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Antitumor Activity and Biomarker Analysis of Sunitinib in Patients With Bevacizumab-Refractory Metastatic Renal Cell Carcinoma

Brian I. Rini, M. Dror Michaelson, Jonathan E. Rosenberg, Ronald M. Bukowski, Jeffrey A. Sosman, Walter M. Stadler, Thomas E. Hutson, Kim Margolin, Charles S. Harmon, Samuel E. DePrimo, Sindy T. Kim, Isan Chen, Daniel J. George

From the Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Massachusetts General Hospital, Boston, MA; University of California, San Francisco; City of Hope, Los Angeles; Pfizer Global Research and Development, La Jolla, CA; Vanderbilt University, Nashville, TN; University of Chicago, Chicago, IL; Baylor-Sammons/Texas Oncology, Dallas, TX; and Duke University Medical Center, Durham, NC

Corresponding author: Brian I. Rini, MD, Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, Desk R35, Cleveland, OH 44195; e-mail: rinib2{at}ccf.org

	ABSTRACT

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Purpose To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response.

Patients and Methods Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured.

Results Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome.

Conclusion Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting.

	INTRODUCTION

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An increased understanding of the molecular and genetic aspects of angiogenesis and tumorigenesis associated with metastatic renal cell carcinoma (mRCC) has led to the recent development of therapies targeted to various elements of the vascular endothelial growth factor (VEGF) pathway.¹ Sunitinib malate (SUTENT; Pfizer Inc, New York, NY) is an oral, multitargeted tyrosine kinase inhibitor of VEGF receptors (VEGFR-1, -2, and -3) and platelet-derived growth factor receptors (PDGFR- and -β)² that has been shown to improve progression-free survival (PFS) compared with interferon-alfa (IFN-) in previously untreated patients with clear cell mRCC.³ Similarly, the VEGF-binding agent bevacizumab, in combination with IFN-, has also been shown to provide a PFS advantage over IFN- alone in previously untreated clear-cell mRCC patients.⁴

With multiple VEGF pathway-directed agents available, it becomes important to define the safety and efficacy, as well as clinical cross-resistance, of the sequencing of agents. To this end, we undertook a prospective phase II study to assess the safety and antitumor activity of sunitinib in patients with bevacizumab-refractory mRCC. In addition, this study investigated the potential association of angiogenesis biomarkers with clinical response to sunitinib to further explore pathways involved in bevacizumab resistance and sunitinib response.

	PATIENTS AND METHODS

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Patients
The study population consisted of patients age 18 years or older with histologically proven clear cell mRCC and evidence of unidimensionally measurable disease. Other inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; adequate organ function; radiographic evidence of disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST),⁵ as determined by investigator assessment, during or within 3 months of completion of bevacizumab-based treatment; receipt of at least four doses of bevacizumab; and written informed consent. Patients were ineligible if they had received prior treatment with any antiangiogenic therapy other than bevacizumab; received more than two systemic treatment regimens for mRCC; experienced grade 3 hemorrhage (as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 3.0) within 4 weeks of starting study treatment; had a history of or known brain metastases; or experienced clinically significant cardiovascular events or disease within the previous 12 months—prolongation of the QT_c interval or uncontrolled hypertension.

Study Design and Treatment
In this phase II, single-arm, open-label, multicenter study, patients received sunitinib 50 mg orally once daily in repeated 6-week cycles according to a 4/2 schedule (4 weeks with followed by 2 weeks without treatment). Treatment was continued until RECIST-defined disease progression, unacceptable toxicity, or withdrawal of consent occurred. Sunitinib dose reduction to 37.5 mg/d and then to 25 mg/d was allowed on an individual basis depending on tolerability.

The study was approved by the institutional review board of each of the eight participating US centers and was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

Baseline Evaluations
Baseline evaluations included medical history and physical examination, assessment of ECOG performance status, cardiac function (12-lead ECG and multigated acquisition scan), laboratory parameters (hematology, blood chemistry, and urinalysis), and tumor imaging (computed tomography [CT] scan or magnetic resonance imaging [MRI] of the chest, abdomen, and pelvis; bone scan; and brain CT or MRI scan).

Efficacy and Safety Assessments
The primary end point was objective response rate (ORR), defined as the percentage of patients with either a complete response (CR) or a partial response (PR), as confirmed by subsequent assessments carried out at least 4 weeks after an initial response was observed. Tumor assessments were performed according to RECIST on day 28 of cycles 1 through 4 and every other cycle thereafter until withdrawal or the end of treatment. Secondary end points included PFS, duration of response (DR), overall survival (OS), and safety (severity graded using NCI-CTCAE version 3.0). In addition, ECOG performance status, cardiac function, body weight and vital signs, as well as hematology and blood chemistry profiles, were monitored throughout the study.

Assessment of Biomarkers
The soluble proteins evaluated were VEGF-A, VEGF-C, soluble VEGF receptor (sVEGFR)-3, and placental growth factor (PlGF). These were selected based on their established or putative roles in VEGF-related signaling and/or angiogenic processes,^6-8 and previous analyses that indicated a pharmacodynamic effect of sunitinib on circulating levels.^9,10

Plasma samples were collected on days 1, 14, and 28 of cycle 1 and days 1 and 28 of cycles 2 through 4. VEGF-A (the VEGF-A₁₆₅ and VEGF-A₁₂₁ isoforms), sVEGFR-3, PlGF, and VEGF-C were analyzed using validated enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, Minneapolis, MN). sVEGFR-3 was quantified by an ELISA that measured the extracellular (soluble) domain of VEGFR-3.¹⁰

Statistical Methods
For this single-stage study, 60 patients were required to test the null hypothesis that the true response rate is no more than 5% versus the alternative hypothesis that the true response rate is 15% or greater. All analyses included patients who received at least one dose of sunitinib (intention-to-treat population) and were performed using SAS Version 8.2 (SAS Institute, Cary, NC). The number and percentage of patients experiencing a CR or PR were summarized, along with the corresponding two-sided 95% CIs. Time-to-event variables were summarized using the Kaplan-Meier method, and two-sided 95% CIs for the median were provided for each variable. Correlations between efficacy end points and plasma biomarkers were analyzed with graphical analyses, Wilcoxon rank-sum and t test significance tests, and the Kaplan-Meier method.

	RESULTS

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Patient Characteristics
Patient baseline characteristics are summarized in Table 1. Sixty-one patients were enrolled onto this study. All patients had received prior bevacizumab-based therapy and had subsequently experienced progression during or within 3 months of completing bevacizumab treatment. The median duration of prior bevacizumab therapy was 16 weeks; 8% of patients experienced a PR to bevacizumab. Median time between cessation of bevacizumab and commencement of sunitinib therapy was 8 weeks (range, 3.9 to 38.3 weeks). All patients enrolled onto the study received at least one dose of sunitinib, qualifying for inclusion in the intention-to-treat population.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Maximum tumor reduction in target lesions (n = 57; excludes four patients without a baseline scan).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimate of progression-free survival.

Overall, 41 patients (67%) discontinued treatment during the study: 33 (54%) because of disease progression and seven (12%) because of adverse events (AEs); one patient withdrew consent. Twenty patients (33%) completed 1 year of therapy, of whom 16 (26%) patients have continued receiving sunitinib as part of a separate continuation protocol. Overall, the median duration of treatment was 6.7 months (range, 0.6 to 26.5 months).

We looked for examples within the cohort where patients had demonstrated no response to previous treatment with bevacizumab and subsequently showed a sustained response to sunitinib. As an example, Figure 3 depicts CT scan images of a patient at the time of disease progression after bevacizumab (Fig 3A), at baseline, before receiving sunitinib (Fig 3B), and after almost 9 months of sustained response to sunitinib treatment (Fig 3C).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Computed tomography scan of a responding patient.

Of the seven patients who discontinued treatment due to AEs, one patient died as a result of cerebral hemorrhage. This was a 48-year-old woman with a history of hypertension who had been treated previously with bevacizumab and IFN-. The patient initiated sunitinib therapy 10.6 weeks after she received her last dose of bevacizumab and IFN-, and she completed 4 weeks of sunitinib treatment before being hospitalized with mental status changes. MRI showed a small focus of hemorrhage in the left posterior frontal lobe, but CNS involvement with RCC was not confirmed. The patient died shortly thereafter as a result of disease progression, 5 weeks after the last dose of sunitinib.

Analysis of Plasma Biomarkers
As in earlier studies,¹⁰ significant changes in the mean plasma levels of VEGF-A, sVEGFR-3, and PlGF were observed within the first cycle of sunitinib therapy in this study. After 28 days, mean plasma VEGF-A levels increased 2.8-fold (range, 0.4- to 13.6-fold) greater than baseline and PlGF levels increased 3.9-fold (range, 0.8- to 20.4-fold). In contrast, mean sVEGFR-3 levels decreased by 37.6% and VEGF-C levels decreased by 22.7%. VEGF-A and sVEGFR-3 returned to near-baseline levels after the 2-week off-treatment period and then exhibited similar changes in subsequent cycles. PlGF and VEGF-C levels were measured only in cycle 1.

Correlative analyses were performed to assess the influence of prior bevacizumab exposure on baseline levels or subsequent modulation of biomarkers. Baseline levels of VEGF-A and PlGF plasma levels were inversely correlated with time since last bevacizumab treatment, and were significantly higher in patients with more recent bevacizumab exposure (< 10 weeks) versus more remote exposure (> 10 weeks; median VEGF-A, 579 pg/mL v 240 pg/mL [P < .0001]; median PlGF, 40 pg/mL v 24 pg/mL [P = .0008]). In contrast, baseline plasma levels of VEGF-C and sVEGFR-3 showed no significant differences in this comparison (data not shown). During sunitinib treatment, changes in VEGF-A, PlGF, and sVEGFR-3 levels were greater in patients with a longer time since bevacizumab exposure (P < .05 at various time points).

To explore the predictive potential of these biomarkers, we analyzed the relationship between sunitinib efficacy and baseline levels of these soluble proteins. Patients with baseline sVEGFR-3 and VEGF-C levels less than the median baseline values (sVEGFR-3, 47,000 pg/mL; VEGF-C, 722.1 pg/mL) had longer PFS than did patients with levels greater than the median (Figs 4A and 4B). In contrast, there was no correlation between baseline plasma VEGF-A or PlGF levels and PFS (data not shown). Similarly, baseline levels of sVEGFR-3 and VEGF-C were significantly lower in patients with PR compared with patients with SD or PD, whereas baseline levels of VEGF-A and PlGF showed no significant correlation with ORR (data not shown).

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Correlation of progression-free survival (PFS) with baseline levels of (A) sVEGFR-3 (median baseline value, 47,000 pg/mL) and (B) VEGF-C (median baseline value, 722.1 pg/mL). Median PFS was calculated from patient subgroups with baseline levels of sVEGFR-3 and VEGF-C that were less than or greater than the median baseline values.

	DISCUSSION

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In this study, sunitinib demonstrated substantial antitumor activity in patients with bevacizumab-refractory mRCC. AEs were manageable, although notable for a higher incidence of grade 3 fatigue and hypertension compared with other single-agent sunitinib studies in mRCC patients.^3,12 To our knowledge, this study represents the first prospective investigation of sequential VEGF pathway-targeted therapies in mRCC. Prior retrospective reviews suggested tolerability and clinical activity with these agents, but such reports are subject to several biases.^13,14 Despite this lack of prospective data, sequential treatment with VEGF pathway-targeted therapies has become the de facto standard in mRCC based on availability of multiple agents. Thus, prospective investigation of the safety and efficacy of a given targeted agent in the setting of prior exposure to another targeted agent is needed to accurately define tolerability and clinical benefit of this practice algorithm. Furthermore, as combinations of targeted agents undergo investigation, it will be critical for these combinations to demonstrate clinical benefits above and beyond those of sequential monotherapy with the same agents to justify the added toxicity and risk. The current data provide information that begins to define the clinical benefit of sequential VEGF pathway–targeted monotherapies.

In this prospective study, important safety data relevant to the clinical care of patients with mRCC were identified. The incidences of fatigue and hypertension were higher in this study than in earlier trials in patients without prior VEGF pathway-targeted therapy. There was no statistically significant correlation between increased fatigue or hypertension and the duration of prior bevacizumab treatment or time since cessation of prior therapy. However, there is a persistent concern that prior bevacizumab exposure may influence the AE profile of sunitinib in this setting.

It has been hypothesized that, as an inhibitor of multiple angiogenic factor pathways, sunitinib would demonstrate activity even in patients who experienced disease progression on or after a specific VEGF-A inhibitor (bevacizumab). The observed activity in the current study (ORR of 23% and PFS of 30 weeks) is somewhat less than that reported in untreated mRCC patients.³ Nevertheless, it is substantial, and strongly suggests that sunitinib can overcome resistance mechanisms that develop in response to exposure to VEGF-binding agents. Whether this depends on its inhibitory properties against VEGFR or against PDGFR and other tyrosine kinases remains to be determined.

We explored potential associations between biologic activity and clinical response with angiogenesis-related proteins that are either directly or indirectly targeted by bevacizumab (VEGF-A) and/or sunitinib (VEGFR-3, VEGF-C, and PlGF). We observed increases in plasma VEGF-A and PlGF levels associated with sunitinib treatment and subsequent restoration to near-baseline levels at the end of the off-treatment periods. Levels of sVEGFR-3 and, to a lesser extent, VEGF-C tended to decrease. These patterns suggest that the expression and secretion of these proteins may be differentially regulated by intracellular signaling mechanisms.

Higher baseline levels of both VEGF-A and PlGF were significantly correlated with shorter times since cessation of bevacizumab treatment. This finding may be the result of a residual bevacizumab effect, given that bevacizumab treatment can increase VEGF levels,¹⁵ resulting from reduced clearance as a result of bevacizumab binding,¹⁶ and/or potentially because of feedback induction after bevacizumab withdrawal. The ELISA assay used in the present study does not readily detect VEGF bound to bevacizumab (Pfizer Inc, data on file),^17,18 and thus feedback induction may be a more likely explanation. In addition, because bevacizumab does not bind to PlGF, the similar pattern seen with this growth factor would support a feedback induction rather than simply VEGF-A sequestration. Similar findings were observed in a study of sunitinib in patients with metastatic colorectal cancer.^19,20

Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS with sunitinib treatment. These findings support the potential significance of the VEGF-C/VEGFR-3 pathway in mRCC. Sunitinib inhibits VEGFR-3; however, the in vivo importance of this inhibition is not fully understood. Further research to confirm the clinical significance and underlying biologic mechanisms behind these observations is warranted. It is unknown whether the association of plasma VEGF-C and VEGFR-3 levels with sunitinib response reported here is specific to the bevacizumab-refractory population and reflective of a bevacizumab resistance mechanism, or indicative of a subset of patients who are intrinsically less responsive to sunitinib.

This study has several limitations. First, there is no consensus clinical or biologic definition of bevacizumab-refractory mRCC patients. Although standard RECIST criteria were employed, current targeted agents such as bevacizumab are unique in the evaluation of response and resistance compared with chemotherapy, on which RECIST was formulated. For example, such newer agents often produce tumor changes independent of changes in size that may indicate response or progression. Secondly, large initial reductions in tumor burdens can be followed by slow increases, often crossing the arbitrary 20% increase from lowest tumor burden defining PD according to RECIST, and yet the agent may still be exerting an antitumor effect. In addition, mixed responses, in which new lesions appear while existing tumors continue to regress, are defined as PD. A more comprehensive evaluation of treatment effect, possibly including metabolic, physiologic, and biologic assessments, may improve our classification and understanding of tumor responsiveness. Nonetheless, a consistent definition of disease progression on or after bevacizumab treatment was employed for all patients in this trial. Finally, this was a single-agent, nonrandomized study without a control arm, which has limitations in determining the relative benefit of other strategies, such as re-treatment with bevacizumab, continuing bevacizumab, adding sunitinib, or treatment with an agent that targets a different pathway. Prospective randomized trials will be required to provide insight into the most effective option after disease progression with a particular targeted agent. In addition, adequately sized prospective trials, or pooled data from multiple trials, are needed (eg, for use in multivariate analyses) to further examine and independently confirm the correlations between biomarkers and clinical outcome observed in this study.

In summary, sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC, supporting the hypothesis that sunitinib may inhibit signaling pathways involved in bevacizumab resistance. Sunitinib treatment is associated with circulating biomarkers which demonstrate a correlation with efficacy.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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.

Employment or Leadership Position: Samuel E. DePrimo, Pfizer Inc (C); Sindy T. Kim, Pfizer Inc (C); Isan Chen, Pfizer Inc (C) Consultant or Advisory Role: Brian I. Rini, Pfizer, Inc (C); M. Dror Michaelson, Pfizer Inc (C); Jonathan E. Rosenberg, Pfizer Inc (U); Ronald M. Bukowski, Pfizer, Inc (C), Bayer (C), Wyeth (C), Novartis (C), Onyx (C), Genentech (C); Jeffrey A. Sosman, Bayer/Onyx (C), Genentech (C), Wyeth (C); Walter M. Stadler, Pfizer Inc (C), Genentech (C), Bayer (C), Wyeth (C), Novartis (C); Thomas E. Hutson, Pfizer Inc (C), Bayer/Onyx (C), Wyeth (C); Charles S. Harmon, Pfizer Inc (C); Daniel J. George, Pfizer Inc (C) Stock Ownership: Charles S. Harmon, Pfizer Inc; Samuel E. DePrimo, Pfizer Inc; Sindy T. Kim, Pfizer Inc; Isan Chen, Pfizer Inc Honoraria: M. Dror Michaelson, Pfizer Inc; Ronald M. Bukowski, Pfizer Inc, Wyeth, Genentech, Bayer, Novartis; Walter M. Stadler, Bayer; Thomas E. Hutson, Pfizer Inc Bayer/Onyx, Wyeth; Daniel J. George, Pfizer Inc Research Funding: Brian I. Rini, Pfizer Inc; M. Dror Michaelson, Pfizer Inc; Jonathan E. Rosenberg, Pfizer Inc; Ronald M. Bukowski, Pfizer Inc, Bayer, Wyeth, Genentech; Jeffrey A. Sosman, Pfizer Inc; Walter M. Stadler, Pfizer Inc Genentech, Bayer, Wyeth, Novartis, Amgen; Thomas E. Hutson, Pfizer Inc Bayer/Onyx, Wyeth Expert Testimony: None Other Remuneration: Jonathan E. Rosenberg, Pfizer Inc

	AUTHOR CONTRIBUTIONS

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Conception and design: Brian I. Rini, M. Dror Michaelson, Samuel E. DePrimo, Sindy T. Kim, Isan Chen, Daniel J. George

Administrative support: Sindy T. Kim, Isan Chen

Provision of study materials or patients: Brian I. Rini, M. Dror Michaelson, Jonathan E. Rosenberg, Ronald M. Bukowski, Jeffrey A. Sosman, Walter M. Stadler, Thomas E. Hutson, Kim A. Margolin, Sindy T. Kim, Daniel J. George

Collection and assembly of data: Brian I. Rini, M. Dror Michaelson, Jonathan E. Rosenberg, Ronald M. Bukowski, Walter M. Stadler, Thomas E. Hutson, Charles S. Harmon, Samuel E. DePrimo, Sindy T. Kim, Daniel J. George

Data analysis and interpretation: Brian I. Rini, M. Dror Michaelson, Ronald M. Bukowski, Thomas E. Hutson, Charles S. Harmon, Samuel E. DePrimo, Sindy T. Kim, Isan Chen, Daniel J. George

Manuscript writing: Brian I. Rini, M. Dror Michaelson, Ronald M. Bukowski, Jeffrey A. Sosman, Thomas E. Hutson, Samuel E. DePrimo, Sindy T. Kim, Daniel J. George

Final approval of manuscript: Brian I. Rini, M. Dror Michaelson, Jonathan E. Rosenberg, Ronald M. Bukowski, Jeffrey A. Sosman, Walter M. Stadler, Thomas E. Hutson, Kim A. Margolin, Samuel E. DePrimo, Sindy T. Kim, Isan Chen, Daniel J. George

	ACKNOWLEDGMENTS

 
We thank all of the patients and their families for their participation in this study, investigators and their staff from participating sites, and ACUMED of Tytherington, United Kingdom, for editorial assistance.

	NOTES

 
Supported by Pfizer Inc.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; and the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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

Clinical Trials repository link available on www.JCO.org.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
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3. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115-124, 2007[Abstract/Free Full Text]

4. Escudier B, Koralewski P, Pluzanska A, et al: A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-2a vs placebo/interferon-2a as first-line therapy in metastatic renal cell carcinoma. J Clin Oncol 25:2s, 2007 (suppl; abstr 3)

5. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

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10. Deprimo SE, Bello CL, Smeraglia J, et al: Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: Modulation of VEGF and VEGF-related proteins. J Transl Med 5:32, 2007[CrossRef][Medline]

11. 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[Abstract/Free Full Text]

12. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516-2524, 2006[Abstract/Free Full Text]

13. 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 24:18s, 2006 (suppl; abstr 4597)[CrossRef]

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15. Willett CG, Boucher Y, Duda DG, et al: Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: Continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23:8136-8139, 2005[Free Full Text]

16. Hsei V, Deguzman GG, Nixon A, et al: Complexation of VEGF with bevacizumab decreases VEGF clearance in rats. Pharm Res 19:1753-1756, 2002[CrossRef][Medline]

17. Verheul HM, Lolkema MP, Qian DZ, et al: Platelets take up the monoclonal antibody bevacizumab. Clin Cancer Res 13:5341-5347, 2007[Abstract/Free Full Text]

18. Karp JE, Gojo I, Pili R, et al: Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: Therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res 10:3577-3585, 2004[Abstract/Free Full Text]

19. Saltz LB, Rosen LS, Marshall LJ, et al: Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. J Clin Oncol 25:4793-4799, 2007[Abstract/Free Full Text]

20. DePrimo SE, Harmon C, Saltz LB, et al: Variations in circulating levels of VEGF and sVEGFR-2, sVEGFR-3, and sKIT in metastatic CRC patients treated with sunitinib after failure of prior chemotherapy with or without bevacizumab. Presented at the of the American Association for Cancer Research Annual Meeting, April 14-18, 2007, Los Angeles, CA

Submitted December 3, 2007; accepted April 21, 2008.

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