the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Departments of Medicine and Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY
    Massachusetts General Hospital
    Dana-Farber Cancer Institute, Boston, MA
    University of Michigan, Ann Arbor, MI
    Fox Chase Cancer Center, Philadelphia, PA
    University of Wisconsin, Madison, WI
    University of California Los Angeles, Los Angeles
    Pfizer Inc, La Jolla
    University of California San Francisco, San Francisco, CA

    ABSTRACT

    PURPOSE: Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC.

    PATIENTS AND METHODS: Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off. Overall response rate was the primary end point, and time to progression and safety were secondary end points.

    RESULTS: Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting  3 months. Median time to progression in the 63 patients was 8.7 months. Dosing was generally tolerated with manageable toxicities.

    CONCLUSION: SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.

    INTRODUCTION

    Renal cell carcinoma (RCC) accounts for more than 30,000 new cases of cancer and more than 12,000 deaths in the United States annually.1 Patients with RCC metastases have a poor prognosis, with few other solid tumor cell types showing such uniform resistance to cytotoxic chemotherapy agents.2 Over decades of drug testing, only interleukin-2 (IL-2) has demonstrated enough clinical activity to warrant a US Food and Drug Administration indication for treatment of metastatic RCC.1,2 In pivotal trials, high-dose intravenous IL-2 administered in an intensive care unit setting demonstrated a 14% partial or complete response rate.3 Other cytokine regimens, including lower doses of subcutaneously administered interferon alfa (IFN-), have demonstrated the same or lower response rates, but with better tolerance.4,5 These two strategies represent the near sum of options available to patients with metastatic RCC, and no proven treatments exist for patients whose disease has progressed despite cytokine therapy. Overall median survival after progression after cytokine therapy is only 12 months, and the median survival is approximately 7 months in patients with an unfavorable clinical feature, such as anemia or decreased performance status.6

    There are several recognized subtypes of RCC, but more than 80% of all tumors demonstrate clear-cell carcinoma histology. Cytogenetic studies have demonstrated frequent and early loss of heterozygosity in chromosome 3p 25-26 in 90% or more of spontaneous clear cell carcinomas.7,8 The high frequency of clear cell RCC in patients with von Hippel Lindau (VHL) syndrome led investigators to identify the VHL gene in this setting.9 Subsequent sequencing analyses have demonstrated additional VHL mutations in the remaining allele in 50% to 60% of clear cell carcinomas.10 Further second-hit silencing by hypermethylation and other epigenetic mechanisms likely account for even higher rates of bi-allelic gene loss.11 Restoration of VHL function in VHL (–/–) RCC cell lines suppresses their ability to form tumors in nude mice xenograft models, supporting the hypothesis that VHL is a renal cancer tumor suppressor gene, which when inactivated leads to disease progression.12

    Elucidation of VHL protein function in cells has identified targets for therapy in this highly resistant malignancy.13 The VHL gene product normally forms stable complexes with elongin B, elongin C, cullin 2, and Rbx1 that regulate the protein degradation of hypoxia inducible factor-alpha (HIF-).14 When VHL protein function is absent, HIF- is allowed to accumulate and bind with constitutively present HIF-,13 forming a transcriptional factor complex resulting in unregulated expression of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). These growth factors are secreted and bind to specific tyrosine kinase receptors on the surface of endothelial cells and vascular pericytes, respectively, resulting in cell migration, proliferation, and survival. Phenotypically, these growth factors promote tumor angiogenesis that may contribute to the hypervascular histology of RCC.1 Consequently, inhibition of VEGF and PDGF signaling pathways may reverse in part the physiologic consequences of losing VHL protein function and may inhibit tumor growth.

    SU11248 (sunitinib malate) is a highly potent, selective inhibitor of certain protein tyrosine kinases, including VEGF-R types 1 to 3, PDGF-R-, and PDGF-R-.15-19 Preclinical data suggest that SU11248 has antitumor activity that may result from both inhibition of angiogenesis and direct antiproliferative effects on certain tumor cell types.15-19 A phase I clinical study of SU11248 demonstrated evidence of antitumor activity in several patients with metastatic RCC, supporting the working hypothesis that RCC represented an ideal proof-of-concept tumor type for further study of this dual VEGF and PDGF receptor inhibitor.20 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.20,21 Using this schedule, a multicenter, phase II clinical trial was conducted to assess the clinical efficacy and safety of SU11248 in patients with cytokine-refractory metastatic RCC.

    PATIENTS AND METHODS

    Patients

    Sixty-three patients were enrolled onto the study between January and July 2003. Eligibility criteria included informed consent, histologic confirmation of RCC, measurable disease with evidence of metastases, failure of one cytokine (IFN-, IL-2) -based therapy because of disease progression or unacceptable toxicity, Eastern Cooperative Oncology Group performance status of 0 or 1, normal serum amylase and lipase, a normal adrenocorticotropic hormone stimulation test, and adequate hematologic, hepatic, renal, and cardiac function. The latter was determined as a normal left ventricular ejection fraction by echocardiogram or multigated acquisition (MUGA) scan. Patients were excluded for the presence of brain metastases or ongoing cardiac dysrhythmia, prolongation of QTc interval, or any significant cardiac event within the previous 12 months.

    The study was approved by the institutional review board at each of the seven participating centers and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.

    Study Design and Treatment

    The starting dose of SU11248 was 50 mg per day administered in repeated 6-week cycles of daily therapy for 4 weeks, followed by 2 weeks off. SU11248 was self-administered orally once daily without regard to meals. Intrapatient dose escalation by 12.5 mg/d (up to 75 mg/d) was permitted in the absence of treatment-related toxicity. Dose reduction for toxicity was allowed to 37.5 mg/d and then to 25 mg/d, according to a nomogram for grade 3 to 4 severity.

    Evaluation

    Baseline evaluations included medical history and physical examination; computed tomography scan of the chest, abdomen, and pelvis; bone scan (in patients with known bone metastases); assessment of Eastern Cooperative Oncology Group performance status; CBC; biochemical profile (including serum amylase and lipase); cardiac function (12-lead ECG and either an echocardiogram or MUGA scan); and adrenocorticotropic hormone stimulation test. The rigorous evaluations of cardiac, adrenal, and pancreatic function were incorporated in the study as safety assessments based on preclinical data.

    Assessment of Efficacy, Safety, and Quality of Life

    Objective clinical response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) using computed tomography or magnetic resonance imaging scan and bone scan (if bone metastases were present at baseline) after cycles 1, 2, and 4, and every two cycles thereafter until the end of treatment. CBC, cardiac enzymes, and biochemical profiles were obtained throughout the study. Cardiac function was assessed by ECG and echocardiogram or MUGA scan on day 28 of each treatment cycle. Quality of life was assessed using the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-Fatigue) and the EuroQoL EQ-5D instrument (EQ-5D). Patients completed the FACIT-Fatigue questionnaire before receiving SU11248 on day 1 (as the baseline assessment) and weekly for cycles 1 through 4 and the EQ-5D on days 1 and 28 of each cycle.

    SU11248 treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Individual patients continued SU11248 treatment after progression if the investigator felt that the patient continued to derive clinical benefit. However, for purposes of analysis, the patient was considered to have met the study end point of disease progression. Response was assessed by investigators according to RECIST criteria and severity of adverse events according to the National Cancer Institute Common Toxicity Criteria version 2.0.

    Assessment of SU11248 Levels and Biomarkers

    Plasma concentrations of SU11248 and its active metabolite, SU12662, were determined on days 1 and 28 of cycles 1 to 4. Plasma concentrations of SU11248 and SU12662 were determined predose by a liquid chromatography/mass spectrometry method at BASi (West Lafayette, IN), with a lower limit of detection of 0.1 ng/mL for SU11248 and SU12662.

    Plasma samples were collected on days 1 and 28 of each cycle for assessment of soluble proteins that may be correlates of angiogenic activity and/or pharmacodynamic inhibition of VEGF receptor-mediated signaling.20-22 Each cycle consisted of 4 weeks of treatment followed by 2 weeks off. Soluble proteins were analyzed with enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, Minneapolis, MN). The VEGF-A ELISA assay measured the VEGF-A165 and VEGF-A121 isoforms. A soluble form of VEGF-R2 (sVEGF-R2) was quantified with an ELISA that measured the extracellular (soluble) domain of VEGF-R2.23 An ELISA assay for placenta growth factor (PlGF) was also used (PlGF is a VEGF family member and a specific ligand of VEGF-R1).24

    Statistical Evaluations

    The primary end point was objective tumor response rate (complete response or partial response, as defined by RECIST). Sample size was determined using Simon's Minimax two-stage design.25 Sixty-three treated patients were required for evaluation of the hypothesis that the objective tumor response rate was  15%, with an alpha level of 5% and 85% power. Time-to-event variables were estimated using the Kaplan-Meier method.26

    RESULTS

    Patient Characteristics

    Sixty-three patients were treated with SU11248 (Table 1). The median age was 60 years, and 55 patients (87%) had clear cell histology. Only four patients (6%) had achieved a complete or partial response to the prior cytokine therapy.

    Efficacy

    All 63 patients received the study drug and were included in the analysis of efficacy end points. Partial responses determined by RECIST were achieved in 25 patients (40%; 95% CI, 28% to 53%; Table 1). Best response of stable disease for  3 months was observed in an additional 17 patients (27%). Twenty-one patients (33%) had either progressive or stable disease of less than 3 months duration or were not assessable.

    The majority of patients had a reduction in measurable disease. Figure 1 shows each patient's maximum percentage of tumor reduction at the time of analysis achieved during treatment with SU11248. Percentages were calculated using the summed unidimensional measurements of target lesions per RECIST.

    Each of the patients with a partial response had evidence of progressive disease at the time of study entry. The median time to first observation of partial response was 2.3 months. Twenty-four partial responders had clear cell histology, and one had a papillary-cell type. Responding lesions included sites of local recurrence and lymphatic, hepatic, pulmonary, bone, and adrenal metastases, examples of which are shown in patients who achieved partial responses (Fig 2). These images highlight responses in multiple metastatic sites, as well as in the large primary tumor in patient 1 (Figs 2A, 2B, and 2C), multiple hepatic, lung, and pleural metastases in patient 2 (Figs 2D and 2E), and a large retroperitoneal lymphadenopathy and hepatic metastases in patient 3 (Figs 2F and 2G). Also noted in images of patient 3 (Fig 2F), there is decreased attenuation of the retroperitoneal masses consistent with tumor necrosis and response.

    Tumor images suggested treatment with SU11248 resulted not only in regression in tumor size, but also in qualitative changes in contrast uptake that accompanied or preceded tumor regressions. This observation raises the possibility that changes in tumor perfusion may be a pharmacodynamic marker of SU11248 effect. Figure 3 demonstrates an example in which lack of contrast enhancement and marked central low attenuation within the hepatic masses after initial treatment led to an apparent increase in tumor size, reflecting interval response with tumor necrosis. Soft tissue and pulmonary lesions concomitantly regressed, and subsequent scans revealed regression of hepatic metastases and an overall partial response after three cycles.

    Of 25 patients who achieved a partial response, 15 patients experienced disease progression, two patients discontinued treatment due to adverse events, and eight patients remain on therapy and are progression free at 21+ to 24+ months from the start of therapy at the time of analysis. Median time to progression for the 63 patients was 8.7 months (95% CI, 5.5 to 10.7; Fig 4A) and median survival was 16.4 months (95% CI, 10.8 to NA [not yet attained]; Fig 4B).

    Treatment Administration and Adverse Events

    Median duration of treatment was 9 months (range, < 1 to 24+ months). The most common adverse event was fatigue, which was categorized as grade 3 severity in seven patients (11%; Table 2). The most frequently occurring grade 3 to 4 laboratory abnormalities included lymphopenia without infection (32%) and elevated serum lipase (21%) without clinical signs or symptoms of pancreatitis. No patient developed adrenal insufficiency associated with SU11248 treatment. Four patients were removed from the study per protocol for a decline in cardiac ejection fraction; three patients were without clinical signs and symptoms, and the fourth patient was noted to have dyspnea.

    Dose reductions were performed in 22 patients (35%) from 50 to 37.5 mg/d, and the dose for two of these patients was further reduced to 25 mg/d. Common reasons for dose reductions included asymptomatic hyperlipasemia or hyperamylasemia (11 patients, per protocol) and fatigue (five patients). The dose was escalated in five patients from 50 to 62.5 mg/d and in one patient to 75 mg/d, with no evidence of improved response.

    Quality of Life

    Assessable baseline EQ-5D questionnaires were received from 60 patients. Questionnaires were consistently returned from ongoing patients, with compliance rates at or above 95% at each assessment on days 1 and 28 of cycles 1 through 4. Mean and median baseline health state visual analog scale scores (77.1 and 80.0, respectively, of a possible 100) indicated that the study population's quality of life before SU11248 treatment was similar to that of an age-matched US general population.27 Mean and median health state visual analog scale scores were similar to the baseline scores through 24 weeks of treatment (data not shown).

    Valid baseline questionnaires for the FACIT-Fatigue scale were received from 62 patients. Questionnaires were consistently returned from ongoing patients, with compliance rates at or greater than 90% for each weekly assessment from cycle 1 through the end of cycle 4 dosing. Mean and median baseline scores for the study population were 40.4 and 44, respectively, which is similar to the scores (40.0 and 42, respectively) of a nonanemic cancer population but lower than the scores (43.6 and 47, respectively) of a general United States population.28 Median and mean fatigue scores were similar to the baseline scores through 24 weeks of treatment, although the fatigue level seemed to increase during the treatment period and to return to baseline during the 2 weeks off, suggesting a mild and reversible treatment effect on fatigue (Fig 5).

    Assessment of Plasma SU11248 Levels and Biomarkers

    Patients achieved and maintained steady-state trough plasma concentrations (Cmin) of SU11248 and its active metabolite throughout the dosing periods for multiple cycles. Median Cmin (SU11248 and SU12662 combined) in all patients was 84.3 ng/mL, which is within the range of 50 to 100 ng/mL shown to inhibit target receptor tyrosine kinases in preclinical models.19 Accumulation of study drug or its active metabolite was not observed across dosing cycles.

    As putative biomarkers of VEGF-R inhibition, plasma VEGF-A, sVEGF-R2, and PlGF levels were serially measured in patients on study. In the majority of cases, both VEGF-A and PlGF levels increased and sVEGF-R2 levels decreased by the end of each dosing cycle (day 28); after the 2 weeks off, the levels of all three biomarkers returned to near baseline levels (Fig 6). The differences between days 1 and 28 levels for all biomarkers were highly significant in all cycles through cycle 8 (P  .002). In the PlGF assay, sample readings below the lowest level of quantitation (26.2 pg/mL) were omitted from the plot.

    DISCUSSION

    Over the past decade, the discovery of genetic alterations in the VHL gene that occur in the vast majority of clear cell RCC tumors, together with elucidation of the biochemical consequences of these changes, has led to the identification of rational therapeutic targets. Loss of the VHL gene product results in dysregulation and aberrant activation of HIF complex and overexpression of VEGF, PDGF, and other growth factor signals important to tissue perfusion and hypoxic survival. Inhibition of these downstream growth factor signals may in part mitigate the physiologic consequences of HIF activation in clear cell RCC. Based on this hypothesis, SU11248, a multitargeted inhibitor of VEGF and PDGF receptors, was tested in patients with cytokine-resistant, metastatic RCC.

    The concept of therapeutically targeting vasculature of solid tumors has been clinically established.29 Bevacizumab, a VEGF-A–neutralizing monoclonal antibody, has demonstrated activity against RCC.30 A randomized phase II trial of bevacizumab versus placebo showed that high-dose bevacizumab therapy produced a 10% partial response rate and prolonged time to progression by 2.3 to 4.8 months compared with placebo.30 Although these results are of modest clinical benefit, the study established proof-of-principle for VEGF-targeted therapy in metastatic RCC. In colorectal cancer, bevacizumab combined with cytotoxic chemotherapy resulted in more robust improvements in objective response rate, progression-free survival, and overall survival.31

    Historically, RCC is one of the most uniformly resistant solid tumors in oncology. Cytokines are the only drugs that have been shown to induce tumor regressions in some patients.1 However, because most patients do not respond, RCC is considered a priority malignancy for development and study of novel therapies.32 This multicenter, phase II study demonstrated a high percentage of partial responses (25 [40%] of 63 patients). Regressions were seen in many patients without a RECIST-defined partial response, which suggests a departure from the natural history of this disease. Currently, SU11248 as a treatment of metastatic RCC is being further investigated in a confirmatory single-arm trial in second-line therapy and in a randomized, phase III trial in first-line therapy compared with IFN-.

    Responses to SU11248 as second-line therapy were achieved in patients after cytokine failure. Patients in this setting are generally managed by supportive care (including radiation therapy) or treatment in clinical trials of experimental agents. After disease progression with an initial treatment with IFN- or IL-2, second-line treatment with the alternative cytokine is associated with response rates in fewer than 5% of patients treated.33 Further, in a series of 251 patients treated in 29 clinical trials of various new agents given as second-line therapy for metastatic RCC, only 4% of patients achieved a partial response.6 The observed median time to progression in this study (8.7 months) compares favorably with the median times of 2.4 months for treatment in second-line therapy at Memorial Sloan-Kettering Cancer Center (New York, NY)6 and 2.5 months for treatment with placebo after cytokine failure in a phase II trial.30

    Direct or surrogate measures of VEGF- and PDGF-receptor inhibition are difficult in clinical settings. As a potential biomarker correlate of tissue hypoxia or biochemical inhibition of VEGF activity, serial plasma VEGF-A, PlGF, and sVEGF-R2 levels were measured in patients in this study. There were increases of VEGF-A and PlGF and decreases of sVEGF-R2 after SU11248 exposure during each cycle of treatment. VEGF levels are known to increase in response to hypoxia and pharmacologic angiogenesis inhibition.34-37 The mechanism behind the consistent decrease in sVEGF-R2 levels observed in the SU11248 clinical studies is not entirely understood at present, as biochemical characterization of the naturally occurring sVEGF-R2 protein has only recently begun.23 However, the results from the phase I trials20-21 and this phase II study clearly indicate that sVEGF-R2 levels change in response to SU11248 treatment, perhaps reflective of a feedback regulatory loop.

    The clinical effectiveness of small-molecule receptor tyrosine kinase inhibitors to date has largely been predicated on the inhibition of a dominant mutated signaling pathway, such as BCR-ABL rearrangements in chronic myelogenous leukemia, KIT mutations in gastrointestinal stromal tumors, and epidermal growth factor mutations in lung cancer.38-41 In contrast, the drug targets for SU11248 in RCC are thought to be nonmutated proteins present largely on endothelial cells and pericytes. To date, there is little clinical evidence of direct mitogenic or antiapoptotic activity for either VEGF or PDGF receptor signaling on RCC cells. These findings support the hypothesis that loss of tumor-suppressor gene function can be clinically mitigated in part by inhibition of downstream targets, and that such an approach can have clinically relevant antitumor effects. Alternatively, an off-target effect of SU11248 may account for its clinical activity; however, the consistent qualitative changes in contrast uptake seen in tumors, coupled with the frequent and reproducible changes in plasma VEGF-A, sVEGF-R2, and PlGF levels, and prior results of bevacizumab in this disease setting, all support the hypothesis that SU11248 inhibits VEGF signaling in vivo.

    Why might SU11248 result in such a high frequency of tumor regressions in RCC tumors One possibility is that inhibition of VEGF and PDGF receptors targets two compartments of tumor vasculature, endothelial cells, and pericytes. Preclinical studies support this rationale, demonstrating additional antitumor efficacy with the combination of VEGF- and PDGF-receptor inhibition over VEGF-receptor inhibition alone.42 Moreover, a preliminary report of another agent with a similar profile of VEGF-R and PDGF-R inhibitory properties is also reporting antitumor activity against RCC.43

    In summary, SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates robust antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that nonmutated VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC and a promising new treatment strategy.

    Authors' Disclosures of Potential Conflicts of Interest

    Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

    AuthorsEmploymentLeadershipConsultantStockHonorariaResearch FundsTestimonyOther

    Robert J. MotzerPfizer Inc (B)

    Gary R. HudesPfizer Inc (A)

    Sindy T. KimPfizer Inc (N/R)Pfizer Inc (B)

    Charles M. BaumPfizer Inc (N/R)Pfizer Inc (B)

    Samuel E. DePrimoPfizer Inc (N/R)Pfizer Inc (A)

    Jim Z. LiPfizer Inc (N/R)Pfizer Inc (B)

    Carlo L. BelloPfizer Inc (N/R)Pfizer Inc (A)

    Charles P. TheuerPfizer Inc (N/R)

    Daniel J. GeorgePfizer Inc (B)

    Brian I. RiniPfizer Inc (B)

    Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)  $100,000 (N/R) Not Required

    Author Contributions

    Conception and design: Robert J. Motzer, M. Dror Michaelson, Bruce G. Redman, Gary R. Hudes, Sindy T. Kim, Charles M. Baum, Samuel E. DePrimo, Jim Z. Li, Carlo L. Bello, Charles P. Theuer, Brian I. Rini

    Adminastrative support: Sindy T. Kim, Charles M. Baum, Jim Z. Li, Charles P. Theuer

    Provision of study materials or patients: Robert J. Motzer, M. Dror Michaelson, Bruce G. Redman, Gary R. Hudes, George Wilding, Robert A. Figlin, Michelle S. Ginsberg, Charles M. Baum, Samuel E. DePrimo, Jim Z. Li, Carlo L. Bello, Charles P. Theuer, Daniel J. George, Brian I. Rini

    Collection and assembly of data: George Wilding, Robert A. Figlin, Michelle S. Ginsberg, Charles M. Baum, Samuel E. DePrimo, Jim Z. Li, Carlo L. Bello, Daniel J. George, Brian I. Rini

    Data analysis and interpretation: Robert J. Motzer, M. Dror Michaelson, Bruce G. Redman, Gary R. Hudes, George Wilding, Robert A. Figlin, Charles M. Baum, Samuel E. DePrimo, Jim Z. Li, Carlo L. Bello, Daniel J. George, Brian I. Rini

    Manuscript writing: Robert J. Motzer, M. Dror Michaelson, Bruce G. Redman, Gary R. Hudes, George Wilding, Robert A. Figlin, Michelle S. Ginsberg, Sindy T. Kim, Charles M. Baum, Samuel E. DePrimo, Jim Z. Li, Carlo L. Bello, Charles P. Theuer, Daniel J. George, Brian I. Rini

    Final approval of manuscript: Robert J. Motzer, M. Dror Michaelson, Bruce G. Redman, Gary R. Hudes, George Wilding, Robert A. Figlin, Michelle S. Ginsberg, Sindy T. Kim, Charles M. Baum, Samuel E. DePrimo, Jim Z. Li, Carlo L. Bello, Charles P. Theuer, Daniel J. George, Brian I. Rini

    Acknowledgment

    We thank Joy Zhu, MD, PhD, for her role in the design and conduct of this study.

    NOTES

    Supported by Pfizer Inc, La Jolla, CA.

    Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

    D.J.G. and B.I.R. contributed equally to the study.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

    REFERENCES

    Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 335:865-875, 1996

    Motzer RJ, Russo P: Systemic therapy for renal cell carcinoma. J Urol 163:408-417, 2000

    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 13:688-696, 1995

    Negrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, recombinant human interferon alpha-2a, or both in metastatic renal-cell carcinoma. N Engl J Med 338:1272-1278, 1998

    Medical Research Council and Collaborators: Interferon-alpha and survival in metastatic renal carcinoma: Early results of a randomized controlled trial. Lancet 353:14-17, 1999

    Motzer RJ, Bacik J, Schwartz LH, et al: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454-463, 2004

    Süksd F, Kuroda N, Beothe T, et al: Deletion of chromosome 3p14.2-p25 involving the VHL and FHIT genes in conventional renal cell carcinoma. Cancer Res 63:455-457, 2003

    Kondo K, Yao M, Yoshida M, et al: Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: Relationship to clinicopathological parameters. Genes Chromosomes Cancer 34:58-68, 2002

    Latif F, Tory K, Gnarra J, et al: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317-1320, 1993

    Gnarra JR, Tory K, Weng Y, et al: Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 7:85-90, 1994

    Herman JG, Latif F, Weng Y, et al: Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 91:9700-9704, 1994

    Iliopoulos O, Kibel A, Gay S, et al: Tumor suppression by the human von Hippel-Lindau gene product. Nat Med 1:822-826, 1995

    Kaelin WG Jr: The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res 10:6290S-6295S, 1994

    Kim W, Kaelin WG Jr: The von Hippel-Lindau tumor suppressor protein: New insights into oxygen sensing and cancer. Curr Opin Genet Dev 13:55-60, 2003

    O'Farrell AM, Abrams TJ, Yuen HA, et al: SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597-3605, 2003

    O'Farrell AM, Foran JM, Fiedler W, et al: An innovative phase 1 clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 9:5465-5476, 2003

    Schueneman AJ, Himmelfarb E, Geng L, et al: SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res 63:4009-4016, 2003

    Abrams TJ, Murray LJ, Pesenti E, et al: Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. Mol Cancer Ther 2:1011-1021, 2003

    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: Determination of a pharmacokinetic/ pharmacodynamic relationship. Clin Cancer Res 9:327-337, 2003

    Raymond E, Faivre S, Vera C, et al: Final results of a phase I and pharmacokinetic study of SU11248, a novel multi-target tyrosine kinase inhibitor, in patients with advanced cancers. Proc Am Soc Clin Oncol 22:192, 2003 (abstr 769)

    Manning WC, Bello CL, Deprimo SE, et al: Pharmacokinetic and pharmacodynamic evaluation of SU11248 in a phase I clinical trial of patients with imatinib-resistant gastrointestinal stromal tumor (GIST). Proc Am Soc Clin Oncol 22:192, 2003 (abstr 768)

    Fiedler W, Serve H, Dohner H, et al: A phase I 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 105:986-993, 2005

    Ebos JM, Bocci G, Man S, et al: A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol Cancer Res 2:315-326, 2004

    Tjwa M, Luttun A, Autiero M, et al: VEGF and PlGF: Two pleiotropic growth factors with distinct roles in development and homeostasis. Cell Tissue Res 314:5-14, 2003

    Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989

    Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457-481, 1958

    Johnson JA, Coons SJ: Comparison of the EQ-5D and SF-12 in an adult Unites States sample. Qual Life Res 7:155-166, 1998

    Cella DF, Lai JS, Chang CH, et al: Fatigue in cancer patients compared with fatigue in the general United States population. Cancer 94:528-538, 2002

    Ellis LM: Antiangiogenic therapy at a crossroads: Clinical trial results and future directions. J Clin Oncol 21:281s-283s, 2003 (suppl 23)

    Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003

    Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004

    Motzer RJ: Renal cell carcinoma; priority malignancy for development and study of novel therapies. J Clin Oncol 21:1193-1194, 2003

    Escudier B, Chevreau C, Lasset C, et al: Cytokines in metastatic renal cell carcinoma: Is it useful to switch to interleukin-2 or interferon after failure of a first treatment Groupe Francais d'Immunotherape. J Clin Oncol 17:2039-2043, 1999

    George DJ, Kaelin WG: The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med 349:419-421, 2003

    Semenza GL: Angiogenesis in ischemic and neoplastic disorders. Annu Rev Med 54:17-28, 2003

    Drevs J: Soluble markers for the detection of hypoxia under antiangiogenic treatment. Anticancer Res 23:1159-1161, 2003

    Bocci G, Man S, Green SK, et al: Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies. Cancer Res 64:6616-6625, 2004

    Drucker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031-1037, 2001

    Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002

    Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004

    Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004

    Bergers G, Song S, Meyers-Morse N, et al: Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287-1295, 2003

    Ratain M, Flaherty K, Stadler W et al: Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial. Proc Am Soc Clin Oncol 4: 23:381, 2004 (abstr 4501)

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《临床肿瘤学医学期刊》2006年1月第24卷第1期