Hot Topics in Oncology - Editor-in-chief: TBD - Formerly Dan L. Longo

Ali-Reza Golshayan, Ronald M. Bukowski

Correspondence to:
Ronald M. Bukowski - MD
Director
Experimental Therapeutics
Cleveland Clinic Taussig Cancer Center
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
of Case Western Reserve University
Cleveland, Ohio, USA
E-mail: bukowsr@ccf.org

DOI: 10.4147/HTO-080407

Abstract

Following the improved understanding of the biology and pathogenesis of renal cell carcinoma (RCC), small molecule tyrosine kinase inhibitors have been introduced to target the specific pathways involved in this disease. Sunitinib maleate is an oral, highly potent, multitarget tyrosine kinase inhibitor that exhibits direct antitumor and antiangiogenic activity. Sunitinib can produce durable responses and significant tumor shrinkage in patients with RCC.
In a large phase III trial conducted in treatment-naïve patients with good- and intermediate-risk metastatic RCC, sunitinib significantly improved progression-free survival, overall response rate, and health-related quality of life compared to interferon-alpha, with a trend toward improved overall survival. Following these results, sunitinib is now considered the standard first-line treatment for patients with favorable-prognosis metastatic RCC. The exact role of sunitinib in sequential treatment and its combination with other novel agents will become clearer as ongoing clinical trials and clinical experience mature.
This article summarizes all the relevant results recently obtained with sunitinib in clinical trials for patients with RCC.

Summary

• HISTOLOGY
• PATHOLOGY
• TREATMENT
• Sunitinib
• Sunitinib as first-line therapy
• Sunitinib after cytokine therapy
• Sunitinib after targeted therapy
• Continuous dosing
• Combination therapy
• Sunitinib in non-clear cell RCC
• Biomarkers
• Toxicity
• CONCLUSION
• REFERENCES

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Full text

Renal cell carcinoma (RCC) is the most common malignancy of the kidney. It accounts for 2-3% of all solid tumors in adults, and approximately 50,000 new cases were diagnosed in the United States in 2007 [1]. This malignancy occurs primarily in individuals between 40 and 70 years of age, and more often in men, at a ratio of 1.6:1 compared to women [1]. Over the past 3 decades, the incidence of RCC has increased by about 3% per year [2]. Most patients will present with solitary renal masses. However, 30% of patients will present with locally advanced or metastatic disease, and over one-third of those who present with localized cancer will relapse after nephrectomy. Traditionally, patients with metastatic disease have a poor prognosis, with 5-year survival rates of 5-10% [3]. Risk factors include smoking, hypertension, obesity, environmental exposures and end-stage renal disease with acquired cystic disease [3]. Smoking may account for 24-30% of all cases, and smoking cessation is the most important preventive measure for RCC.

HISTOLOGY

RCCs generally arise from the renal cortex and account for 85% of all primary renal cancers. There are a variety of histological subtypes of RCC, each with distinct mutations. The most common subtype, clear cell carcinoma, is diagnosed in approximately 70% of patients and arises from the proximal convoluted tubule [4]. Clear cell carcinoma is associated with defects in the von Hippel-Lindau (VHL) gene on chromosome 3, and can either be hereditary or occur sporadically. Less than 3% of cases present as part of an inherited cancer syndrome, such as von Hippel-Lindau syndrome, Birt-Hogg-Dube syndrome or constitutional chromosome 3 translocation [5]. Papillary RCCs originate from the distal tubule, account for 10-20% of cases and comprise 2 histological subtypes. Type 1 papillary RCC is associated with c-MET mutations and is seen in the hereditary papillary renal cancer syndrome, whereas type 2 is more often seen sporadically, has a less favorable prognosis and has been associated with trisomy 7q3 and mutations of fumarate hydratase [4,6]. Other renal cell cancer diagnostic categories include chromophobic carcinoma, oncocytoma, collecting duct tumors, and undifferentiated carcinoma [7]. Sarcomatoid and rhabdoid differentiation can occur in any RCC histology and are associated with more aggressive tumors with a poor prognosis [5,8].

PATHOLOGY

In clear cell RCC, the inactivation of the VHL tumor-suppressor gene by either mutation or deletion results in the loss or dysfunction of the VHL protein [9]. Under normal conditions, this protein is involved in the oxygen-dependent ubiquination and degradation of hypoxia-inducible factor-1-alpha (HIF-1α), which is a protein transcription factor responsible for the regulation of hypoxia-responsive genes.
Therefore, the defective VHL gene results in increased HIF-1α translation and expression. This accumulation leads to the transcription and over-expression of hypoxia-inducible products including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), epidermal growth factor receptor (EGFR) and other proangiogenic growth factors [10]. The activity of HIF-1α may also be regulated by the EGFR-phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway. This pathway is stimulated by the binding of TGFα to EGFR, which results in increased HIF-1α expression [11]. A positive feedback loop is activated under these conditions, since HIF-1α also regulates transcription of EGFR and TGFα.
VEGF is a dimeric glycoprotein that interacts with transmembrane tyrosine kinase receptors present on the cell surface and is regulated by hypoxia. After VEGF binds to the extracellular domain of the receptor, there is dimerization and autophosphorylation of the intracellular receptor for tyrosine kinases, and a cascade of downstream proteins is activated. VEGF is involved in angiogenesis and is believed to stimulate the proliferation, migration and survival of endothelial cells [10]. VEGF is the most potent proangiogenic protein that has thus far been implicated in driving RCC. PDGF promotes the survival and proliferation of pericytes surrounding blood vessels, thereby stabilizing new immature blood vessels [12]. The expression of these and other growth factors as a result of the loss of VHL protein results in the hypervascular nature of RCC.

TREATMENT

The primary treatment for RCC is surgical resection. However, in the context of advanced or metastatic disease, drug therapy is often utilized. Chemotherapy has been largely ineffective to date, with response rates of 4-6% [13]. Immunomodulator therapy in the form of interleukin-2 (IL-2) and interferon alpha (IFN-α) have often been used, but with modest clinical and meaningful benefits. High dose IL-2 has demonstrated response rates of 15-23%, with a median duration of response of 54 months and long-term survival in about 5% of patients [14,15]. However, its use has been limited because of significant associated toxicities. Single-agent IFN-α has achieved response rates of about 10-15%, regardless of dose [13]. Complete responses are seen in 1-2% of patients. The median duration of response is about 6 months, but because of its less toxic side effect profile, it is viewed as a useful drug for use in combination therapy in an experimental context. More recently, based upon improved understanding of the biology and pathogenesis of RCC, small molecule tyrosine kinase inhibitors have been introduced to target the specific pathways involved in this disease.

Sunitinib

Sunitinib maleate (Sutent^®, previously known as SU11248) is an oral, highly potent, multi-target tyrosine kinase inhibitor that exhibits direct antitumor and anti-angiogenic activity. It prevents cell membrane signals from being relayed into the cell to activate gene transcription. Biochemical analysis has shown that sunitinib suppresses the signaling function of VEGF receptor types 1-3, PDGF receptor (PDGFRα, PDGFRβ), c-Kit (stem-cell factor), FLT3 (FMS-like tyrosine kinase-3 receptor), and RET (glial cell line derived neurotrophic factor receptor) [16-18]. Of these, the inhibition VEGFR-2 and PDGFRβ are felt to be the most clinically significant [10,18], thus providing a rational basis for its use in renal cell cancer. Sunitinib may also boost immune effector mechanisms that contribute to its anti-tumor effect in metastatic RCC [19].
The recommended dose for sunitinib was defined in phase I trials as 50 mg orally once daily for 4 weeks, followed by 2 weeks off, (4/2 schedule) in repeated 6-week cycles [17,20].
In the phase III trial, 8% of patients discontinued therapy due to adverse events, and 38% required dose interruption [21]. Dose reductions from 50 mg to 37.5 mg were required in 16-35% of patients, and reductions to 25 mg were required in 3-6% of patients [16,21]. Sunitinib has good oral bioavailability and is excreted via the fecal route. It is metabolized by the hepatic CYP3A4 system to the active metabolite SU12662 [18]. Therapeutic plasma concentrations (50-100 mg/mL) were achieved in the majority of patients with daily doses of 50 mg [17]. It has a long half-life, ranging from 41 to 86 hours [17]. Sunitinib appears to have an exposure-response relationship in metastatic RCC [22]. Pharmacokinetic studies have demonstrated that the steady-state area under the curve of sunitinib and SU12662 correlate with the probability of tumor regression [23]. Studies also show that patients with the highest drug exposure have a longer time to progression and overall survival, suggesting that increased exposure to the drug is associated with clinical benefit [23]. It has been estimated that a dose of 50 mg/day could result in up to 62% of patients achieving a partial response [23].

Sunitinib as first-line therapy

Motzer and colleagues reported the results of a phase III trial of sunitinib in treatment-naïve patients with good- and intermediate-risk metastatic RCC, as defined by Memorial Sloan-Kettering Cancer Center (MSKCC) risk group categorization [21] (see Table 1). A total of 750 patients were randomly assigned in a 1:1 ratio to receive either sunitinib 50 mg daily for 4 weeks, followed by 2 weeks without treatment; or IFN-α 9 million units subcutaneously 3 times weekly in 6-week cycles. Patients were required to have quantifiable disease, a good performance status and clear cell histology. Patients were stratified based upon lactate dehydrogenase, Eastern Cooperative Oncology Group performance status (ECOG PS) and the absence of prior nephrectomy. The primary endpoint of the trial was progression-free survival; this was assessed according to the response evaluation in solid tumors criteria (RECIST). Secondary endpoints were overall response rate, overall survival, safety and patient-related outcomes. The treatment arms were well-balanced. Approximately 35% had good-risk disease, 58% had intermediate-risk disease, and 7% had poor-risk disease. Sunitinib therapy significantly improved progression-free survival (median 11 months versus 5 months, p <.000001) and overall response rate (39% versus 8%, p <.000001). There was only 1 complete response, which occurred in the sunitinib arm. Median overall survival had not been reached at the time of analysis, but there was a trend towards improved survival in the sunitinib group (hazard ratio for death, 0.65; 95% CI, 0.45 to 0.94; p = .02). Additionally, patients who received sunitinib had a greater health-related quality of life compared to those who were treated with IFN-α. The marked improvement in progression-free survival and overall response rate provided strong evidence for the use of sunitinib as first-line therapy in metastatic RCC. The results of this phase III trial were utilized by the FDA to grant full approval to sunitinib for the treatment of advanced RCC.

TABLE 1. Clinical trials of sunitinib in metastatic RCC

The investigators analyzed this trial for prognostic factors. They demonstrated that the following risk factors significantly predicted for progression-free survival: pretreatment ECOG PS (0 versus ≥1), time from diagnosis to treatment (≤1 year versus >1 year), hemoglobin (≤ lower limit of normal versus > lower limit of normal), corrected serum calcium (≤10 mg/dL versus >10 mg/dL) and number of metastatic sites (≤1 versus >1) [24]. The median progression-free survival for patients with 0, 1-2 and 3 or more risk factors was 14 months, 9 months, and 4 months, respectively [24].
Although most responses to sunitinib are in the form of partial response or stable disease, some complete responses are seen. In a retrospective review of metastatic RCC patients who received sunitinib therapy, 2/74 patients (2.7%) achieved a RECIST-defined complete response lasting for more than 15 months [25]. These 2 patients were treated in the first-line setting, had non-bulky pulmonary metastases and favorable or intermediate MSKCC risk status.

Sunitinib after cytokine therapy

Sunitinib has demonstrated significant clinical activity in metastatic RCC. Two phase II trials have been reported in patients who previously failed cytokine therapy (Table 1). All patients had measurable disease, good performance status, and adequate organ function. The first trial included 63 patients with all RCC histologies. The primary endpoint of the study was objective response rate. The results demonstrated an objective response rate of 40% and stable disease for more than 3 months in an additional 27% of patients, most of whom showed some evidence of disease regression [16]. Disease progression was seen in 21 patients (33%).
The second trial was a pivotal study to confirm the results of the previous trial. In it were enrolled 106 patients with clear cell histology, prior nephrectomy and disease progression on cytokine therapy. This trial reported 1 complete and 43 partial responses, although the objective response rate was 34% by independent third-party assessment [26]. In addition, 23% of patients had stable disease, and 34% had progressive disease or stable disease of less than 3 months. A pooled analysis of the 2 trials was performed on 168 patients, demonstrating a partial response rate of 42%, stable disease rate of 24%, and progressive disease rate of 34%. Median progressionfree survival in the combined analysis was 8.2 months, and the median progression-free survival of those patients who achieved a response was 14.8 months (95% CI, 10.9-24.2) [26]. Accelerated approval for the treatment of advanced RCC was granted by the FDA in January 2006 based upon the results of these studies.
The pooled data were recently updated, reporting an overall response rate of 45%, median progression-free survival of 8.4 months, and median overall survival of 22.3 months (95% CI 14.8-36.0 months) [27]. The median response duration was 11.6 months. By multivariate analysis, prognostic factors for survival were: ECOG PS (0 versus ≥1), time from diagnosis to treatment (≤1 year compared to >1 year) serum hemoglobin (≤ LLN compared to > LLN).

Sunitinib after targeted therapy

Rini and colleagues recently reported the activity of sunitinib in 60 patients who had demonstrated objective disease progression following treatment with bevacizumab [28] (Table 1). Bevacizumab is a neutralizing human monoclonal antibody against VEGF, and it was hypothesized that the signaling pathways that contribute to bevacizumab resistance may be sensitive to sunitinib. The primary endpoint was tumor response by RECIST criteria. Approximately 50% of patients had previously received cytokines. They all had good- or intermediate-risk disease and had undergone nephrectomy. The study found that 72% had some degree of tumor shrinkage (16% PR and 56% with less than 50% regression) and a median PFS of 23.6 weeks. This study suggests that tumor resistance to 1 mechanism of VEGF signaling inhibition may be overcome with a multi-targeted kinase inhibitor.
A second report identified 72 patients with metastatic RCC who had previously been treated with anti-angiogenic therapy (bevacizumab, thalidomide, lenalidomide, M200, AG-013736, sunitinib or sorafenib), and evaluated their response to sunitinib or sorafenib [29]. Twenty-seven of these patients were treated with sunitinib, of whom 31% had partial response, and 44% had stable disease.
The issue of sequential therapy with sorafenib and sunitinib has been addressed. In a retrospective analysis, 23 patients were noted to have been treated with sorafenib followed by sunitinib, while 14 received sunitinib and then sorafenib [30]. The median duration of disease control in the treatment groups was 42 weeks and 30.5 weeks, respectively. The first group (sorafenib followed by sunitinib) demonstrated a significantly lower rate of progression, even when other risk factors were controlled for. A similar study from France reviewed 90 patients, 68 of whom received sorafenib and then sunitinib (So-Su), and 22 of whom were treated with sunitinib followed by sorafenib (Su-So) [31]. Median progression-free survivals were 26 and 22 weeks, respectively. There were appreciable responses to the second treatment (So-Su: partial response 15%, stable disease 51%; Su-So: partial response 9%, stable disease 55%). Activity was observed in both groups when the first treatments achieved partial response or stable disease. The use of sunitinib after a best response of progressive disease (PD) with sorafenib resulted in 20% partial response and 30% stable disease. By comparison, treatment with sorafenib after a best response of PD with sunitinib achieved no partial responses, and 60% stable disease. These studies indicate that disease control may be achieved with sunitinib after progression on sorafenib therapy, and suggests a lack of cross-resistance between these 2 compounds. The authors suggested that the use of sorafenib first appeared to be superior. However, this question will have to be addressed by larger prospective trials.

Continuous dosing

Efforts to build upon the results achieved with sunitinib have included alternative dosing schedules. Sunitinib has been administered in a continuous daily regimen to patients with metastatic RCC. In a phase II study, 107 patients with prior cytokine therapy received 37.5 mg daily [32] (Table 1). On this schedule, few patients required treatment breaks or dose reductions, and the safety profile appeared comparable to the standard regimen. The ORR was 19%, with 40% of patients having stable disease of at least 6 months. The median progression-free survival was 8.3 months [32]. When compared to the standard 4/2 regimen, continuous dosing appeared to result in similar time to progression (TTP) and overall survival [23]. The EFFECT trial is a phase III study now underway to compare standard intermittent schedule sunitinib with this continuous daily dosing regimen.

Combination therapy

It is reasonable to consider targeting multiple pathways in order to enhance the anti-tumor and anti-angiogenic effects of therapy. Bevacizumab has been reported to have activity in metastatic RCC [14], and is known to rapidly decrease circulating VEGF, but does not affect receptor-bound VEGF. The combination of a monoclonal antibody, VEGF binding ligand and a multi-targeted tyrosine kinase inhibitor may provide clinical synergistic activity. The safety of this combination is being addressed in a current phase I trial [33]. The maximum tolerated dose was sunitinib 50 mg on a 4/2 schedule, and bevacizumab 10 mg/kg every 2 weeks. Nineteen patients have been evaluated for toxicity and best response. Hypertension was the most common serious adverse event, occurring in 63% of patients. Two grade 4 hemorrhages and 1 fatal myocardial infarction were reported. Preliminary reports note partial response of 37% and stable disease of 53%. A randomized phase II, placebo-controlled trial of sunitinib and bevacizumab is planned.
Sunitinib has been combined with gefitinib, a small molecule tyrosine kinase EGFR inhibitor, in a phase I/II trial [34]. Preclinical data have suggested that combining VEGF and EGFR inhibition may be synergistic in inhibiting tumor growth. The maximum tolerated doses were established as sunitinib 37.5 mg on a 4/2 schedule, and gefitinib 250 mg daily. Forty-two patients were enrolled on this study, and 36% of patients achieved partial response, while 48% achieved stable disease. Median duration of response was 9.2 months [34]. Median progression-free survival was 11.2 months (95% C. I. 5.7-16 months) although more mature data results are anticipated. The most common adverse events were diarrhea (48%), rash (26%), nausea (14%), hand-foot syndrome (14%) and hypertension (9%). Sunitinib is also being combined with erlotinib (another EGFR inhibitor) in a phase II trial of patients with unresectable or metastatic RCC that began recruiting as of November 11^th 2006, and is still accruing patients at this time.
The combination of IFN-α and sunitinib was tested in a preliminary phase I trial. Twenty-five treatment-naïve patients with metastatic clear cell RCC were treated. However, the toxicity profile appeared too unfavorable, and the maximum tolerated dose of sunitinib was 37.5 mg. Further evaluation of this combination was not recommended.
A trial of sunitinib (25 mg - 50 mg, 4/2 schedule) combined with temsirolimus (10-25 mg weekly administered intravenously) has been completed, and results will be released shortly. A trial of sunitinib and RAD-001, another mTOR inhibitor, is ongoing.

Sunitinib in non-clear cell RCC

The majority of trials involving sunitinib in RCC have limited their patients to clear cell histology; however, some data are available. In an abstract at the 2007 American Society of Clinical Oncology meeting, 20 patients with chromophobe and papillary RCC were evaluated after treatment with sunitinib. These patients had an overall response rate of 15%, and a progression-free survival of 11.9 months, compared to 33 patients who received sorafenib, who had an overall response rate and progression-free survival of 6% and 5.5 months respectively [35]. However, minimal activity was noted with regard to papillary RCC. Phase II studies of sunitinib in patients with metastatic papillary RCC and non-clear cell RCC are currently underway.

Biomarkers

Certain biomarkers may have predictive potential in individuals who receive sunitinib. In a phase II study involving patients who progressed after cytokines, plasma levels of VEGF-A, soluble sVEGFR-2, and placental growth factor levels were serially measured in patients treated with sunitinib [16]. In the majority of cases, VEGF-A and placental growth factor levels increased, and sVEGF-R2 levels decreased by the end of each dosing cycle (day 28); after 2 weeks off, the levels of all 3 biomarkers returned to near baseline levels [16,17]. A larger proportional increase in VEGF levels was observed in patients exhibiting partial response compared with those with stable disease or progression. In the phase II trial assessing the activity of sunitinib in bevacizumab-refractory metastatic RCC patients, plasma levels of VEGF were shown to increase from baseline levels by a mean of threefold. Conversely, plasma sVEGFR-3 levels decreased from baseline during therapy. Patients who responded to sunitinib had lower pretreatment sVEGFR-3 levels and demonstrated a greater reduction in sVEGFR-3 levels compared to those who had disease progression [36]. The mechanism underlying the changes in these biomarkers is not clear, and the clinical utility of these findings remains to be defined.

Toxicity

Dose-limiting toxicities from phase I trials, including fatigue, gastrointestinal toxicity, cytopenias, and skin toxicity, were reversible upon discontinuation of treatment [17]. Toxicities in phase II trials were most commonly grade 1 or 2, and included nausea, diarrhea, stomatitis, cytopenias and asthenia [16,26]. These are described in detail in Table 2. Sunitinib was generally well-tolerated. Grade 3 adverse events that occurred in approximately 5% of patients included anemia, thrombocytopenia, fatigue, stomatitis, hand-foot syndrome, and hypertension. Grade 3 neutropenia was reported in approximately 15%, but there were no reports of fever or sepsis. Increased serum lipase was not associated with clinical signs or symptoms of pancreatitis. Yellow skin discoloration can be seen in 14% of patients [21]. Hair changes due to sunitinib include color changes rather than hair loss [17]. The syndrome of reversible posterior leukoencephalopathy has recently been attributed to sunitinib [37].

TABLE 2. Toxicities associated with sunitinib therapy

A decrease in cardiac left ventricular ejection fraction (LVEF) has been reported in 4.7-10% of patients, the majority of whom had recovery of function after drug discontinuation [21,26]. A report at the 2007 American Society of Clinical Oncology meeting has suggested that cardiac abnormalities such as elevated cardiac enzymes, and abnormal ECG and echocardiography findings may be discovered in up to 23% of patients who received sunitinib or sorafenib, although the underlying mechanism is unclear [38]. The abnormal biomarkers and ECG changes may be predictor of future decreases in LVEF, and one could consider routine cardiac monitoring for patients receiving sunitinib, but no formal recommendations have been made.
Abnormal thyroid function tests after treatment with sunitinib were first reported during the treatment of gastrointestinal stromal tumors in up to 62% patients, with 36% developing persistent, primary hypothyroidism [39]. A report by Shaheen et al described 62 RCC patients treated with sunitinib, of whom 33/55 (60%) had abnormal thyroid function tests and signs and symptoms attributable to hypothyroidism [40]. Another study prospectively evaluated 11 patients with RCC on sunitinib of whom 3 (27%) developed increased TSH after 6 weeks of treatment [41]. Sixty-six patients with metastatic RCC were treated with sunitinib at the Cleveland Clinic Taussig Cancer Center, and had thyroid function test results available. Fifty-six (85%) had at least one thyroid function abnormality consistent with hypothyroidism, and 47 (84%) of the 56 patients with abnormal thyroid function tests had signs and/or symptoms possibly related to hypothyroidism. Thyroid hormone replacement improved symptoms in 9/17 patients [29]. The risk of developing hypothyroidism appeared to correlate with the duration of exposure to sunitinib. The potential contribution of hypothyroidism to fatigue in these patients is unclear. Because of the concerns for development of hypothyroidism, regular surveillance of thyroid function is warranted in patients receiving this drug.
In the sunitinib expanded access trial, nearly 5000 patients with metastatic RCC have been enrolled in 52 countries [42]. This includes many patient populations who were not enrolled in previous trials, such as ECOG PS ≥ 2, older age, non-clear cell histology, prior anti-angiogenic therapy and brain metastases. Over 2300 patients were recently analyzed for toxicity [42]. Treatment interruptions were required in 17% of patients and dose reductions in 37.6%. Sunitinib was discontinued due to adverse events in 12% of cases. The most common toxicities observed were nausea, diarrhea and fatigue (Table 2). A lower incidence of hematologic toxicities was reported compared to previous trials, and this may be partly explained by a less rigid treatment protocol. Preliminary results suggest that sunitinib is associated with acceptable toxicity across a diverse patient population.

CONCLUSION

The advances in understanding the molecular biology underlying RCC have led to the identification of targeted therapy for this tumor. The development of tyrosine kinase inhibitors has represented a significant advance in the treatment of metastatic RCC. Sunitinib can produce durable responses and significant tumor shrinkage. The current clinical evidence indicates that sunitinib should be considered as a standard of care in metastatic RCC because of demonstrated improvement in progression-free survival and overall response rate in the randomized phase III trial. The use of this agent in combination with a variety of other drugs, its role in sequential TKI therapy, and in a variety of other clinical circumstances is being explored (see Figure 1). These studies will provide additional information on its clinical efficacy and toxicity. The role of sunitinib monotherapy and its combination with other novel agents will become clearer as the ongoing clinical trials and clinical experience matures.

Figure 1. Ongoing and/or planned clinical trials with sunitinib in patients with renal cell carcinoma.

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