Pazopanib and sorafenib are both orally available multikinase inhibitors (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, and c-KIT for pazopanib and cRAF, bRAF, KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β for sorafenib) and have also been approved for the treatment of patients with advanced renal cell carcinoma.
Pazopanib was evaluated in a randomized, placebo-controlled, international trial that enrolled 435 patients with clear cell or predominantly clear cell renal cell carcinoma. Nearly half of the patients had previously received cytokine therapy while the remainder were treatment naïve. PFS was significantly prolonged in the pazopanib arm at 9.2 months versus 4.2 months in the placebo arm. The HR for progression was 0.46 (95% CI, 0.34–0.62; P < .0001), and the median duration of response was longer than 1 year.
In an international, multicenter, randomized trial with the primary endpoints of PFS and OS, 769 patients were stratified by the Memorial Sloan-Kettering Cancer Center prognostic risk category and by country and were randomly assigned to receive either sorafenib (400 mg bid) or a placebo. Approximately 82% of the patients had received prior IL-2 and/or interferon-alpha in both arms of the study. The median PFS for patients randomly assigned to sorafenib was 167 days compared with 84 days for patients randomly assigned to placebo (P < .001). The estimated HR for the risk of progression with sorafenib compared with a placebo was 0.44 (95% CI, 0.35–0.55). There was no significant difference in OS.[Level of evidence: 1iDiii] A subsequent phase II study of 189 patients randomly assigned to either sorafenib or interferon-alpha reported no difference (5.7 months vs. 5.6 months) in PFS, but sorafenib was associated with better quality of life than interferon-alpha.
Responses to cytotoxic chemotherapy generally have not exceeded 10% for any regimen that has been studied in adequate numbers of patients.
Because of the lack of curative therapy for metastatic disease and the promise of targeted therapies, patients should be considered for the many ongoing clinical trials testing single or combination therapies, including the following:
- Radical nephrectomy (for T4, M0 lesions).
- Cytoreductive nephrectomy.[2,3]
- Bevacizumab with or without interferon-alpha.[27,28,29,33]
- Everolimus (for patients who have previously been treated with sunitinib and/or sorafenib).
- Palliative EBRT.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV renal cell cancer and recurrent renal cell cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89.
- 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 345 (23): 1655-9, 2001.
- 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 358 (9286): 966-70, 2001.
- Murthy SC, Kim K, Rice TW, et al.: Can we predict long-term survival after pulmonary metastasectomy for renal cell carcinoma? Ann Thorac Surg 79 (3): 996-1003, 2005.
- van der Poel HG, Roukema JA, Horenblas S, et al.: Metastasectomy in renal cell carcinoma: A multicenter retrospective analysis. Eur Urol 35 (3): 197-203, 1999.
- Eggener SE, Yossepowitch O, Kundu S, et al.: Risk score and metastasectomy independently impact prognosis of patients with recurrent renal cell carcinoma. J Urol 180 (3): 873-8; discussion 878, 2008.
- Kwak C, Park YH, Jeong CW, et al.: Metastasectomy without systemic therapy in metastatic renal cell carcinoma: comparison with conservative treatment. Urol Int 79 (2): 145-51, 2007.
- Russo P, O'Brien MF: Surgical intervention in patients with metastatic renal cancer: metastasectomy and cytoreductive nephrectomy. Urol Clin North Am 35 (4): 679-86; viii, 2008.
- Hofmann HS, Neef H, Krohe K, et al.: Prognostic factors and survival after pulmonary resection of metastatic renal cell carcinoma. Eur Urol 48 (1): 77-81; discussion 81-2, 2005.
- Wroński M, Arbit E, Russo P, et al.: Surgical resection of brain metastases from renal cell carcinoma in 50 patients. Urology 47 (2): 187-93, 1996.
- Coppin C, Porzsolt F, Awa A, et al.: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev (1): CD001425, 2005.
- Rosenberg SA, Lotze MT, Muul LM, et al.: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316 (15): 889-97, 1987.
- Fisher RI, Coltman CA Jr, Doroshow JH, et al.: Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. A phase II clinical trial. Ann Intern Med 108 (4): 518-23, 1988.
- Weiss GR, Margolin KA, Aronson FR, et al.: A randomized phase II trial of continuous infusion interleukin-2 or bolus injection interleukin-2 plus lymphokine-activated killer cells for advanced renal cell carcinoma. J Clin Oncol 10 (2): 275-81, 1992.
- Rosenberg SA, Yang JC, Topalian SL, et al.: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271 (12): 907-13, 1994 Mar 23-30.
- Fyfe G, Fisher RI, Rosenberg SA, et al.: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13 (3): 688-96, 1995.
- McDermott DF, Regan MM, Clark JI, et al.: Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 23 (1): 133-41, 2005.
- Yang JC, Topalian SL, Parkinson D, et al.: Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol 12 (8): 1572-6, 1994.
- Sleijfer DT, Janssen RA, Buter J, et al.: Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis. J Clin Oncol 10 (7): 1119-23, 1992.
- Atkins MB, Sparano J, Fisher RI, et al.: Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol 11 (4): 661-70, 1993.
- Negrier S, Perol D, Ravaud A, et al.: Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: results of a randomized controlled trial. Cancer 110 (11): 2468-77, 2007.
- Hudes G, Carducci M, Tomczak P, et al.: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356 (22): 2271-81, 2007.
- 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 372 (9637): 449-56, 2008.
- 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 378 (9807): 1931-9, 2011.
- Motzer RJ, Hutson TE, Tomczak P, et al.: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356 (2): 115-24, 2007.
- 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 27 (22): 3584-90, 2009.
- Yang JC, Haworth L, Sherry RM, et al.: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349 (5): 427-34, 2003.
- 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 26 (33): 5422-8, 2008.
- 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 370 (9605): 2103-11, 2007.
- Nexavar® [label information]. Rockville, Md: Center for Drug Evaluation and Research, FDA, 2007. Available online. Last accessed February 9, 2012.
- 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 28 (6): 1061-8, 2010.
- 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 27 (8): 1280-9, 2009.
- 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 28 (13): 2144-50, 2010.
- Escudier B, Eisen T, Stadler WM, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356 (2): 125-34, 2007.
- Pyrhönen S, Salminen E, Ruutu M, et al.: Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 17 (9): 2859-67, 1999.
- Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 353 (9146): 14-7, 1999.