ABSTRACT: Recent advances in the understanding of the biology of renal cell carcinoma (RCC) have been translated into clinical treatment options in metastatic disease. The introduction of targeted therapy against the vascular endothelial growth factor (VEGF) pathway and related elements has produced robust clinical effects, exceeding those of historical treatment options. Sunitinib (Sutent) and bevacizumab (Avastin) plus interferon have established roles in the initial treatment of metastatic RCC. Sorafenib (Nexavar) is established for cytokine-refractory RCC and is being explored in other settings. Temsirolimus (Torisel) is the only agent to extend overall survival to date, although this finding has been restricted to a poor-risk population. Several clinical questions have thus emerged in regard to the optimal timing, type, and sequence of targeted therapy in metastatic RCC. Novel agents targeting the VEGF or alternative pathways have also emerged and are beginning to undergo clinical testing.
The medical management of metastatic renal cell carcinoma (RCC) has undergone a transformation in recent years. Initial attempts at treatment with hormonal or chemotherapeutic agents produced little success. The historical standard of cytokine immunotherapy, including interleukin (IL)-2 (Proleukin) and interferon (IFN)-alpha, resulted in limited clinical benefit in unselected cohorts. More recently, systemic therapy targeted at the vascular endothelial growth factor (VEGF) protein and related pathway elements has produced robust clinical effects in metastatic RCC, leading to regulatory approval of sorafenib (Nexavar), sunitinib (Sutent), and temsirolimus (CCI-779, Torisel), an inhibitor of the mammalian target of rapamycin (mTOR). Bevacizumab (Avastin) has also demonstrated antitumor activity in metastatic RCC and is awaiting regulatory approval in the United States.
It is useful to review the existing data from each of these approaches to formulate an overall management strategy of metastatic RCC patients. Further, we will discuss ongoing investigative efforts including sequencing, combination therapy and novel agents.
Systemic anticancer agents such as medroxyprogesterone acetate and cytotoxic chemotherapy were initially applied to metastatic RCC patients. These agents produced minimal objective response rates of approximately 2% to 5%.[1-4] While symptom palliation can be observed in some patients, the benefit for the entire cohort of RCC patients is extremely low. Despite combination chemotherapy regimens resulting in slightly higher response rates, such regimens are not in routine use pending further study of novel agents or additional patient selection efforts.
The immunogenic nature of RCC and the lack of benefit from chemotherapy and hormone therapy resulted in the clinical application of immunotherapeutic cytokines. Two phase III randomized trials have examined the benefit of high-dose IL-2 and low-dose cytokine (IL-2 monotherapy or IL-2 plus IFN-alpha) regimens (Table 1).[5,6] Both studies demonstrated an objective response rate advantage for the high-dose IL-2 arms, without any difference in disease-free or overall survival. Taken together, these data suggest that high-dose IL-2 has a higher overall and complete response rate compared with low-dose cytokines, with the majority of benefit realized in patients who experience a durable complete response. The limited benefit, however, precluded demonstration of a disease-free or overall survival advantage with high-dose IL-2 for the entire cohort. Further, the lack of applicability of high-dose IL-2 to the broad RCC population has dampened enthusiasm for this approach.
Low-dose IFN-alpha monotherapy has also been investigated (Table 1). A meta-analysis that reviewed 53 randomized controlled trials with IL-2 or IFN-alpha in metastatic RCC provides the most comprehensive view. Four trials (N = 644) randomized patients to IFN-alpha vs a non–IFN-alpha control arm. The weighted median survival improvement with IFN-alpha treatment vs the control group was 3.8 months (P = .007), with an odds ratio for death at 1 year of 0.56 for IFN-alpha (95% confidence interval = 0.40–0.77). The investigators found no evidence of a dose-response relationship and no correlation between response rate and overall survival. Despite multiple attempts, no prospective randomized trial has demonstrated a benefit to adding any additional cytokine/immunotherapeutic or noncytokine agent to cytokine monotherapy, with the notable exception of IFN-alpha plus bevacizumab trials.
The role of cytokine therapy in metastatic RCC is currently evolving and unclear. As noted above, cytokine monotherapy is of modest benefit in unselected populations, but select patients should be considered for high-dose IL-2 therapy, solely on the basis of the small but real chance of a durable complete response. Whether or not this durable complete response benefit is preserved when high-dose IL-2 is given after targeted therapy is not clear at present. Current investigative efforts are appropriately focused on additional patient selection efforts and combination therapy. For example, tumors expressing carbonic anhydrase IX (CAIX, also called G250) have been associated with a higher rate of objective response to IL-2 in retrospective analyses, and further prospective trials are ongoing.[8,9] In addition, based on nonoverlapping mechanisms of action, cytokines are being investigated in combination with targeted therapy, as discussed below.
The premise of targeted therapy in all oncologic endeavors is the fundamental reliance of tumor cells on given biologic pathways that drugs can be designed to disrupt. A growing understanding of the underlying molecular biology of RCC has established the VEGF and mTOR pathways as relevant therapeutic targets.
The pathogenesis of RCC was elucidated by the discovery of the von Hippel-Lindau (VHL) gene, which is named for the familial cancer syndrome in which it is implicated. VHL is a tumor-suppressor gene in which biallelic gene inactivation promotes a tumor phenotype. One allele is inactivated through a deletion (also known as loss of heterozygosity) observed in over 90% of sporadic clear cell RCC cases.[11,12] The remaining VHL allele can be inactivated either through a gene mutation (approximately 50% of clear cell RCC[13,14]) or through gene silencing by methylation (approximately 5% to 10% of cases).[15,16])
Under normal conditions, VHL encodes a protein that targets a crucial transcription factor called hypoxia-inducible factor (HIF) for proteolysis. As a result of the VHL gene inactivation, a defective VHL protein is produced and HIF is not subject to proteolysis and inactivation. Activated HIF then translocates into the nucleus and leads to the transcription of a variety of genes that play a central role in tumor progression. Transcription genes include VEGF, platelet-derived growth factor (PDGF), transforming growth factor (TGF)-alpha, and basic fibroblast growth factor (bFGF). Clinical testing has identified the VEGF protein and its receptor (VEGFR) as the most relevant targets in anti-RCC therapy.
Sunitinib is a small-molecule inhibitor of the tyrosine kinase portion of VEGFR and related receptors. Updated data from the initial phase II trials of sunitinib in metastatic RCC patients (N = 169) who had failed prior cytokine-based therapy demonstrated an investigator-assessed pooled objective response rate of 45%, a median duration of response of 11.9 months, and median progression-free survival (PFS) of 8.4 months (Table 1).
A phase III trial in untreated, metastatic RCC patients (N = 750) of sunitinib vs IFN-alpha demonstrated a significant advantage in objective response rate (39% vs 8%, P < .000001) and PFS (11 vs 5 months, P < .000001) for sunitinib-treated patients (Table 1). Baseline clinical features predictive of improved PFS at 12 months in sunitinib-treated patients identified Eastern Cooperative Oncology Group (ECOG) performance status 0, time from diagnosis ≥ 1 year and corrected serum calcium ≤ 10 mg/dL as favorable characteristics.
Based on these data, sunitinib has emerged as a front-line standard of care in metastatic RCC. This drug is notable for a superior objective response rate compared to other agents, balanced against toxicity including fatigue, hand-foot syndrome, and diarrhea. Final analysis of the survival data from this trial is pending
Sorafenib is a small-molecule inhibitor of VEGFR and related receptors in addition to inhibition of an intracellular-signaling enzyme, raf kinase. A phase III trial of sorafenib randomized 900 treatment-refractory metastatic RCC patients to sorafenib at 400 mg twice daily or placebo. A PFS advantage in the treatment arm was observed (5.5 vs 2.8 months, P < .000001; Table 1). Although overall survival was similar between the two arms (17.8 vs 15.2 months, P = .15), a preplanned analysis demonstrated improved survival with sorafenib after the censoring of placebo patients who crossed over to the sorafenib arm (17.8 vs 14.3 months, P = .03).
It is likely for this trial and other phase III trials that patient crossover to active therapy may obscure the overall survival benefit of targeted therapy in a single trial. The phase III data contrast somewhat with the results of a smaller, randomized phase II study of sorafenib vs IFN-alpha in 189 previously untreated metastatic RCC patients. In this smaller trial, median PFS was 5.7 months with sorafenib vs 5.6 months with IFN-alpha. The reason for the lack of significant effect vs IFN-alpha in the front-line setting is not entirely clear but may result from weaker inhibition of VEGFR compared to sunitinib. Although there may be patients in whom sorafenib would be the preferred initial agent, for example, due to toxicity profile, sorafenib use has moved toward second-line and later therapy. Investigators need to identify the phenotype of patients in whom sorafenib is the preferred initial treatment.
1. Papac RJ, Ross SA, Levy A: Renal cell carcinoma: Analysis of 31 cases with assessment of endocrine therapy. Am J Med Sci 274:281-290, 1977.
2. Pizzocaro G, Di Fronzo G, Cappelletti V, et al: Hormone treatment and sex steroid receptors in metastatic renal cell carcinoma: Report of a multicentric prospective study. Tumori 69:215-220, 1983.
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, Russo P: Systemic therapy for renal cell carcinoma. J Urol 163:408-417, 2000.
5. 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 23:133-141, 2005.
6. Yang JC, Sherry RM, Steinberg SM, et al: Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21:3127-3132, 2003.
7. Coppin C, Porzsolt F, Awa A, et al: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev (1):CD001425, 2005.
8. Atkins M, Regan M, McDermott D, et al: Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 11:3714-3721, 2005.
9. Bui MH, Seligson D, Han KR, et al: Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: Implications for prognosis and therapy. Clin Cancer Res 9:802-811, 2003.
10. Latif F, Tory K, Gnarra J, et al: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317-1320, 1993.
11. Gnarra JR, Lerman MI, Zbar B, et al: Genetics of renal-cell carcinoma and evidence for a critical role for von Hippel-Lindau in renal tumorigenesis. Semin Oncol 22:3-8, 1995.
12. Kondo K, Yao M, Yoshida M, et al: Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: Relationship to clinicopathological parameters. Genes Chromosomes Cancer 34:58-68, 2002.
13. Gallou C, Joly D, Mejean A, et al: Mutations of the VHL gene in sporadic renal cell carcinoma: Definition of a risk factor for VHL patients to develop an RCC. Hum Mutat 13:464-475, 1999.
14. Schraml P, Struckmann K, Hatz F, et al: VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma. J Pathol 196:186-193, 2002.
15. Clifford SC, Prowse AH, Affara NA, et al: Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: Evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer 22:200-209, 1998.
16. Herman JG, Latif F, Weng Y, et al: Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 91:9700-9704, 1994.
17. Kibel A, Iliopoulos O, DeCaprio JA, et al: Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 269:1444-1446, 1995.
18. Gnarra JR, Duan DR, Weng Y, et al: Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma. Biochim Biophys Acta 1242:201-210, 1996.
19. Kourembanas S, Hannan RL, Faller DV: Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J Clin Invest 86:670-674, 1990.
20. de Paulsen N, Brychzy A, Fournier MC, et al: Role of transforming growth factor-alpha in von Hippel-Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci U S A 98:1387-1392, 2001.
21. Rosenberg JE, Motzer RJ, Michaelson MD, et al: Sunitinib therapy for patients (pts) with metastatic renal cell carcinoma (mRCC): Updated results of two phase II trials and prognostic factor analysis for survival (abstract 5095). J Clin Oncol 25(18S):258s, 2007.
22. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115-124, 2007.
23. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007.
23. Bukowski RM, Kabbinavar FF, Figlin RA, et al: Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol 25:4536-4541, 2007.
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. 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 349:427-434, 2003.
27. Bukowski RM, Kabbinavar FF, Figlin RA, et al: Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol 25:4536-4541, 2007.
28. 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 370:2103-2111, 2007.
29. Rini BI, Halabi S, Rosenberg JE, et al: CALGB 90206: A phase III trial of bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in metastatic renal cell carcinoma (abstract 350). Genitourinary Cancers Symposium, San Francisco, Feb 14-16, 2008. Available at www.asco.org/. Accessed March 5, 2008.
30. Atkins MB, Hidalgo M, Stadler WM, et al: 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 22:909-918, 2004.
31. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002.
32. 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.
33. 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.
34. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505-2512, 2006.
35. Amato RJ, Misellati A, Khan M, et al: A phase II trial of RAD001 in patients with metastatic renal cell carcinoma (abstract 4530). J Clin Oncol 24(18S):224s, 2006.
36. 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.
37. Rixe O, Bukowski RM, Michaelson MD, et al: Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: A phase II study. Lancet Oncol 8:975-984, 2007.
38. 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.
39. Stephenson J, Schreeder M, Waples J, et al: Perifosine (P), active as a single agent for renal cell carcinoma (RCC), now in phase I trials combined with tyrosine kinase inhibitors (TKI) (abstract 15622). J Clin Oncol 25(18S):659s, 2007.
40. Oliner J, Min H, Leal J, et al: Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6:507-516, 2004.
41. Tamaskar I, Garcia JA, Elson P, et al: Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol 179:81-86, 2007.
42. George DJ, Michaelson MD, Rosenberg JE, et al: Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): Updated results and analysis of circulating biomarkers (abstract 5035). J Clin Oncol 25(18S):243s, 2007.
43. Rini BI, Hutson TE, Elson P, et al: A prospective trial of sorafenib in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) refractory to prior sunitinib or bevacizumab (abstract 346). Genitourinary Cancers Symposium, San Francisco, Feb 14-16, 2008. Available at www.asco.org/. Accessed March 5, 2008.
44. Gollob JA, Rathmell WK, Richmond TM, et al: 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 25:3288-3295, 2007.
45. Ryan CW, Goldman BH, Lara PN Jr, et al: Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: A phase II study of the Southwest Oncology Group. J Clin Oncol 25:3296-3301, 2007.
46. Finke JH, Rini B, Ireland J, et al: Sunitinib reverses type 1 immune suppression and decreases T regulatory cells in renal cell carcinoma patients. Clin Cancer Res. In press.
47. Sosman JA, Flaherty K, Atkins MB, et al: A phase I/II trial of sorafenib (S) with bevacizumab (B) in metastatic renal cell cancer (mRCC) patients (Pts) (abstract 3031). J Clin Oncol 24(18S):128s, 2006.
48. Feldman DR, Kondagunta GV, Ronnen EA, et al: Phase I trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC) (abstract 5099). J Clin Oncol 2007 25(18S):259s, 2007.
49. Garcia JA, Cooney MM, Mekhail T, et al: Sunitinib and bevacizumab in advanced solid tumors: Preliminary results of a phase I trial. (abstract 352). Genitourinary Cancers Symposium, San Francisco, Feb 14-16, 2008. Available at www.asco.org/. Accessed March 5, 2008.
50. Merchan JR, Liu G, Fitch T, et al: Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: Phase I safety and activity results (abstract 5034). J Clin Oncol 25(18S):243s, 2007.
51. Rini BI, Tamaskar I, Shaheen P, et al: Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99:81-83, 2007.