The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease. In particular, the hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have been exploited. Sunitinib malate (Sutent), sorafenib tosylate (Nexavar), bevacizumab (Avastin)/interferon alfa, and temsirolimus (Torisel) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways. Combinations and sequences of these agents are being evaluated. Other novel multitargeted tyrosine kinase inhibitors (pazopanib and axitinib) and mTOR inhibitors (everolimus) are in clinical development. Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC.
In the United States, more than 50,000 new cases of renal cell carcinoma (RCC) and 13,000 associated deaths are predicted for 2007.[1,2] Although surgery is a potential cure for patients with localized RCC, many patients experience recurrence after surgery or have metastatic disease at the time of initial diagnosis. In these patients, few treatment options have been available. A highly vascular disease, RCC is known to be resistant to chemotherapy, with no single agent showing significant antitumor activity.[3,4] Interferon alfa (IFN-α) and interleukin-2 (IL-2, Proleukin) have been widely utilized as treatment for metastatic RCC. However, the majority of patients do not benefit from IFN-α or IL-2, and the few responses seen are not durable—only about 10% of patients remain progression-free at 3 years.[5,6]
An improved understanding of the biology of RCC has resulted in the development of novel targeted agents that are changing the natural history of this disease. In particular, the hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have been exploited. Sunitinib malate (Sutent), sorafenib tosylate (Nexavar), bevacizumab (Avastin)/IFN-α, and temsirolimus (Torisel) have improved clinical outcomes in randomized phase III trials (Table 1), leading to the first new drug approvals for the treatment of advanced RCC in almost 2 decades.
Combinations and sequences of these agents are being evaluated. Other novel targeted agents have also demonstrated activity in early studies (Table 2). Given the availability of multiple treatment options, many questions emerge as to how to best integrate these new therapies into the management of metastatic RCC. Ongoing and planned clinical trials should help answer important questions that will allow the selection of patients most likely to respond to these agents. Herein, we review the rapidly evolving role of targeted therapy for RCC.
Prognostic Factors and Risk Stratification
Although pathologic stage (TNM stage) is the most powerful predictor of survival in RCC, other tumor- and patient-related factors have been demonstrated to be significant predictors of outcome in multivariate analysis. The widely used Memorial Sloan-Kettering Cancer Center (MSKCC) risk group categorization in untreated patients with metastatic RCC defines the five poor-risk features as a Karnofsky performance status (KPS) < 80, a serum calcium level > 10 mg/dL (corrected for albumin), a hemoglobin below normal, absence of prior nephrectomy, and a lactate dehydrogenase (LDH) > 1.5 times the upper limit of normal.[8,9] In the original MSKCC analysis, the median survivals were 20, 10, and 4 months for good-risk (no risk factors), intermediate-risk (1-2 risk factors), and poor-risk patients (≥ 3 risk factors), respectively.
Similar prognostic factors were subsequently demonstrated to be important for pretreated patients. Pretreatment features associated with a shorter survival were low KPS, low hemoglobin, and high serum calcium. The median time to death in patients with zero risk factors was 22 months, with one of these prognostic factors was 11.9 months, and with two or more risk factors was 5.4 months. The application of the MSKCC risk group categorization or its modification has been widely applied in the pivotal trials of targeted therapy for RCC. Patient selection has allowed for risk group stratification that will enable the practicing oncologist to more appropriately select treatment options for utilizing targeted approaches in the patient cohort most likely to benefit.
1. Pickle LW, Hao Y, Jemal A, et al: A new method of estimating United States and state-level cancer incidence counts for the current calendar year. CA Cancer J Clin 57:30-42, 2007.
2. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43-66, 2007.
3. Yagoda A, Abi-Rached B, Petrylak D: Chemotherapy for advanced renal cell carcinoma: 1983-1993. Semin Oncol 22:42-60, 1995.
4. Motzer RJ, Vogelzang NJ: Chemotherapy for renal cell carcinoma, in Raghavan D, Scher HI, Leibel SA, et al (eds): Principles and Practice of Genitourinary Oncology, pp 885-896. Philadelphia, Lippincott-Raven, 1997.
5. McDermott DF, Atkins MB: Application of IL-2 and other cytokines in renal cancer. Expert Opin Biol Ther 4:455-468, 2004.
6. Hutson TE, Quinn D: Cytokine therapy—the standard of care in metastatic RCC? Clin Genitourinary Cancer 4:181-186, 2005.
7. Hutson TE, Figlin RA: Tyrosine kinase inhibitors in renal cell carcinoma, in DeVita VT, Lawrence TS, Rosenberg SA (eds): Principles & Practice of Oncology Updates, Wolters Kluwer Health-Lippincott Williams & Wilkins, New York, 21(1):1-8, 2007.
8. Motzer RJ, Mazumdar M, Bacik J, et al: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17:2530-2540, 1999.
9. Mekhail TM, Abou-Jawde RM, Boumerhi G, et al: Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 23:832-841, 2005.
10. Motzer RJ, Bacik J, Schwartz LH, et al: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454-463, 2004.
11. Hudson CC, Liu M, Chiang GG, et al: Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004-7014, 2002.
12. Mita MM, Mita A, Rowinsky EK: The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther 2:S169-S177, 2003.
13. Motzer RJ, Michaelson MD, Redman BG, et al: 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, 2006.
14. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516-2524, 2006.
15. Motzer RJ, Hutson TE, Tomczak P, et al: Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma. N Engl J Med 356:115-124, 2007.
16. Motzer RJ, Figlin RA, Hutson TE, et al: Sunitinib versus interferon-alfa (INF-α) as first-line treatment of metastatic renal cell carcinoma (mRCC): Updated results and analysis of prognostic factors (abstract 5024). J Clin Oncol 25(18S):241s, 2007.
17. Wilhelm SM, Carter C, Tang L, et al: BAY 43-9006 exhibits broad spectrum oral anti-tumor activity and targets the Raf/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099-7109, 2004.
18. Strumberg D, Richly H, Hilger RA, et al: 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, 2005.
19. Moore MJ, Hirte HW, Siu L, et al: 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, 2005.
20. Awada A, Hendlisz A, Gil T, et al: 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, 2005.
21. Clark JW, Eder JP, Ryan D, et al: 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 11:5472-5480, 2005.
22. Escudier B, Eisen T, Stadler WM, et al: Treatment Approaches in Renal cancer Global Evaluation Trial (TARGETs): A randomized, double-blind, placebo-controlled phase III trial of sorafenib, an oral multi-kinase inhibitor in advanced renal cell carcinoma. N Engl J Med 356:125-134, 2007.
23. Eisen T, Bukowski RM, Staehler M, et al: Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): Impact of crossover on survival (abstract 4524). J Clin Oncol 24(18S):223s, 2006.
24. Bukowski RM, Eisen T, Szczylik C, et al: Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysis (abstract 5023). J Clin Oncol 25(18S):240s, 2007.
25. Szczylik C, Demkow T, Staehler M, et al: Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: Final results (abstract 5025). J Clin Oncol 25(18S):241s, 2007.
26. Amato RJ, Harris P, Dalton M, et al: A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell carcinoma (MRCC) (abstract 5026). J Clin Oncol 25(18S):241s, 2007.
27. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an antivascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003.
28. Hainsworth JD, Sosman JA, Spigel DR, et al: Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 23:7889-7896, 2005.
29. Bukowski RM, Kabbinavar F, Figlin RA, et al: Bevacizumab with or without erlotinib (abstract 4523). J Clin Oncol 24(18S):222s, 2006.
30. Escudier B, Koralewski P, Pluzanska A, et al: A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon-α2a as first-line therapy in metastatic renal cell carcinoma (abstract 3). J Clin Oncol 25(18S):2s, 2007.
31. Gibbons JJ, Discafani C, Peterson R: The effect of CCI-779, a novel macrolide anti-tumor agent, on growth of human tumor cells in vitro and in nude mouse xenografts in vivo (abstract 1000). Proc Am Assoc Cancer Res 40:301, 1999.
32. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa or both for advanced renal cell carcinoma. N Engl J Med 356:2271-2281, 2007.
33. Boulay A, Zumstein-Mecker S, Stepha C, et al: Antitumor efficacy of intermittent treatment schedules with rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252-261, 2004.
34. Di Cosimo S, Matar P, Rojo F, et al: Schedule dependent effects of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory gefitinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001) (abstract 3074). Proc Am Soc Clin Oncol 23:213, 2004.
35. Hutson TE, Davis ID, Machiels JP, et al: Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT) (abstract 5031). J Clin Oncol 25(18S):242s, 2007.
36. Rini B, Rixe O, Bukowski R, et al: AG-013736, a multitarget tyrosine kinase receptor inhibitor, demonstrates antitumor activity in a phase 2 study of cytokine-refractory, metastatic renal cell cancer (abstract 4509). J Clin Oncol 23(16S):380s, 2005.
37. Rini BI, Wilding GT, Hudes G, et al: Axitinib (AG-013736; AG) in patients (pts) with metastatic renal cell cancer (RCC) refractory to sorafenib (abstract 5032). J Clin Oncol 25(18S):242s, 2007.