME (2012) Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study. Eur J Cancer (Oxford, England : 1990) 48(4):527–537. doi:10.1016/j.ejca.2011.12.022

    Article  CAS  Google Scholar 

  72. Hadoux J, Vignot S, De La Motte Rouge T (2010) Renal cell carcinoma: focus on safety and efficacy of temsirolimus. Clin Med Insights Oncol 4:143–154. doi:10.4137/cmo.s4482

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP (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(12):2336–2347. doi:10.1200/jco.2004.08.116

    Article  CAS  PubMed  Google Scholar 

  74. Hidalgo M, Buckner JC, Erlichman C, Pollack MS, Boni JP, Dukart G, Marshall B, Speicher L, Moore L, Rowinsky EK (2006) A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12(19):5755–5763. doi:10.1158/1078-0432.ccr-06-0118

    Article  CAS  PubMed  Google Scholar 

  75. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML (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(5):909–918. doi:10.1200/jco.2004.08.185

    Article  CAS  PubMed  Google Scholar 

  76. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281. doi:10.1056/NEJMoa066838

    Article  CAS  PubMed  Google Scholar 

  77. Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, Sridhara R, Pazdur R (2010) FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 15(4):428–435. doi:10.1634/theoncologist.2009-0178

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Barthelemy P, Hoch B, Chevreau C, Joly F, Laguerre B, Lokiec F, Duclos B (2013) mTOR inhibitors in advanced renal cell carcinomas: from biology to clinical practice. Crit Rev Oncol Hematol 88(1):42–56. doi:10.1016/j.critrevonc.2013.02.006

    Article  PubMed  Google Scholar 

  79. O’Donnell A, Faivre S, Burris HA 3rd, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brock C, Jones S, Raymond E, Judson I (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26(10):1588–1595. doi:10.1200/jco.2007.14.0988

    Article  PubMed  Google Scholar 

  80. Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP (2009) A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 115(11):2438–2446. doi:10.1002/cncr.24280

    Article  CAS  PubMed  Google Scholar 

  81. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372(9637):449–456. doi:10.1016/s0140-6736(08)61039-9

    Article  CAS  PubMed  Google Scholar 

  82. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer 116(18):4256–4265. doi:10.1002/cncr.25219

    Article  CAS  PubMed  Google Scholar 

  83. Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, Stalter S, Shak S, Adelman D (2001) Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19(3):843–850

    CAS  PubMed  Google Scholar 

  84. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349(5):427–434. doi:10.1056/NEJMoa021491

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370(9605):2103–2111. doi:10.1016/s0140-6736(07)61904-7

    Article  PubMed  Google Scholar 

  86. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (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):2137–2143. doi:10.1200/jco.2009.26.5561

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O’Bryant C, Chow LQ, Serkova NJ, Meropol NJ, Lewis NL, Chiorean EG, Fox F, Youssoufian H, Rowinsky EK, Eckhardt SG (2010) Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 28(5):780–787. doi:10.1200/jco.2009.23.7537

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383(9911):31–39. doi:10.1016/s0140-6736(13)61719-5

    Article  CAS  PubMed  Google Scholar 

  89. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Perol M (2014) Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384(9944):665–673. doi:10.1016/s0140-6736(14)60845-x

    Article  CAS  PubMed  Google Scholar 

  90. Poole RM, Vaidya A (2014) Ramucirumab: first global approval. Drugs 74(9):1047–1058. doi:10.1007/s40265-014-0244-2

    Article  CAS  PubMed  Google Scholar 

  91. Garcia JA, Hudes GR, Choueiri TK, Stadler WM, Wood LS, Bhatia S, Youssoufian H, Rowinsky EK, Schwartz JD, Thompson JA (2010) Phase II study of IMC-1121B in patients with metastatic renal cancer (mRCC) following VEGFR-2 tyrosine kinase inhibitor (TKI) therapy (IMCL CP12-0605/NCT00515697). Genitourin Cancers Symposium:Abstr. 326

  92. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi:10.1056/NEJMoa1200690

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Topalian SL, Drake CG, Pardoll DM (2012) Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24(2):207–212. doi:10.1016/j.coi.2011.12.009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Robert C, Soria JC, Eggermont AM (2013) Drug of the year: programmed death-1 receptor/programmed death-1 ligand-1 receptor monoclonal antibodies. Eur J Cancer (Oxford, England : 1990) 49(14):2968–2971. doi:10.1016/j.ejca.2013.07.001

    Article  CAS  Google Scholar 

  95. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144. doi:10.1056/NEJMoa1305133

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL (2010) 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 28(19):3167–3175. doi:10.1200/jco.2009.26.7609

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. European Institute of Cancer Research (EICR), Carrer del Passeig, 2, 08221, Terrassa, Spain

    Joan Minguet, Katherine H. Smith & Peter Bramlage

  2. Institute of Pharmacology and Preventive Medicine (IPPMED), Bahnhofstr. 20, 49661, Cloppenburg, Germany

    Joan Minguet, Carsten P. Bramlage & Peter Bramlage

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Minguet, J., Smith, K.H., Bramlage, C.P. et al. Targeted therapies for treatment of renal cell carcinoma: recent advances and future perspectives. Cancer Chemother Pharmacol 76, 219–233 (2015). https://doi.org/10.1007/s00280-015-2770-3

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