UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma

Author
Michael B Atkins, MD
Section Editor
Jerome P Richie, MD, FACS
Deputy Editor
Michael E Ross, MD

INTRODUCTION

Surgical resection can be curative for localized renal cell carcinoma (RCC), but many patients recur after surgery. In addition, many RCCs are clinically silent until unresectable, locally advanced, or metastatic disease is present. The long-term prognosis for advanced RCC is generally poor.

RCCs can evoke an immune response, which occasionally results in dramatic, sustained remissions. High-dose, bolus interleukin-2 (IL-2) induces durable complete remissions in about 10 percent of carefully selected patients with favorable-risk disease, but its use is limited by severe toxicity and the need for specialized care during treatment. Nivolumab, an inhibitor of programmed cell death 1 (PD-1), has established efficacy in patients who have progressed following molecularly targeted therapy, and this approach has become the preferred therapy for patients who have progressed following an initial course of molecularly targeted therapy and have not had prior immunotherapy.

Understanding the molecular pathogenesis of RCC has identified targets for therapeutic intervention (figure 1) and led to the development of multiple agents that have an important role in the management of patients with advanced RCC. Anti-angiogenic and molecularly targeted agents and their application in patients with advanced RCC will be reviewed here, with the primary focus on the treatment of clear cell RCC because much of the data have been derived from clinical trials in these patients.

Other related topics include:

(See "Overview of the treatment of renal cell carcinoma".)

                                      

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Fri Oct 14 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Furge KA, Lucas KA, Takahashi M, et al. Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles. Cancer Res 2004; 64:4117.
  2. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol 2003; 170:2163.
  3. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 2014; 32:2765.
  4. Voss MH, Hakimi AA, Pham CG, et al. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin Cancer Res 2014; 20:1955.
  5. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010; 28:1061.
  6. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115.
  7. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27:3584.
  8. Patil S, Figlin RA, Hutson TE, et al. Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol 2011; 22:295.
  9. Bjarnason GA, Khalil B, Hudson JM, et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol 2014; 32:480.
  10. Atkinson BJ, Kalra S, Wang X, et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol 2014; 191:611.
  11. Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014; 50:1084.
  12. Lee JL, Kim MK, Park I, et al. RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial. Ann Oncol 2015; 26:2300.
  13. Bracarda S, Iacovelli R, Boni L, et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol 2015; 26:2107.
  14. Motzer RJ, Hutson TE, Olsen MR, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012; 30:1371.
  15. Hutson TE, Bukowski RM, Rini BI, et al. Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma. Br J Cancer 2014; 110:1125.
  16. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369:722.
  17. Motzer RJ, Hutson TE, McCann L, et al. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 2014; 370:1769.
  18. Escudier B, Porta C, Bono P, 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; 32:1412.
  19. Choueiri TK, Pal SK, McDermott DF, et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 2014; 25:1603.
  20. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373:1814.
  21. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208692s000lbl.pdf.
  22. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016.
  23. Choueiri TK, Halabi S, Sanford B, 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 2016.
  24. Rini BI, Grünwald V, Fishman MN, et al. Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study. J Clin Oncol 30, 2012 (suppl; abstr 4503).
  25. Rini BI, Melichar B, Ueda T, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol 2013; 14:1233.
  26. Motzer RJ, Hutson TE, Glen H, 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; 16:1473.
  27. Turner KJ, Moore JW, Jones A, et al. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res 2002; 62:2957.
  28. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27:1280.
  29. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125.
  30. Escudier B, Eisen T, Stadler WM, 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; 27:3312.
  31. Eisen T, Oudard S, Szczylik C, et al. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst 2008; 100:1454.
  32. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol 2013; 14:1287.
  33. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378:1931.
  34. Motzer RJ, Escudier B, Tomczak P, et al. 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 2013; 14:552.
  35. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370:2103.
  36. Escudier BJ, Bellmunt J, Negrier S, et al. Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon- 945;2a (IFN) in metastatic renal cell carcinoma (mRCC) (abstract #5020). J Clin Oncol 2009; 27:239s.
  37. Melichar B, Koralewski P, Ravaud A, et al. First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma. Ann Oncol 2008; 19:1470.
  38. Escudier B, Bellmunt J, Négrier S, et al. 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 2010; 28:2144.
  39. Bracarda S, Bellmunt J, Melichar B, et al. Overall survival in patients with metastatic renal cell carcinoma initially treated with bevacizumab plus interferon-α2a and subsequent therapy with tyrosine kinase inhibitors: a retrospective analysis of the phase III AVOREN trial. BJU Int 2011; 107:214.
  40. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008; 26:5422.
  41. Rini BI, Halabi S, Rosenberg JE, 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; 28:2137.
  42. Flaherty KT, Manola JB, Pins M, et al. BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell Carcinoma--A Trial of the ECOG-ACRIN Cancer Research Group (E2804). J Clin Oncol 2015; 33:2384.
  43. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009; 27:4462.
  44. Di Lorenzo G, Cartenì G, Autorino R, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol 2009; 27:4469.
  45. Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol 2009; 182:29.
  46. Izzedine H, Derosa L, Le Teuff G, et al. Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma. Ann Oncol 2015; 26:1128.
  47. McKay RR, Rodriguez GE, Lin X, et al. Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015; 21:2471.
  48. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:2271.
  49. Hutson TE, Escudier B, Esteban E, 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; 32:760.
  50. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372:449.
  51. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer 2010; 116:4256.
  52. Motzer RJ, Barrios CH, Kim TM, et al. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 31, 2013 (suppl; abstr 4504).
  53. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373:1803.
  54. Hutson TE, Figlin RA, Kuhn JG, Motzer RJ. Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist 2008; 13:1084.
  55. Torisel (temsirolimus) injection: Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm262796.htm (Accessed on May 28, 2014).
  56. Gore ME, Hariharan S, Porta C, et al. Sunitinib in metastatic renal cell carcinoma patients with brain metastases. Cancer 2011; 117:501.
  57. Massard C, Zonierek J, Gross-Goupil M, et al. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol 2010; 21:1027.
  58. Pouessel D, Culine S. High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor. Eur Urol 2008; 53:376.
  59. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001; 345:1655.
  60. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001; 358:966.
  61. Haas NB, Manola J, Uzzo RG, et al. Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol 2015; 33 (suppl 7; abstract 403).