Targeting Growth Factor and Antiangiogenic Pathways in Clear-Cell Renal Cell Carcinoma: Rationale and Ongoing Trials

Targeting Growth Factor and Antiangiogenic Pathways in Clear-Cell Renal Cell Carcinoma: Rationale and Ongoing Trials Thomas E. Hutson1,2 Guru Sonpavde2 Matthew D. Galsky2

Abstract

1Genitourinary Oncology Program, Texas Oncology, PA, Dallas, TX 2Genitourinary Oncology Program, US Oncology Research Network, Houston, TX

Clinical Genitourinary Cancer, Vol. 5, Suppl. 1, S31-S39, 2006 Key words: Axitinib, Bevacizumab, Lapatinib, Lenalidomide, Mammalian target of rapamycin, Pazopanib, Sorafenib, Sunitinib, Temsirolimus, Tyrosine kinase inhibitors, Vascular endothelial growth factor inhibitors, Vatalanib, Volociximab Submitted: Oct 13, 2006; Revised: Oct 31, 2006; Accepted: Nov 14, 2006 Address for correspondence: Thomas E. Hutson, DO, PharmD Genitourinary Oncology Program, Texas Oncology, PA Baylor Sammons Cancer Center, Collins Building 3535 Worth St, Suite 240 Dallas, TX 75246 Fax: 214-370-1190 E-mail: [email protected] Dr Hutson has received research support from Bayer/Onyx, Pfizer, and GlaxoSmithKline. He is also a member of the Speaker’s Bureau of Bayer/Onyx, Pfizer, Genentech, and Novartis and has served as a paid consultant for or been on the Advisory Board of Bayer/Onyx, Pfizer, and Genentech. Dr Sonpavde has received research support from Pfizer, Eli Lilly, and AstraZeneca. He is also a member of the Speaker’s Bureau of Pfizer, sanofi-aventis, and Novartis. Dr Galsky is a member of the Speaker’s Bureau of Pfizer. This article includes the discussion of investigational and/or unlabeled uses of drugs, including the use axitinib; vatalanib; lapatinib; pazopanib; temsirolimus alone or in combination with interferon; lenalidomide, bevacizumab alone or in combination with erlotinib, VEGF Trap, and volociximab in patients with metastatic renal cell carcinoma.

Clear-cell renal cell carcinoma is characterized by the inactivation of the von Hippel–Lindau tumor suppressor gene, which results in an overproduction of vascular endothelial growth factor that promotes tumor angiogenesis, growth, and metastasis after binding with its receptor. The mammalian target of rapamycin signal transduction pathway is involved in the translation of hypoxia inducible factor–1 and vascular endothelial growth factor. Sunitinib, sorafenib, bevacizumab, and temsirolimus have improved clinical outcomes by inhibiting these tumorigenic pathways. Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib, pazopanib) and antiangiogenic agents (lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. Clinical trials designed to further assess these and other agents need to be vigorously supported.

Introduction In the United States, 38,890 new cases of renal cell carcinoma (RCC) are expected in 2006.1 Approximately 50% of patients will present with or develop metastatic disease, and the majority of these patients will die from their illness. Observations of late relapses after nephrectomy, prolonged stabilization of disease in the absence of treatment, and a small number of spontaneous remissions led to trials exploring immunotherapy. Indeed, until recently, immunotherapy has been the mainstay of systemic therapy for metastatic RCC. Trials demonstrating a small proportion of durable complete responses (CRs) with high-dose interleukin (IL)–2 led to approval of this therapy by the US Food and Drug Administration.2-7 However, a minority of patients are eligible for high-dose IL-2 therapy because of prohibitive toxicities, including toxic deaths. Attempts to preserve the efficacy of immunotherapy but lessen the toxicity led to trials exploring outpatient interferon (IFN).8-10 Based on these trials, IFN became a standard first-line treatment approach in metastatic RCC.11 Despite the advances made with immunotherapy in RCC, the median overall survival (OS) for first-line cytokine therapy has historically been approximately 1012 months. Cytotoxic chemotherapy has displayed marginal activity but continues to have a role in rare subtypes of RCC (chromophobe, collecting duct, and rapidly progressing RCC).12,13 Recent advances engendered by a better understanding of biology have radically altered the outlook for patients with metastatic clear-cell RCC.14 The vascular endothelial growth factor (VEGF), its receptors (VEGFR), and the mammalian target of rapamycin (mTOR) signal transduction pathway have particularly been exploited. Sunitinib, sorafenib tosylate, and temsirolimus have improved

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Targeting Growth Factors in RCC

Figure 1 Clear-Cell Renal Cancer Tumorigenic Pathways and Inhibitors

Risk Stratification of Renal Cell Carcinoma

Tumor Cell EGFR

TEMSR

Lapatinib Erlotinib

VHL mTOR HIF VEGF

Tumor Proliferation

Angiogenesis

Bevacizumab VEGFR

VEGF

Sorafenib Sunitinib Axitinib Pazopanib

PDGFR Endothelial Cell Pericyte

Abbreviation: TEMSR = temsirolimus

clinical outcomes in randomized trials resulting in the first new drug approvals for treatment of advanced-stage RCC in almost 2 decades. This review will provide an update of novel agents targeting growth factor and angiogenic pathways for the therapy of metastatic clear-cell RCC.

Molecular Biology of Clear-Cell Renal Cell Carcinoma Clear-cell RCC is characterized by its frequent loss of the von Hippel–Lindau (VHL) tumor suppressor gene. One allele is inactivated by a deletion (loss of heterozygosity) observed in > 90% of clear-cell RCC.14-16 The remaining VHL allele can be inactivated through a gene mutation or methylation of the CpG-rich DNA region. von Hippel–Lindau normally encodes a protein (p-VHL) that targets hypoxia-inducible factor (HIF) for proteolysis.17-22 As a result of VHL gene inactivation, a defective p-VHL is produced, and HIF is upregulated.23 Activated HIF then translocates into the nucleus and leads to the transcription of several genes that play a central role in tumorigenesis. These genes include VEGF, platelet-derived growth factor (PDGF), transforming growth factor–_, basic fibroblast growth factor, CAIX or G250, erythropoietin, and others.24-30 Angiogenesis is stimulated, in part, by VEGF binding its receptor (VEGFR), and this pathway has been heavily exploited for the therapy of RCC.31 The Raf/MEK/ERK pathway is another important downstream convergence point for signaling through VEGFR, PDGF receptor (PDGFR), and epidermal growth factor receptor (EGFR). It also has important antiapoptotic effects.32-35 Tumor angiogenesis is also stimulated by growth factors through the phosphatidylinositol-3 kinase PI3K/AKT/mTOR signal transduction pathway.36,37 mTOR is a central modulator that relays proliferative and anabolic signals to downstream transcriptional and translational machinery. Additionally, the PI3K/AKT/mTOR pathway has been

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shown to upregulate HIF. Agents targeting these pathways can be expected to have antitumor efficacy (Figure 1).

Several retrospective analyses have identified clinical variables that predict the outcome of patients with metastatic RCC. The widely used Memorial Sloan-Kettering Cancer Center (MSKCC) risk group categorization in metastatic patients defines the 5 poor risk features as a Karnofsky performance status (PS; KPS) < 80, a serum calcium > 10 (corrected for albumin), a hemoglobin (Hb) level below normal, absence of previous nephrectomy, and a lactate dehydrogenase level > 1.5 times upper limit of normal.38-40 The median survivals were 20, 10, and 4 months for good- (no risk factors), intermediate- (1-2 risk factors), and poor-risk patients (* 3 risk factors), respectively. Other studies from University of California, Los Angeles and the French Group were able to identify similar prognostic groupings.41,42 In an effort to define outcomes in patients treated with standard cytokine therapy, to serve as a context for interpreting the results of phase II trials exploring novel therapies, and to serve in risk stratification of phase III trials, Motzer et al conducted a retrospective analysis in patients treated on 6 clinical trials with first-line IFN therapy.11 In this analysis, similar pretreatment variables were found to be predictive of outcome as previously defined by the MSKCC prognostic model. These risk groupings have been critical in the design and stratification of the recent phase III trials in metastatic RCC. Whether these same variables will predict the outcomes of patients treated with the recently approved multitargeted tyrosine kinase inhibitors (TKIs) and other novel therapies is under investigation.

Multitargeted Receptor Tyrosine Kinase Inhibitors Sunitinib Sunitinib is a highly potent, selective inhibitor of certain receptor tyrosine kinases (RTKs), including VEGFR types 1-3, PDGFR-_, and PDGFR-`. Preclinical data suggest that sunitinib has antitumor activity that might result from inhibition of angiogenesis and direct antiproliferative effects on certain tumor cell types.43 The recommended dose for phase II trials was defined in phase I trials as 50 mg orally once daily for 4 weeks, followed by 2 weeks off, in repeated 6-week cycles.44,45 Good oral bioavailability with CYP3A4 mediated metabolism to the active metabolite, SU12662, was observed. There were no food effect and no evidence of drug accumulation. Therapeutic plasma concentrations (50-100 ng/mL) were achieved in the majority of patients with daily doses * 50 mg. Pharmacodynamic studies indicated evidence of target receptor modulation at therapeutic drug levels and increased plasma VEGF levels after drug exposure. Dose-limiting toxicities included fatigue, gastrointestinal toxicity, cytopenias, and skin toxicity, which were reversible upon discontinuation of treatment. Two phase II trials have been reported in patients experiencing progression after previous cytokine therapy.46,47 A pooled analysis

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Thomas E. Hutson et al

Table 1 Reported Randomized Trials of Novel Agents in Clear-Cell Renal Cell Carcinoma50-56 Eligibility

N

Experimental Arm

Control Arm

Median PFS

Median OS

First-line, good and intermediate risk

750

Sunitinib

IFN-_

11 vs. 5 months*

Not available

Escudier et al51

Second-line, good and intermediate risk

905

Sorafenib

Placebo

24 vs. 12 weeks*

19.3 vs. 15.9 months*

Escudier et al52

First-line, good risk

189 (II)

Sorafenib

IFN-_

Not available

Not available

Ravaud et al53

Second-line, EGFR and/or ErbB2 expression

417

Lapatinib

Hormonal

15.3 vs. 15.4 weeks†

46.9 vs. 43.1 weeks

Yang et al54

Second-line, IL-2 refractory 116 (II) Bevacizumab (high-dose)‡

Placebo

4.8 vs. 2.5 months*

Not available

First-line

104 (II)

Bevacizumab/Erlotinib

Bevacizumab

9.9 vs. 8.5 months

Not available

First-line, poor risk

626

Temsirolimus§

IFN-_

3.7 vs. 1.9 months*

10.9 vs. 7.3 months*

Study Motzer et al50

Bukowski et

al55

Hudes et al56

*Statistically significant. †Median survival was 46 weeks for lapatinib versus 37.9 weeks for hormonal therapy (P = 0.02) in the major subgroup of 241 patients with 3+ EGFR overexpression. ‡Study contained another low-dose bevacizumab arm that did not extend PFS. §Study contained another arm of temsirolimus/IFN that did not extend survival.

Abbreviation: II = randomized phase II trial

of prognostic features for response and progression-free survival (PFS) based on investigator assessment was performed on the total of 168 evaluable patients. The median age was 57 years with an Eastern Cooperative Oncology Group (ECOG) PS of 0/1, and nearly all patients had undergone previous nephrectomy. Overall, 71 patients (42%) were responders; 40 (24%) had stable disease (SD) of * 3 months; and 57 (34%) had SD < 3 months, progressive disease, or were not evaluable. The median PFS for all 168 patients was 8.2 months and in responding patients was 14.8 months. A longer PFS was observed in patients with favorable ECOG PS and normal serum Hb levels with the multivariate analysis demonstrating low Hb to be an independent predictor of a shorter PFS. Sunitinib was generally well tolerated with infrequent grade * 3 toxicities. Fatigue was a common treatment-related adverse event (approximately 10% grade 3 fatigue). Recently, thyroid function abnormalities have been found to be common in patients treated with sunitinib. The potential contribution of hypothyroidism to fatigue in these patients in unclear.48 Other 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. Approximately 5% of patients experienced a decrease in left ventricular ejection fraction, but there were no reports of clinical congestive heart failure. Dose reductions from 50 mg to 37.5 mg were required in 16%-32% of patients, and reductions to 25 mg were required in 3%-6%. Plasma levels of VEGF-A, soluble (s) VEGFR2, and placental growth factor levels were serially measured in patients treated with sunitinib.46 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. A larger proportional increase in VEGF levels was observed in patients exhibiting partial response (PR) compared with those

with SD or progression. The mechanism underlying the changes in these biomarkers is not clear, although it might be related to a feedback regulatory loop. Whether sustained changes in these biomarkers with continuous sunitinib dosing will improve outcomes with this agent is the focus of ongoing studies. Rini and colleagues recently reported the activity of sunitinib in 60 patients who were bevacizumab (anti-VEGF monoclonal antibody [MoAb]) refractory (defined as disease progression within 3 months of bevacizumab), approximately 50% of whom had also received previous cytokines; were with good or intermediate risk; and had undergone nephrectomy.49 The study found that 72% had some degree of tumor shrinkage (16% PR and 56% < 50% regression) with a median PFS of 24 weeks. Grade 3 fatigue appeared more frequently (31%) in this more heavily pretreated population. The investigators hypothesized that sunitinib might inhibit pathways involved in bevacizumab resistance. Motzer and colleagues reported the results of a phase III trial of sunitinib versus IFN as first-line therapy in 750 patients with good- and intermediate-risk clear-cell RCC, as assessed by MSKCC risk group categorization.50 To qualify for the study, patients were required to have good PS and measurable disease. The primary endpoint was PFS with secondary endpoints of patient-related outcomes, OS, response rate, and safety. Stratification factors were lactate dehydrogenase, PS, and nephrectomy status. Patients were randomized 1:1 to receive oral sunitinib 50 mg per day for 4 weeks followed by a 2-week off period (6-week cycles) or IFN 9 MU subcutaneously 3 times weekly (3 MU per dose given the first week and 6 MU per dose given the second week). The treatment arms were well balanced; patients had a median age of 60 years, and 90% had undergone previous nephrectomy. Approximately 35% had good-risk disease, 58% had intermediate-risk disease, and 7% had poor-risk disease. The median PFS was 11 months for the sunitinib arm and 5 months for the IFN arm (hazard ratio [HR], 0.415; P < 0.000001; Table 1).50-56 The objective response rate assessed by independent review was 31% versus 6% (P < 0.000001). There was only

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Targeting Growth Factors in RCC

Table 2 Ongoing and Planned Trials of Novel Agents for Clear-Cell Renal Cell Carcinoma Primary Molecular Targets

Current Status

Sunitinib

VEGFR, PDGFR, c-Kit

FDA approved

Phase III intermittent versus continuous schedule

Sorafenib

VEGFR, Raf kinase

FDA approved

Phase II combination with temsirolimus or bevacizumab*

VEGFR, PDGFR, c-Kit

Phase II

Drug

Axitinib Pazopanib

Ongoing/Planned Trial

After sorafenib failure Phase II RDT for ” 1 previous therapy

VEGFR, PFGFR, c-Kit

Phase II, III

Temsirolimus

mTOR

Phase II

Bevacizumab

VEGF

Phase II, III

Phase II in combination with IL-2

VEGF Trap

VEGF

Phase II

Randomized phase II comparing 2 doses in previously treated patients

Lapatinib

EGFR, ErbB-2

Phase I

Feasibility of combining lapatinib with pazopanib or everolimus (mTOR inhibitor) in solid tumors

Phase III placebo-controlled first/second-line Phase II combination with bevacizumab or sorafenib* Phase II alone or in combination with temsirolimus or sorafenib* Phase III IFN versus IFN/bevacizumab

*BEST randomized 4-arm trial comparing bevacizumab, bevacizumab/temsirolimus, bevacizumab/sorafenib, and sorafenib/temsirolimus. Abbreviations: FDA = Food and Drug Administration; RDT = randomized discontinuation trial

1 CR, which occurred in the sunitinib arm. Severe adverse events (grade 3/4 toxicities) were acceptable with neutropenia (12%), thrombocytopenia (8%), hyperamylasemia (5%), diarrhea (5%), hand-foot syndrome (5%), and hypertension (8%) being noteworthy in the sunitinib arm, whereas fatigue was more common with IFN (12% vs. 7%). Adverse events leading to withdrawal from the study occurred in 8% of patients on sunitinib and 13% on IFN. Although survival endpoints are still premature, the HR was 0.65 (P < 0.02) in favor of sunitinib. The investigators concluded that sunitinib could be considered a new standard of care for the first-line treatment of metastatic clear-cell RCC. Efforts to build upon the results achieved with sunitinib have included combination regimens and alternative dosing schedules. Studies combining sunitinib with IFN, bevacizumab, and temsirolimus are under way. The combination of IFN and sunitinib appears problematic because of additive toxicities. Preliminary results of a phase II study of sunitinib administered in a continuous daily regimen (37.5 mg daily) have been presented.57 On this schedule, few patients required treatment breaks and/or dose reductions, and the preliminary efficacy data were encouraging. The EFFECT trial is a planned phase III trial to compare standard intermittent schedule sunitinib with this continuous daily dosing regimen (Table 2).

Sorafenib Sorafenib is an oral agent that was designed as a c-Raf and b-Raf kinase inhibitor, but was also found to inhibit several RTKs, including VEGFR-2, PDGFR-`, Flt3, and c-Kit.58-62 A phase II randomized discontinuation trial evaluated the effects of sorafenib in 202 patients, most of whom had received previous systemic cytokines.63 Patients received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were < 25% were randomized to receive sorafenib or placebo for an additional 12 weeks; patients with 25% tumor

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shrinkage continued open-label sorafenib; patients with 25% tumor growth discontinued treatment. The primary endpoint was PFS at 24 weeks after the initiation of sorafenib. Seventythree patients had tumor shrinkage of 25%. Sixty-five patients with SD at 12 weeks were randomly assigned to receive sorafenib or placebo. At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = 0.0077). Median PFS from randomization was significantly longer with sorafenib than placebo (24 weeks vs. 6 weeks; P = 0.0087). Median overall PFS was 29 weeks for the entire study population. These encouraging results led to a phase III placebo-controlled randomized trial, known as TARGET (Treatment Approaches in RCC Global Evaluation Trial).51,64 Nine hundred five patients with measurable disease, clear-cell histology, having failed to respond to 1 previous systemic therapy in the past 8 months, and with good or intermediate prognosis, ECOG PS of 0/1, were entered in this largest randomized trial of advanced-stage RCC conducted to date (Table 1).50-56 Almost all patients had undergone nephrectomy. The primary aim of the trial was to assess OS, and the secondary endpoint was PFS. In a preliminary report, tumor control (SD or PR) with sorafenib was achieved in 80% of patients, although only 2% attained a PR. Sorafenib significantly prolonged median PFS compared with placebo (24 weeks vs. 12 weeks; P < 0.000001), and median survival improvement was preliminarily reported (19.3 months vs. 15.9 months; HR, 0.77; P = 0.015). Notably, this did not meet the specified significant P value for the interim analysis, and it is premature to draw conclusions from these data. Benefit was evident across all subsets evaluated. Crossover from the placebo to sorafenib arm has been allowed because of the magnitude of effect on PFS. The patients who crossed over to sorafenib also demonstrated a 30% improvement in survival. With the placebo arm censored at the time of crossover, median survival was 19.3 months for sorafenib versus

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Thomas E. Hutson et al 14.3 months for placebo (HR, 0.74; P = 0.01). Adverse effects were manageable with grade 3/4 hand-foot syndrome, fatigue, and hypertension observed in 5%, 2%, and 1%, respectively. A randomized phase II trial of first-line sorafenib versus IFN has been conducted, and results are awaited.52 Progressing patients in this trial on the IFN arm cross over to sorafenib, and patients on the sorafenib arm are dose escalated to 600 mg twice daily. Ryan and colleagues presented a phase II trial of first-line sorafenib plus IFN conducted by the Southwest Oncology Group.65 The combination was predicated on known individual activity of both drugs and combined mitogen-activated protein kinase and angiogenesis inhibition. The study accrued 61 evaluable patients and demonstrated a PR rate of 19% and a 6-month PFS of 53%. Dose reductions of IFN were frequently necessary, and grade 3 fatigue was notably seen in 30%. Another phase II trial of 39 patients with ) 1 previous regimen (except IFN) reported a response rate of 42%; the single institution nature of this study potentially explains the discrepancy in outcomes.66 Separate phase I/II studies conducted by Sosman et al and Azad et al reported preliminary encouraging results of bevacizumab combined with sorafenib.67,68 In the Sosman et al trial, PRs were seen in 4 of the 14 evaluable patients with RCC. However, problematic toxicities were encountered with this combination at doses below the standard single-agent doses, particularly proteinuria and uncontrolled grade 3 hypertension. Randomized trials of sorafenib in combination therapy are being pursued. The efficacy of sorafenib or sunitinib after failure of previous antiangiogenic agents (thalidomide, lenalidomide, M200-anti-_5`1 integrin MoAb, bevacizumab, axitinib, sunitinib, or sorafenib) was recently reported.69 Twentyseven patients were evaluable, of whom 22 (63%) demonstrated tumor regression including 7 (20%) with PRs. Of the 27 evaluable patients, 6 had disease that did not respond to a previous RTK inhibitor and received a subsequent RTK inhibitor, and all had evidence of tumor shrinkage less than PR. Association between response to previous therapy and current therapy could not be determined, and further studies are warranted.

Axitinib Axitinib is an oral multitarget RTK inhibitor against VEGFR-1, VEGFR-2, and PDGFR-`. Phase I trials were promising, with dynamic contrast-enhanced magnetic resonance imaging revealing a linear change in dynamic contrast-enhanced magnetic resonance imaging parameters and axitinib drug levels, supporting a greater effect on tumor vasculature with increasing axitinib drug exposure.70,71 Subsequently, a phase II trial was presented, including patients with advanced-stage, cytokine-refractory RCC treated with 4-week cycles of axitinib at 5 mg twice daily.72 Most patients had undergone previous nephrectomy and had clear-cell histology. Of 52 patients, 24 (46%) exhibited PR. At a median follow-up of 18 months, 16 patients (31%) experienced progression and 6 (12%) discontinued therapy because of adverse events. The median PFS has not been reached after a 12-18 month follow-up, and only 3 patients with PR have experienced relapse after > 232 days of therapy. Grade 3/4 hypertension was the most important toxicity observed in 15% of patients. No cases of neutropenia or thrombocytopenia grade

> 1 were found. A phase II trial using axitinib is under way in patients with sorafenib-refractory RCC, because it might provide more potent VEGFR inhibition than sorafenib (Table 2).

Lapatinib Lapatinib is an orally administered reversible inhibitor of EGFR/ErbB-2 tyrosine kinases. A randomized phase III trial (EGF20001) compared lapatinib (1250 mg daily) with hormone therapy (tamoxifen or megestrol acetate) in patients with advanced-stage RCC expressing EGFR and/or ErbB-2 by immunohistochemistry.53 Patients with advanced-stage RCC of any histology whose disease did not respond to cytokine therapy were stratified by KPS and number of metastatic sites. The primary efficacy endpoint was time to progression (TTP), and 417 patients were randomized (Table 1).53 Demographic characteristics were similar between both arms with a median age of 61 years and previous nephrectomy in 94%. No unexpected toxicities were observed, and drug-related adverse events (all grades) for lapatinib included rash (44%) and diarrhea (40%). When results from all patients were analyzed, median TTP was 15.3 weeks for lapatinib and 15.4 weeks for hormones (P = 0.6), and median survival was 46.9 weeks for lapatinib versus 43.1 weeks for hormones (P = 0.29). In a retrospective analysis of subgroups based on the level of EGFR overexpression, patients with 3+ EGFR expression achieved a median TTP of 15.1 weeks with lapatinib versus 10.9 weeks with hormonal therapy (P = 0.06), and median survival of 46 weeks with lapatinib versus 37.9 weeks with hormone therapy (P = 0.02; Table 1).50-56 This retrospective subgroup analysis must be interpreted with caution, and further development of this agent in RCC is unclear at the present time. Phase I trials combining lapatinib with other agents in solid tumors are under way (Table 2).

Pazopanib Pazopanib (GW 786034) is being investigated in the treatment of multiple tumor types including RCC. Pazopanib is an orally administered multitargeted inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-_, PDGFR-`, and c-Kit.73 In a phase I trial, tumor shrinkage (PR and minimal responses) was observed in 6 of 7 patients with RCC treated with > 800 mg daily.74,75 The most frequent drug-related adverse events have been hypertension, diarrhea, nausea, fatigue, anorexia, vomiting, and hair depigmentation. Two global studies are being conducted in patients with advanced-stage or metastatic RCC. A phase II randomized discontinuation design trial will accrue 160-230 patients who have received ) 1 previous therapy (Table 2). VEG105192 study is a randomized placebo-controlled, multicenter, international phase III study evaluating pazopanib in patients with locally advanced and/or metastatic RCC who are untreated or whose disease has not responded to or been intolerant of cytokines. The primary endpoint is PFS, and approximately 350 patients will be randomized in a 2:1 ratio to receive pazopanib 800 mg once daily or placebo (Table 2).

Vatalanib Vatalanib (PTK787) is an orally administered potent inhibitor of all known VEGFR tyrosine kinases and also inhibits other

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Targeting Growth Factors in RCC kinases, such as PDGFR-` and c-Kit tyrosine kinase, but at higher concentrations.76 In a phase I study of 37 patients with metastatic RCC, 1 PR and 6 minor responses were reported, and SD was observed in 46% of patients.77 The OS rate at 1 year was 63.7%. The Duke Cancer Center is planning a phase II trial assessing the combination of vatalanib and everolimus (RAD001, an orally administered mTOR inhibitor).

Vascular Endothelial Growth Factor Monoclonal Antibodies Bevacizumab Bevacizumab (rhuMAb VEGF) is a recombinant MoAb that binds and neutralizes all biologically active isoforms of VEGF and demonstrated preliminary evidence of efficacy against RCC in a phase I trial.78,79 In an earlier phase II randomized trial, 116 patients with metastatic RCC refractory to IL-2 were randomized to receive bevacizumab at 2 different dose levels (10 mg/kg or 3 mg/kg every 2 weeks) or placebo.54 Bevacizumab 10 mg/kg yielded a 10% response rate (many others had prolonged periods of stability or minor response) and led to prolonged PFS of 4.8 months versus 2.5 months with placebo (Table 1).54 No difference in PFS was seen with low-dose bevacizumab. Hypertension was observed in 36% (21% grade 3) of patients in the high-dose bevacizumab arm, 3% of the lower-dose arm, and 5% of the placebo arm. Proteinuria (without renal dysfunction) and epistaxis were also significantly higher in the high-dose bevacizumab group. There was a consistent increase in VEGF levels with both doses of bevacizumab, suggesting a possible feedback mechanism activated by effective VEGF blockade, although the assay methodology that measured free and unbound VEGF might account for it. An update demonstrated no further toxic side effects, including 4 patients who have continued on therapy without progression for 3-5 years.80 Subsequently, a multicenter 63-patient phase II study combining bevacizumab 10 mg/kg intravenously (I.V.) every 2 weeks with an oral EGFR TKI, erlotinib 150 mg orally daily, was performed.81 Eligibility criteria for this study included metastatic RCC (* 75% clear-cell component) and no more than 1 previous systemic regimen. Twenty-five percent of 59 assessable patients had objective responses (1 CR, 14 PRs). The median PFS was 11 months, and the median survival was > 20 months. However, a recently reported, randomized, phase II, 104-patient study suggests that the addition of erlotinib to bevacizumab does not improve outcomes (PFS, approximately 9 months; responses rate, approximately 14%) when compared with bevacizumab alone.55 Two randomized phase III trials in the first-line setting of bevacizumab in combination with IFN compared with IFN alone have completed accrual in the Cancer and Leukemia Group B (90206) and in Europe (BO17705).82 Combination studies of bevacizumab with sunitinib, sorafenib, mTOR inhibitors (ie, temsirolimus and everolimus), and IL-2 (high or low dose) are in progress. The BEST randomized phase II trial sponsored by ECOG will randomize untreated patients to 1 of 4 treatment arms (bevacizumab, bevacizumab/temsirolimus, bevacizumab/sorafenib, and sorafenib/temsirolimus; Table 2).

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Vascular Endothelial Growth Factor Trap Vascular endothelial growth factor Trap (AVE0005) is a potent angiogenesis inhibitor comprising portions of human VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to the Fc portion of human immunoglobulin G.83 Vascular endothelial growth factor Trap potently binds VEGF-A and neutralizes all VEGF-A isoforms plus placental growth factor with a 100-fold increased affinity compared with bavacizumab. It has been administered I.V. and subcutaneously in phase I trials, and early evidence of activity in RCC was observed.84 The ECOG is planning a randomized phase II trial to evaluate 2 doses of VEGF Trap for metastatic or unresectable RCC previously treated with a receptor TKI (Table 2).

Temsirolimus Temsirolimus (CCI-779), an I.V. administered mTOR inhibitor, regulates nutritional needs, cell growth, and angiogenesis by downregulating or upregulating a variety of proteins, including HIF-1.85 In a randomized phase II study of 111 patients with advanced-stage, cytokine-refractory RCC, 25, 75, or 250 mg was administered as a 30-minute weekly I.V. infusion.86 Temsirolimus induced an objective response rate of 7% (1 CR and 7 PRs), a median TTP of 5.8 months, and a median survival of 15 months. Neither toxicity nor efficacy was significantly influenced by dose level. Additional analysis suggested that temsirolimus might be more effective in poor-risk patients. Intermediate and poor-prognosis populations exhibited a 1.6- to 1.7-fold longer median survival than historical IFN-treated patients, whereas no such advantage was observed in the smaller subset of good-prognosis patients. This observation suggests a relationship between Akt and/or mTOR activation in more aggressive disease. Grade 3/4 toxicities were hyperglycemia, hyperphosphatemia, anemia, and hypertriglyceridemia. In addition, 6 patients were reported to have possible nonspecific pneumonitis. A phase I study of temsirolimus/IFN in patients with advanced-stage disease who had received no more than 2 previous systemic therapies was reported.87 Seventy-one patients were enrolled; 96% had undergone previous nephrectomy, and 55% had received previous immunotherapy. The maximum tolerated dose was 15 mg of temsirolimus weekly in combination with 6 MU of IFN subcutaneously 3 times weekly. Dose-limiting toxicities were fatigue, stomatitis, nausea, and vomiting. Eight partial responders (11%) and 21 patients (30%) with SD were present. The median TTP was 9.1 months. A randomized trial was designed for the first-line therapy of patients with RCC with * 3 of 6 poor-risk features (4 from the MSKCC criteria excluding nephrectomy and including > 1 metastatic site and time from diagnosis to therapy < 1 year), and the primary endpoint was survival.38,39,56 Other notable eligibility criteria were KPS * 60, measurable disease, and acceptable lipid levels (fasting cholesterol ) 350 mg/dL, triglycerides ) 400 mg/dL). The trial randomized 626 patients in a 1:1:1 ratio to 3 arms: IFN ) 18 MU subcutaneously 3 times weekly, temsirolimus 25 mg per week I.V., or a combination of temsirolimus 15 mg per week plus IFN 6 MU 3 times weekly. The arms were well balanced, and only approximately 70% were poor risk,

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Thomas E. Hutson et al 80% had predominantly clear-cell histology, and nephrectomy had been performed in 67% of patients. The median survival of patients was superior in the temsirolimus-alone arm compared with IFN (10.9 months vs. 7.3 months; HR, 0.73; P < 0.007), whereas the combination arm was not superior to IFN (8.4 months; HR, 0.95; P = 0.69). The median PFS was statistically superior for both temsirolimus arms (3.7 months) compared with IFN (1.9 months; Table 1). Objective responses occurred in 7%, 9%, and 11% of patients in the IFN, temsirolimus, and combination arms, respectively. Any toxicity grade * 3 was seen in 69% of patients on temsirolimus versus 85%-87% of patients on the IFN-containing arms (P < 0.001). Grade 3 toxicity was primarily asthenia, which occurred less frequently in the temsirolimus arm (12%) than in the IFN arms (approximately 30%). Rash was more common on the temsirolimus arm (37% vs. 5% on IFN and 16% on the combination). Adverse events leading to withdrawal from the study occurred in 7%, 14%, and 22% of patients on temsirolimus, IFN, and the combination arms, respectively. The investigators concluded that temsirolimus should be considered a standard in poor-risk clear-cell RCC, and a potential benefit in a broader population might exist. Combination with VEGF-axis targeted therapy is being evaluated.

Other Agents with Early Evidence of Activity Lenalidomide Lenalidomide is an analogue of thalidomide with enhanced immunomodulatory and antiangiogenic properties. A phase II study in RCC administered lenalidomide orally at 25 mg daily for 21 days of a 28-day cycle.88 All patients had previous nephrectomy, 57% (16 of 28) received previous therapy, and 21 (75%) had clear-cell histology. Three patients (10.7%) demonstrated a PR, 8 (28.5%) had SD, and median TTP was 4 months. Grade 3/4 toxicities included fatigue (11%), skin toxicity (7%), and leukopenia/neutropenia (29%). Further studies are awaited.

Volociximab Volociximab (M200) is an immunoglobulin G4 chimeric MoAb that targets _5`1 integrin, thereby inducing apoptosis of proliferating endothelial cells in tumor neovasculature. M200 activity is independent of growth factor stimulus and is possibly a final common pathway for the development of neovasculature. A multicenter phase II study of 40 heavily pretreated patients who had received no more than 2 previous regimens was reported recently.89 Patients received M200 10 mg/kg I.V. every 2 weeks until disease progression. Tolerability was acceptable (fatigue, 37.5%; nausea, 15%; and hypertension, 7.5%), and SD was observed in 83% of evaluable patients with a median PFS of 3.7 months. A higher dose is being evaluated.

Conclusion The novel multitargeted TKI sunitinib has supplanted cytokines as first-line therapy for good- and intermediate-risk metastatic clear-cell RCC and might also be reasonable for poor-risk disease. Sorafenib might also be considered appropriate for the

same population, although data for first-line therapy are awaited. The activity of these agents without previous nephrectomy remains undefined. First-line therapy with temsirolimus, an mTOR inhibitor, has been proven to improve survival in poorrisk RCC, and data for good- and intermediate-risk disease are awaited. First-line cytokine therapy with high-dose IL-2 might be appropriate for patients with good PS with favorable risk status when the expression of CAIX is high or unknown, and in patients with intermediate-risk status when the expression of CAIX is high. Enrollment in an investigational trial is an appropriate option for all eligible patients. Combinations of these novel active agents are being evaluated, and results from randomized trials evaluating bevacizumab are awaited. Efforts to optimize immunotherapy, including vaccine approaches, allogeneic lymphocytes, and stem cell transplantation, continue. Improving outcomes and cure rates for high-risk localized RCC after nephrectomy also remains an important goal. An ECOG-lead Intergroup trial (ASSURE) will randomize 1300 patients with RCC who are at high risk for recurrence after nephrectomy to receive 1 year of treatment with placebo, sorafenib, or sunitinib with a primary endpoint of disease-free survival. Additionally, the SOURCE trial lead by the Medical Research Council will randomize > 1800 high-risk patients with RCC after nephrectomy to placebo for 3 years, sorafenib for 3 years, or sorafenib for 1 year followed by placebo for 2 years. The future of therapy for RCC appears promising with these advances.

References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56:106-130. 2. 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 1995; 13:688-696. 3. Fisher RI, Rosenberg SA, Sznol M, et al. High-dose aldesleukin in renal cell carcinoma: long-term survival update. Cancer J Sci Am 1997; 3(suppl 1): S70-S72. 4. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma: Groupe Francais d’Immunotherapie. N Engl J Med 1998; 338:1272-1278. 5. 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 2003; 21:3127-3132. 6. 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 2005; 23:133-141. 7. Atkins M, Regan M, McDermott D, et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005; 11:3714-3721. 8. Coppin C, Porzsolt F, Kumpf J, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 2000; CD001425. Review. 9. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomized controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999; 353:14-17. 10. Pyrhonen 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 1999; 17:2859-2867. 11. 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 2002; 20:289-296. 12. Stadler WM, Halabi S, Rini B, et al. A phase II study of gemcitabine and capecitabine in metastatic renal cancer: a report of Cancer and Leukemia Group B protocol 90008. Cancer 2006; 107:1273-1279. 13. George CM, Stadler WM. The role of systemic chemotherapy in the treatment of kidney cancer. In: Figlin R, ed. Kidney Cancer. Norwell, MA:

Clinical Genitourinary Cancer Supplement

December 2006 •

S37

Targeting Growth Factors in RCC Kluwer Academic Publishers; 2003. 14. Cohen HT, McGovern FJ. Medical progress: renal-cell carcinoma. N Engl J Med 2005; 353:2477-2490. 15. 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 1995; 22:3-8. 16. 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 2002; 34:58-68. 17. 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 1999; 13:464-475. 18. 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 2002; 196:186-193. 19. Clifford SC, Prowse AH, Affara NA, et al. Inactivation of the von HippelLindau (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 1998; 22:200-209. 20. 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 1994; 91:9700-9704. 21. Kibel A, Iliopoulos O, DeCaprio JA, et al. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 1995; 269:1444-1446. 22. Krieg M, Haas R, Brauch H, et al. Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 2000; 19:5435-5443. 23. Gnarra JR, Zhou S, Merrill MJ, et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci U S A 1996; 93:10589-10594. 24. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005; 23:1011-1027. 25. 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 1990; 86:670-674. 26. 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 2001; 98:1387-1392. 27. Kuwabara K, Ogawa S, Matsumoto M, et al. Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc Natl Acad Sci U S A 1995; 92:4606-4610. 28. Grabmaier K, de Weijert MC, Verhaegh GW, et al. Strict regulation of CAIX (G250/MN) by HIF-1alpha in clear cell renal cell carcinoma. Oncogene 2004; 23:5624-5631. 29. Lee YS, Vortmeyer AO, Lubensky IA, et al. Coexpression of erythropoietin and erythropoietin receptor in von Hippel-Lindau disease-associated renal cysts and renal cell carcinoma. Clin Cancer Res 2005; 11:1059-1064. 30. Giordano FJ, Johnson RS. Angiogenesis: the role of the microenvironment in flipping the switch. Curr Opin Genet Dev 2001; 11:35-40. 31. Goodsell DS. The molecular perspective: VEGF and angiogenesis. Stem Cells 2003; 21:118-119. 32. Hilger RA, Scheulen ME, Strumberg D. The Ras-Raf-MEK-ERK pathway in the treatment of cancer. Onkologie 2002; 25:511-518. 33. Chen J, Fujii K, Zhang L, et al. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci U S A 2001; 98:7783-7788. 34. Alavi A, Hood JD, Frausto R, et al. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003; 301:94-96. 35. Chen J, Fujii K, Zhang L, et al. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci U S A 2001; 98:7783-7788. 36. 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 2002; 22:7004-7014. 37. Mita MM, Mita A, Rowinsky EK. The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther 2003; 2:169-S177. 38. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17:2530-2540.

S38 • Clinical

39. 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 2005; 23:832-841. 40. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004; 22:454-463. 41. Zisman A, Pantuck AJ, Dorey F, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001; 19:1649-1657. 42. Negrier S, Escudier B, Gomez F, et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d’Immunotherapie. Ann Oncol 2002; 13:1460-1468. 43. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors. Clin Cancer Res 2003; 9:327-337. 44. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006; 24:25-35. 45. Fiedler W, Serve H, Dohner H, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005; 105:986-993. 46. 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. 47. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006; 295:2516-2524. 48. Shaheen PE, Tamaskar IR, Salas RN, et al. Thyroid function tests abnormalities in patients with metastatic renal cell carcinoma treated with sunitinib. J Clin Oncol 2006; 24(18 suppl):242s (Abstract #4605). 49. Rini BI, George DJ, Michaelson MD, et al. Efficacy and safety of sunitinib malate (SU11248) in bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 2006; 24(18 suppl):222s (Abstract #4522). 50. 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. J Clin Oncol 2006; 24(18 suppl):2s (Abstract #LBA3). 51. 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. Eur J Cancer Suppl 2005; 3:226 (Abstract #794). 52. Escudier B, Szczylik C, Demkow T, et al. Randomized phase II trial of the multi-kinase inhibitor sorafenib versus interferon (IFN) in treatment-naïve patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2006; 24(18 suppl):217s (Abstract #4501). 53. Ravaud A, Gardner J, Hawkins R, et al. Efficacy of lapatinib in patients with high tumor EGFR expression: results of a phase III trial in advanced renal cell carcinoma. J Clin Oncol 2006; 24(18 suppl):217s (Abstract #4502). 54. 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 2003; 349:427-434. 55. Bukowski RM, Kabbinavar F, Figlin RA, et al. Bevacizumab with or without erlotinib. J Clin Oncol 2006; 24(18 suppl):222s (Abstract #4523). 56. Hudes G, Carducci M, Tomczak P, et al. A phase III, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line poor-prognosis patients with advanced renal cell carcinoma. J Clin Oncol 2006; 24(18 suppl):2s (Abstract #LBA4). 57. De Mulder PH, Roigas J, Gillessen S, et al. A phase II study of sunitinib administered in a continuous daily regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol 2006; 24(18 suppl):223s (Abstract #4529). 58. 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 2004; 64:7099-7109. 59. 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; 23:965-972. 60. Moore MJ, Hirte HW, Siu L, et al. Phase I study to determine the safety

Genitourinary Cancer Supplement

December 2006

Thomas E. Hutson et al

61. 62.

63. 64. 65. 66. 67. 68. 69.

70. 71.

72.

73.

74.

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 2005; 16:1688-1694. 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 2005; 92:1855-1861. 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 2005; 11:5472-5480. 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 2006; 24:2505-2512. 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. J Clin Oncol 2006; 24(18 suppl):223s (Abstract #4524). Ryan CW, Goldman BH, Lara PN Jr, et al. Sorafenib plus interferon-alpha2b as first-line therapy for advanced renal cell carcinoma: SWOG 0412. J Clin Oncol 2006; 24(18 suppl):223s (Abstract #4525). Gollob J, Richmond T, Jones J, et al. Phase II trial of sorafenib plus interferonalpha 2b (IFN-_2b) as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol 2006; 24(18 suppl):226s (Abstract #4538). Sosman JA, Flaherty K, Atkins MB, et al. A phase I/II trial of sorafenib with bevacizumab in metastatic renal cell cancer patients. J Clin Oncol 2006; 24(18 suppl):128s (Abstract #3031). Azad NS, Posadas EM, Kwitkowski VE, et al. Increased efficacy and toxicity with combination anti-VEGF therapy using sorafenib and bevacizumab. J Clin Oncol 2006; 24(18 suppl):121s (Abstract #3004). Tamaskar I, Shaheen P, Wood L, et al. Antitumor effects of sorafenib and sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC) who had prior therapy with anti-angiogenic agents. J Clin Oncol 2006; 24(18 suppl):240s (Abstract #4597). Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 2005; 23:5474-5483. Liu G, Rugo HS, Wilding G, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol 2005; 23:5464-5473. 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. J Clin Oncol 2005; 23(16 suppl):380s (Abstract #4509). Kumar R, Harrington LE, Hopper TM, et al. Correlation of anti-tumor and anti-angiogenic activity of VEGFR inhibitors with inhibition of VEGFR2 phosphorylation in mice. J Clin Oncol 2005; 23(16 suppl):846s (Abstract #9537). Hurwitz H, Dowlati A, Savage S, et al. Safety, tolerability and pharmacokinetics of oral administration of GW786034 in pts with solid tumors. J Clin

Oncol 2005; 23(16 suppl):195s (Abstract #3012). 75. Suttle AB, Hurwitz H, Dowlati A, et al. Pharmacokinetics (PK) and tolerability of GW786034, a VEGFR tyrosine kinase inhibitor, after daily oral administration to patients with solid tumors. J Clin Oncol 2004; 23:208 (Abstract #3054). 76. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000; 60:2178-2189. 77. George D, Michaelson D, Oh WK. Phase 1 study of PTK787/ZK222584 (PTK/ZK) in metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 2003; 22:385 (Abstract #1548). 78. Presta LG, Chen H, O’Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997; 57:4593-4599. 79. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001; 19:843-850. 80. Yang JC. Bevacizumab for patients with metastatic renal cancer: an update. Clin Cancer Res 2004; 10:6367S-6370S. 81. Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005; 23:7889-7896. 82. Rini BI, Halabi S, Taylor J, et al. Cancer and Leukemia Group B 90206: a randomized phase III trial of interferon-alpha or interferon-alpha plus antivascular endothelial growth factor antibody (bevacizumab) in metastatic renal cell carcinoma. Clin Cancer Res 2004; 10:2584-2586. 83. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002; 99:11393-11398. 84. Dupont J, Rothenberg ML, Spriggs DR, et al. Safety and pharmacokinetics of intravenous VEGF Trap in a phase I clinical trial of patients with advanced solid tumors. J Clin Oncol 2005; 23(16 suppl):199s (Abstract #3029). 85. 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. Proc Am Assoc Cancer Res 1999; 40:301 (Abstract #1000). 86. 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 2004; 22:909-918. 87. Smith JW, Ko Y-J, Dutcher J, et al. Update of a phase I study of intravenous CCI-779 given in combination with interferon-alpha to patients with advanced renal cell carcinoma. Proc Am Assoc Cancer Res 2004; 23:384 (Abstract #4513). 88. Choueiri TK, Dreicer R, Rini BI, et al. Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24(18 suppl):226s (Abstract #4539). 89. Figlin RA, Kondagunta GV, Yazji S, et al. Phase II study of volociximab (M200), an _5`1 anti-integrin antibody in refractory metastatic clear cell renal cell cancer (RCC). J Clin Oncol 2006; 24(18 suppl):225s (Abstract #4535).

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