James MG Larkin
Martin E Gore
Department of Medicine
Royal Marsden Hospital
Renal cell carcinoma (RCC) accounts for 2-3% of all cancers.(1) Localised disease is curable with surgery, but one-third of patients present with metastatic disease that is incurable and the aim of management is palliation. One-third of patients treated surgically for localised disease also subsequently relapse with metastatic disease. The median survival for patients with metastatic RCC is 10-12 months.(2)
Renal cell carcinomas are classified histologically as clear cell (60-80%), papillary (10-15%), chromophobe (5-10%) and collecting duct (<1%). Clear cell histology is associated with a better outcome than papillary or chromophobe histology in the metastatic setting,(3) but the opposite is true for localised disease.(4)
Inactivation of both von Hippel-Lindau (VHL) alleles via mutation or promoter hypermethylation is found in 70-80% of sporadic clear cell renal carcinomas.(5) The VHL protein has an important role in the cellular response to hypoxia. Under conditions of normal oxygen tension, the VHL protein is bound to hypoxia-inducible factors (HIFs) 1alpha and 2alpha which become ubiquitinated and tagged for degradation in the proteasome.(6) Under hypoxic conditions (or in the absence of VHL), HIF-1alpha accumulates in the cell, stimulating the production of growth factors such as transforming growth factor alpha (TGFalpha), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), which stimulate angiogenesis and cellular proliferation. Several strategies have been developed to inhibit VEGF in metastatic RCC. These include inhibition of VEGF receptor signalling through their tyrosine kinases, binding of the VEGF protein or blockade of the VEGF receptor. Such approaches have demonstrated significant activity, placing VEGF blockade approaches at the forefront of current treatment strategies for RCC.
Metastatic RCC is generally resistant to cytotoxic chemotherapy(7) and to hormonal therapy,(8) with response rates generally less than 10%. Interferon (IFN) therapy results in responses in 10-20% of patients, with median durations of remission ranging from 3 to 16 months, and a statistically significant survival advantage for IFN over nonimmunotherapy has been reported in randomised trials.(9) There is now good evidence that only those with good prognostic features benefit from IFNa.(10) Immunotherapy with high dose of intravenous interleukin (IL)-2 results in durable complete responses in approximately 7% of patients,(11) but this treatment is associated with substantial toxicity.
In summary, although RCC can be cured by surgery, metastatic disease is difficult to treat and generally resistant to cytotoxic chemotherapy. A minority of patients with metastatic disease benefit from immunotherapy, but there remains a need for more effective and less toxic systemic treatments. There is evidence that antiangiogenic treatment may be of benefit in the treatment of RCC. A number of strategies have been developed to target angiogenesis in metastatic RCC. These include inhibition of VEGF receptor tyrosine kinases, binding of the VEGF protein and blockade of the VEGF receptor. Such approaches have demonstrated significant activity in phase II and, more recently, phase III trials, placing VEGF antagonist approaches at the forefront of current treatment strategies for RCC. This article will focus on the receptor tyrosine kinases sunitinib and sorafenib.
Kinase inhibitors in metastatic RCC
Kinase inhibitors are drugs that generally inhibit tyrosine kinases (TKs). Tyrosine kinases catalyse the transfer of phosphate groups from adenosine triphosphate (ATP) to tyrosine residues on proteins. For proteins involved in signalling, this can be an activating event leading to increased cellular proliferation and the promotion of angiogenesis and metastasis.
Tyrosine kinases can be categorised as receptor and nonreceptor kinases. Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) are located in the cell membrane and transduce signals from the extracellular environment to the cell interior. Numerous downstream signalling pathways,(12) such as RAS/RAF/MEK/ERK and PI3K (phosphoinositol 3′-kinase)/Akt, may be activated by ligand-binding to a RTK. Nonreceptor tyrosine kinases such as c-ABL are located intracellularly and can be activated by mechanisms such as phosphorylation.
Dysregulation of tyrosine kinase signalling in cancer can occur in a number of ways. Examples of dysregulation of TK signalling as a result of the overexpression of a tyrosine kinase or its ligand are EGFR, the VEGFR or the PDGFR receptor in RCC.(13) Tyrosine kinase inhibitors (TKIs) disrupt TK signalling by preventing the binding of either protein substrates or ATP.
Sorafenib (BAY 43-9006)
Sorafenib inhibits the RTKs VEGFR2, VEGFR3, Flt-3, c-KIT and PDGFR and the nonreceptor serine threonine kinases BRAF and CRAF.(14) The BRAF and CRAF kinases are members of the RAF/MEK/ERK signalling cascade that is involved in the survival and proliferation of tumour cells and is a therapeutic target in cancer, although it is not known to be important in RCC.
The recommended phase II dose of sorafenib is 400mg orally twice daily on the basis of data from phase I studies.(15) Patients with RCC were treated in these studies with an indication of clinical activity.(15) A multicentre phase II randomised discontinuation trial of sorafenib in RCC has been conducted.(16) All histological subtypes were eligible, 90% of patients received sorafenib as second- or third-line therapy, and 56% of patients had undergone prior nephrectomy. Sixty-five patients with stable disease (between 25% tumour growth and 25% tumour reduction) after 12 weeks on sorafenib were randomised to sorafenib or placebo. After 24 weeks, 50% of patients on sorafenib were progression-free, in comparison with 18% of patients on placebo (p=0.0077). This was the primary endpoint of the trial. Median progression-free survival (PFS) after randomisation was greater with sorafenib than placebo (24 versus 6 weeks, p=0.0087). Sorafenib was restarted in 28 patients who had progressed on placebo; median PFS after restarting sorafenib was 24 weeks. The most common adverse events were fatigue (73%), rash (66%) and handï¿½foot skin reaction (62%). It was concluded that sorafenib increases PFS in metastatic RCC with an acceptable toxicity profile.
The interim results of a multicentre, phase III, randomised, placebo-controlled, double-blind trial of sorafenib in RCC in patients who had progressed after one prior systemic therapy have been reported in abstract form.(17) Patients with ECOG performance status 0 or 1 were randomised to sorafenib 400mg twice daily or placebo. The primary endpoint of the trial was overall survival (OS); the results of a planned analysis of a secondary endpoint, progression free survival (PFS) were reported. At the time of the PFS analysis, 769 patients had been randomised and 342 events reported. Median PFS was 24 weeks for those treated with sorafenib, as compared with 12 weeks for those in the placebo arm (hazard ratio 0.44; p<0.00001), and the 12-week progression-free rate was 79% and 50% for patients in the sorafenib and placebo arms, respectively. Adverse events for sorafenib and placebo were, respectively, rash (34% vs 13%), diarrhoea (33% vs 10%), hand-foot skin reaction (27% vs 5%), fatigue (26% vs 23%) and hypertension (11% vs 1%). Grade 3 or 4 adverse events were reported in 30% of patients on sorafenib and 22% of patients on placebo.
The response rate to sorafenib was 10% (one complete and 51 partial responses) and to placebo 2% (eight partial responses). Stable disease was observed in 74% of patients on sorafenib and 53% of patients on placebo. Many patients with stable disease in the sorafenib group had tumour shrinkage, but insufficient in amount to qualify for a partial response by RECIST. Preliminary OS data from a planned interim analysis were also presented (after 220 events). Median OS in the placebo group was 14.7 months and had not been reached in the sorafenib group (hazard ratio 0.72, p=0.018). The threshold for statistical significance for this interim analysis was p<0.0005.
Patients in the placebo arm were permitted to cross over to the sorafenib arm as of May 2005.(18) By November 2005, 216 of 452 patients on placebo had crossed over and there had been 367 deaths overall (171 in the sorafenib arm and 196 in the placebo arm). Median OS at this point was 19.3 months in the sorafenib arm and 15.9 months in the placebo arm (hazard ratio 0.77, p=0.015). The threshold for statistical significance in this interim analysis was p<0.0094, and so this result is not statistically significant. However, the increase in OS in the placebo arm between these interim analyses is consistent with a treatment effect due to sorafenib in the intention-to-treat analysis.
A randomised phase II trial in the first-line setting comparing sorafenib with IFN is currently recruiting.
Sunitinib (SU11248) is an orally bioavailable small molecule that inhibits multiple split kinase domain receptor kinases including VEGF receptor 1 and 2,platelet-derived growth factor (PDGF) alpha and beta, c-Kit and Flt3. A dose of 50mg orally once a day for four weeks followed by a two-week break was the recommended phase II dose based on two phase I studies. Dose-limiting toxicities at higher doses were fatigue, hypertension and skin toxicity. There have been two independent multicentre phase II trials of sunitinib in metastatic RCC. Sixty-three patients were treated in the first trial(19) and 106 in the second.(20) All patients had failed previous cytokine therapy. Partial responses were reported in 25 patients (40%) in the first trial; 24 of the patients had clear cell histology (of 55 patients in the trial with clear cell histology) and one had papillary histology (of four patients in the trial with nonclear cell histology). Median time to progression was 8.7 months. Fatigue was the commonest toxicity, although only 11% of patients had grade 3 fatigue. The second study confirmed the results of the first: 106 patients were treated with a response rate of 34%, and fatigue was the most common side-effect.
The unprecedented efficacy and manageable toxicity profile of sunitinib in the second-line setting in metastatic RCC led to a phase III trial of sunitinib versus interferon as first-line therapy.(21) Seven hundred and fifty patients with ECOG performance status 0 or 1 were randomised to IFN or sunitinib. IFN was given at a dose of 9MU three times a week and sunitinib at 50mg for 28 days followed by 14 days off treatment. The primary endpoint of the trial was PFS and all patients had clear cell histology. Over 90% of patients were of favourable or intermediate prognosis and 90% had undergone prior nephrectomy. The response rate to sunitinib was 31% (103 partial responses) and to IFN 6% (20 partial responses, p<0.000001), as assessed by independent central review. The median PFS was 11 months (95% CI 10-12 months) for sunitinib and five months (95% CI 4-6 months) for IFN (hazard ratio 0.415, p<0.000001); the median OS had not been reached for either drug at the time of reporting. Adverse events were similar in both groups, except that 5-10% of patients in the sunitinib group had grade 3 or 4 diarrhoea, hypertension or hand-foot syndrome (p<0.05). Grade 3 or 4 neutropenia and thrombocytopenia were also more common in the sunitinib group, occurring in about 10% of patients (p<0.05). Interestingly, grade 3 or 4 fatigue was seen in 7% of patients in the sunitinib group and 12% in the IFN group (p<0.05).
This is the first phase III trial demonstrating the benefit of a nonimmune therapeutic agent in first-line therapy in metastatic RCC, and the authors conclude that sunitinib is a new reference standard for the first-line treatment of metastatic RCC.
Over the past few years there have been considerable advances in our understanding of renal cell carcinoma. These have been translated into the development of several drugs with proven efficacy, of which the kinase inhibitors have demonstrated the most significant activity. Oncologists now have real choices regarding treatment options for patients with renal cell carcinoma. The advances in our understanding of the molecular mechanisms underlying disease progression have left us poised to individualise and optimise treatment based on the potential benefits and risks for a given patient. Recent studies have raised many questions with regards to scheduling, dose, duration of treatment, potential combinations, neoadjuvant or adjuvant therapy, and toxicity. A deeper understanding of the relationship between the signalling pathways driving tumour growth and their inhibition is needed in order to optimise the use of these agents and should suggest strategies to delay or prevent resistance and identify appropriate therapeutic combinations. We are in an age of renewed hope with regard to treatment of patients with renal cell carcinoma, and it is already apparent that many groups of patients for whom there was previously been no effective therapy can now benefit from treatment.
- Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999;49:8-31.
- Motzer RJ, Bacik J, Mazumdar M. Prognostic factors for survival of patients with stage IV renal cell ï¿½carcinoma: memorial sloan-kettering cancer center experience. Clin Cancer Res 2004;10:6302S-3S.
- Motzer RJ, Bacik J, Mariani T, et al. Treatment outcome and survival ï¿½associated with metastatic renal cell carcinoma of non-clear-cell histology.J Clin Oncol 2002;20:2376-81.
- Cheville JC, Lohse CM, Zincke H, et al. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma.Am J Surg Pathol 2003;27:612-24.
- Yao M, Yoshida M, Kishida T, et al. VHL tumor suppressor gene ï¿½alterations associated with good prognosis in sporadic clear-cell renal carcinoma.J Natl Cancer Inst 2002;94:1569-75.
- Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000;2:423-7.
- Yagoda A, Bander NH. Failure of cytotoxic chemotherapy, 1983-1988, and the emerging role of monoclonal antibodies for renal cancer. Urol Int 1989;44:338-45.
- Harris DT. Hormonal therapy and chemotherapy of renal-cell carcinoma. Semin Oncol 1983;10:422-30.
- Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999;353:14-7.
- Fossa S, Jones M, Johnson P, et al. Interferon-alpha and survival in renal cell cancer. BJU 1995;76:286-90.
- Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg 1998;228:307-19.
- Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211-25.
- Gunningham SP, Currie MJ, Han C, et al. Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia. Cancer Res 2001;61:3206-11.
- Wilhelm SM, Carter C, Tang L, et al. 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 2004;64:7099-109.
- 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 2005;23:965-72.
- Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled ï¿½randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:2505-12.
- Escudier B, Szczylik C, Eisen, T, et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 2005; 23:380 (Suppl;Abstract 4510).
- Eisen T, Bukowski RM, Staehler M, et al. For The Sorafenib TARGETs Clinical Trial Group. Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): impact of crossover on survival. J Clin Oncol 2006;24 18S: Abstract 4524.
- 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 2006;24:16-24.
- Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295:2516-24.
- Motzer R, Hutson TE, Tomczak P, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alpha (INF-a) as first-line systemic therapy for patients with metastatic renal cell carcinoma (RCC). Proc Am Soc Clin Oncol 2006;24:LBA3.