Originally published as JCO Early Release 10.1200/JCO.2007.14.5375 on March 17 2008

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Phase II Study of Sunitinib Malate, an Oral Multitargeted Tyrosine Kinase Inhibitor, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

Harold J. Burstein, Anthony D. Elias, Hope S. Rugo, Melody A. Cobleigh, Antonio C. Wolff, Peter D. Eisenberg, Mary Lehman, Bonne J. Adams, Carlo L. Bello, Samuel E. DePrimo, Charles M. Baum, Kathy D. Miller

From the Dana-Farber Cancer Institute, Boston, MA; University of Colorado Health Sciences Center, Denver, CO; University of California San Francisco, San Francisco; California Cancer Care Inc, Greenbrae; Pfizer Inc, La Jolla; TRACON Pharmaceuticals Inc, San Diego, CA; Rush University Medical Center, Chicago, IL; Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD; and the Indiana University Simon Cancer Center, Indianapolis, IN

Corresponding author: Harold J. Burstein, MD, PhD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115; e-mail: hburstein{at}partners.org

	ABSTRACT

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Purpose Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC).

Patients and Methods Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary end point was objective response rate. Plasma samples were obtained for pharmacokinetic and biomarker analysis.

Results Seven patients achieved a partial response (median duration, 19 weeks), giving an overall response rate of 11%. Three additional patients (5%) maintained stable disease for 6 months. Median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in triple negative tumors and HER2-positive, trastuzumab-treated patients. Thirty-three patients (52%) required dose interruption during 1 cycle, and 25 patients required dose reduction (39%). Thirty-six patients (56%) had dose modifications due to adverse events (AEs). Treatment was associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. The most common AEs were fatigue, nausea, diarrhea, mucosal inflammation, and anorexia. Most AEs were mild to moderate (grade 1 to 2) in severity and were effectively managed with dose delays or reductions.

Conclusion Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.

	INTRODUCTION

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Treatment options for advanced breast cancer include chemotherapy, antiestrogen interventions, and HER2-directed therapy. Despite the success of these strategies, there is a persistent need for novel and improved therapeutic approaches. Substantial preclinical and indirect clinical evidence has shown that angiogenesis plays an essential role in breast cancer development, invasion, and metastasis.^1,2 Multiple angiogenic factors, including vascular endothelial growth factor (VEGF), are commonly overexpressed by invasive breast cancers.^3,4 Studies have shown that certain breast carcinoma cells directly express VEGF receptor (R)-1 and VEGFR-2,^5,6 with enhanced VEGFR-2 activation observed in malignant breast cancer tissue.⁷ VEGF functions are mediated by binding to one of three receptor tyrosine kinases: VEGFR-1 (flt-1), VEGFR-2 (flk-1/kdr), and VEGFR-3 (flt-4).⁸ VEGF is not the only clinically relevant mediator of angiogenesis in breast cancer; platelet-derived growth factor (PDGF) is another angiogenic growth factor contributing to progression of breast cancer cells through autocrine and paracrine mechanisms. Immunohistochemical studies of breast cancer specimens have shown PDGF expression in cancer cells and PDGF receptor (PDGFR- and PDGFR-β) expression predominantly in stromal cells, signifying a paracrine mechanism for tumor development or maintenance.^9,10 In addition, elevated PDGF levels in plasma and increased PDGF expression in breast tumor tissues correlate with an increased incidence of metastasis, lower response to chemotherapy and shorter patient survival time.^11,12 Overexpression of stem cell factor receptor (KIT), a member of the PDGFR receptor subfamily, has also been documented in breast cancer.¹³ Colony-stimulating factor-1 expressed by breast cancer cells can stimulate tumor-associated macrophages to secrete important growth factors for breast cancers, including epidermal growth factor, interleukin-6, and transforming growth factor-β.¹⁴ Taken together, this evidence highlights tumor angiogenesis as an attractive therapeutic target.¹⁵

Sunitinib malate is an oral tyrosine kinase inhibitor that targets several receptor tyrosine kinases, including VEGFR (VEGFR-1, VEGFR-2 and VEGFR-3), PDGFR (PDGFR- and PDGFR-β), KIT, and colony-stimulating factor-1 receptor.^16-18 Single-agent sunitinib has demonstrated antitumor activity in several preclinical breast cancer models, both alone and in combination with chemotherapy.^18,19 Based on biochemical and preclinical observations with sunitinib, we conducted a phase II, multicenter study to evaluate the efficacy and safety of sunitinib treatment in patients with metastatic breast cancer (MBC) previously treated with anthracycline and taxane therapy. The primary objective was to determine the antitumor activity of sunitinib at a starting dose of 50 mg administered once daily for 4 weeks, followed by 2 weeks off treatment, in repeated 6-week cycles—a dose schedule that resulted in promising clinical activity in phase I studies in patients with advanced solid tumors.^20,21

	PATIENTS AND METHODS

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Patients
The study population comprised women (18 years of age) with a histologically or cytologically confirmed MBC diagnosis. All patients were to have had unidimensionally measurable disease and previous treatment with an anthracycline and a taxane in the adjuvant and/or advanced disease setting (patients only treated in the adjuvant setting must have experienced relapse or disease progression during treatment or within 12 months of the last dose of adjuvant therapy). Anthracycline and taxane treatment could be administered concurrently or sequentially. Patients could have received up to two nonanthracycline or nontaxane chemotherapy regimens in the advanced disease setting, resulting in up to four previous chemotherapy regimens. Prior hormone therapy and immunotherapy were permitted, as were surgery and radiation therapy, provided that they did not affect the only areas of measurable disease. In addition, patients were required to have Eastern Cooperative Oncology Group performance status of 0 or 1, and to have completed all prior chemotherapy and radiotherapy at least 3 weeks before study entry. Patients on bisphosphonate therapy for metastatic bone disease must have initiated therapy 3 months before study entry. All patients had adequate hematologic, hepatic, renal, and cardiac function, and had provided written, informed consent. The main exclusion criteria were prior treatment with tyrosine kinase inhibitors or antiangiogenic agents, radiation to more than 25% of bone marrow, or high-dose chemotherapy requiring hematopoietic stem cell rescue.

This study was performed in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki (1996 version), and applicable local regulatory requirements and laws. The study was approved by the institutional review board or independent ethics committee of each participating center.

Study Design
This was an open-label, single-arm, phase II study conducted at eight centers in the United States. The primary end point was overall objective response rate (ORR) defined as the percentage of all patients who experienced a confirmed complete response or partial response (PR), based on Response Evaluation Criteria in Solid Tumors (RECIST; see Assessments). Secondary end points included safety and tolerability, duration of objective tumor response (DR), time to tumor progression (TTP), 1-year survival rate, measurement of trough sunitinib and SU12662 (active metabolite of sunitinib) plasma levels, as well as exploration of soluble plasma biomarkers of response (VEGF, VEGFR-2, VEGFR-3, and KIT).

Administration of Study Treatment
Patients received a starting dose of sunitinib 50 mg in 6-week cycles, comprising a 4-week treatment period followed by 2 weeks off treatment (schedule 4/2). Sunitinib was self-administered orally once daily in the morning, without regard to meals. Patients were monitored for toxicity, and the sunitinib dose was adjusted (to 37.5 mg/d and then to 25 mg/d) by the study investigator to suit individual patient tolerance. Sunitinib therapy was administered for up to 1 year providing no withdrawal criteria—tumor progression, unacceptable toxicity, toxicity requiring more than a 6-week delay in initiating a treatment cycle, or consent withdrawal—were met. Individual patients could continue sunitinib therapy after disease progression if an investigator thought there was reasonable evidence of clinical benefit. Additional sunitinib treatment beyond 1 year of therapy was permitted if there was reasonable evidence of clinical benefit.

Assessments
Baseline evaluations included medical history, physical examination, tumor imaging with a computed tomography or magnetic resonance imaging scan, laboratory tests (hematology, urinalysis, coagulation, blood chemistry, and pregnancy tests), three 12-lead ECGs, and a multigated acquisition scan. Hematology and blood chemistry evaluations were performed before each treatment cycle. Blood samples were taken for analysis of sunitinib, SU12662, and the biomarkers described earlier, before sunitinib treatment on study days 1, 14, and 28 of the first treatment cycle, on days 1 and 28 of cycles 2 and 3, on day 1 of subsequent cycles and at the end of treatment. Patients were restaged at 10 weeks, and every 12 weeks thereafter.

The response to sunitinib treatment was evaluated by the investigator based on objective tumor assessments using RECIST.²² Adverse events (AEs) were assessed and AE severity was graded in accordance with the Cancer Therapy Evaluation program, Common Terminology Criteria for AEs, version 3.0.

Sunitinib and SU12662 concentrations were analyzed using a validated, sensitive, and specific isocratic liquid chromatographic tandem mass spectrometric method, as previously described.²³ Assay reproducibility and accuracy (expressed as coefficient of variation [CV%] and bias % of quality control samples, respectively) ranged from 2.2% to 6.9% and –7.3% to 0.3%, respectively, for sunitinib, and from 4.0% to 10.4% and –4.7% to 2.4%, respectively, for SU12662. Total drug concentrations were calculated as the sum of sunitinib + SU12662 concentrations.

Plasma levels of four putative biomarkers were analyzed with validated enzyme-linked immunosorbant assay kits or kit components (R&D Systems, Minneapolis, MN). For the biomarker descriptive results, a cut point of 30% was deemed an appropriate conservative threshold that would provide a wide margin beyond the noise levels of the assay performance (which typically has a CV% of < 20%).

Statistical Methods
The sample size was determined using Simon's Minimax two-stage design for phase II studies. The first stage was to include 38 patients; if more than one response was observed, enrollment was to continue to 63 patients. The null hypothesis was that the true ORR was 5% (not considered to be clinically meaningful); the alternative hypothesis was that the true ORR was 15% ( level, 5%; power 85%). At the end of the study, if seven or more objective tumor responses were observed, then the null hypothesis that the true response probability was 5% was to be rejected, and further investigation of sunitinib in this population would be warranted. Time-to-event variables were summarized using the Kaplan-Meier method.

	RESULTS

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Patient Characteristics
A total of 64 patients were enrolled in the study. Patient characteristics at baseline are summarized in Table 1. In 42% of patients (n = 27), tumors were negative for estrogen receptor (ER) overexpression; HER2 was overexpressed in 19% of patients (n = 12). Nearly one third of patients (31%; n = 20) had tumors that were negative for ER, progesterone receptor, and HER2 overexpression. Of the 12 patients with HER2-positive tumors, eight received previous treatment with trastuzumab. All patients had received prior chemotherapy; 95% had received both an anthracycline and a taxane. Three patients had not received previous taxane treatment (Table 1). The most common sites of metastatic disease were lymph nodes, liver, lung, and bone.

Activity
The ORR was 11% (95% CI, 4 to 21), with seven patients achieving a PR (Table 2). A further three patients (5%) had stable disease (SD) for at least 6 months yielding a clinical benefit rate (defined as complete response, PR, or SD for at least 6 months) of 16% (n = 10). The median DR was 19 weeks (95% CI, 18 to 20) and the median TTP was 10 weeks (95% CI, 10 to 11; Fig 1). The overall probability of survival at 1 year was 41% (95% CI, 28 to 54), and median overall survival (OS) was 38 weeks (95% CI, 28 to 63).

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier estimate of time to tumor progression.

Safety
Toxicities encountered on study are presented in Table 3. The most frequently reported AE was fatigue, followed by nausea, diarrhea, mucosal inflammation, and anorexia. Grade 3 AEs reported in five or more patients ( 9%) were fatigue (nine patients) and hand-foot syndrome (six patients). Three patients (5%) reported grade 4 chemistry abnormalities: hyperuricemia (two patients) and increased ALT and alkaline phosphatase (one patient). Grade 3 neutropenia was reported in one third of patients (32.8%), and grade 4 neutropenia in one patient. There were no episodes of neutropenic fever. Transient episodes of grade 3 thrombocytopenia and leukopenia were also observed. All hematologic laboratory abnormalities resolved rapidly during off-treatment periods included in each cycle. Five patients (8%) died within 28 days of last treatment due to disease progression. No treatment-related deaths occurred on study.

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Intrapatient changes in levels of (A) vascular endothelial growth factor (VEGF), (B) soluble vascular endothelial growth factor receptor (sVEGFR)-2, and (C) sVEGFR-3 during sunitinib treatment. Soluble protein plasma level ratios relative to baseline (cycle 1, day 1) are shown as a series of time points, with baseline values normalized to 1.

Pharmacokinetics
Plasma trough concentration (C_trough) of sunitinib, its active metabolite SU12662, and total drug were assessed in 60 patients. At steady-state in cycles 1 to 3, median C_trough sunitinib, SU12662, and total drug concentrations were 53 to 72 ng/mL, 28 to 33 ng/mL and 72 to 103 ng/mL, respectively (Fig 3), exceeding total drug concentrations determined from preclinical studies to inhibit receptor phosphorylation (> 50 ng/mL). No accumulation of or induction of metabolism by sunitinib or SU12662 was observed with repeated cycles. Before the start of treatment during cycle 2 and onward, low median concentration ranges for sunitinib (1.1 to 1.9 ng/mL) and SU12662 (1.9 to 3.2 ng/mL) indicated an almost complete washout during the 2-week off-treatment period.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Median total drug (sunitinib plus SU12662) trough concentration versus time profiles.

	DISCUSSION

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In preclinical models, sunitinib administration resulted in a significant reduction of phosphotyrosine levels of VEGFR-2, PDGFR-β, and KIT, which correlated with tumor growth inhibition.^16,17 In a pharmacodynamic analysis of sunitinib in patients with renal cell carcinoma, significantly greater changes in VEGF and sVEGFR-2 and -3 levels occurred in patients experiencing objective responses, compared with those who had SD or disease progression (all P < .05).²⁷ Sunitinib therapy was also associated with increases in soluble VEGF concentrations and decreases in plasma levels of soluble VEGFRs and KIT in this study. sVEGFR-3 may be a novel marker for the biologic activity of sunitinib,²⁷ while sKIT concentrations were correlated with clinical responses. These correlative findings suggest that strategies simultaneously inhibiting both VEGFR and VEGF may be worth exploring.

Pharmacokinetic analysis of systemic exposure to sunitinib demonstrated sufficient serum exposures so as to inhibit sunitinib-targeted tyrosine kinases in preclinical models. Median C_trough levels of sunitinib (53 to 72 ng/mL) and total drug (sunitinib plus SU12662; 72 to 103 ng/mL) on the last treatment day of cycles 1 to 3 were within the range of 50 ng/mL that was shown to inhibit target receptor tyrosine kinases in preclinical models.¹⁶ These pharmacokinetic data are comparable to those reported in other studies evaluating sunitinib in other malignancies, including renal cell carcinoma and gastrointestinal stromal tumors.^26,28

The noncontinuous dosing regimen (4 weeks on, 2 weeks off) yielded an almost complete washout of sunitinib C_trough levels and of SU12662 during the 2-week period before resumption of therapy. Levels of VEGF, sVEGFR-2, and sVEGFR-3 also displayed a cyclical pattern coinciding with the sunitinib dosing schedule. Investigators reported that these biochemical observations were paralleled in several patients with superficial cutaneous or nodal lesions, whose tumors seemed to respond clinically during periods on sunitinib therapy, but then grew during the 2-week period off treatment. These observations have prompted exploration of continuous daily dosing schedules in patients with breast cancer. Phase II studies of a continuous daily regimen in patients with renal cell carcinoma or gastrointestinal stromal tumors have demonstrated efficacy and safety similar to that observed in previous studies using the 4/2 schedule.^29,30

We believe these data indicate that sunitinib has activity in advanced breast cancer, and is reasonably well tolerated. These findings are encouraging when compared with other recent experience of single-agent angiogenesis inhibitors in MBC. Overall response rates in similar studies were 9% (confirmed response rate, 7%) with bevacizumab and 2% with sorafenib,^31,32 compared with 11% in this study. Median overall survival times in these three trials were 38 weeks for sunitinib, 43 weeks for bevacizumab,³¹ and 8 weeks for sorafenib.³² In addition, discontinuations due to AEs were lowest in the sunitinib study (0% v 6% for bevacizumab and 6% for sorafenib).^31,32 Ongoing trials are evaluating sunitinib in advanced and early-stage breast cancer. These include phase II trials of sunitinib in combination with chemotherapy, and randomized trials comparing chemotherapy/sunitinib combinations against other chemotherapy/angiogenesis inhibitor regimens.

	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: Mary Lehman, Pfizer Inc (C); Carlo L. Bello, Pfizer Inc (C); Samuel E. DePrimo, Pfizer Inc (C); Charles M. Baum, Pfizer Inc (C) Consultant or Advisory Role: Anthony D. Elias, Pfizer Inc (C) Stock Ownership: Mary Lehman, Pfizer Inc; Carlo L. Bello, Pfizer Inc; Samuel E. DePrimo, Pfizer Inc; Charles M. Baum, Pfizer Inc Honoraria: Kathy D. Miller, Pfizer Inc Research Funding: Anthony D. Elias, Pfizer Inc; Hope S. Rugo, Pfizer Inc; Antonio C. Wolff, Pfizer Inc; Peter D. Eisenberg, Pfizer Inc; Kathy D. Miller, Pfizer, Inc Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Hope S. Rugo, Antonio C. Wolff, Mary Lehman, Carlo L. Bello, Samuel E. DePrimo, Charles M. Baum

Financial support: Charles M. Baum

Administrative support: Bonne J. Adams, Kathy D. Miller

Provision of study materials or patients: Harold J. Burstein, Anthony D. Elias, Hope S. Rugo, Melody A. Cobleigh, Antonio C. Wolff, Peter D. Eisenberg, Charles M. Baum

Collection and assembly of data: Harold J. Burstein, Anthony D. Elias, Hope S. Rugo, Peter D. Eisenberg, Mary Lehman, Bonne J. Adams, Samuel E. DePrimo, Charles M. Baum, Kathy D. Miller

Data analysis and interpretation: Harold J. Burstein, Anthony D. Elias, Antonio C. Wolff, Mary Lehman, Carlo L. Bello, Samuel E. DePrimo, Charles M. Baum

Manuscript writing: Harold J. Burstein, Anthony D. Elias, Peter D. Eisenberg, Mary Lehman, Carlo L. Bello, Samuel E. DePrimo

Final approval of manuscript: Harold J. Burstein, Anthony D. Elias, Hope S. Rugo, Melody A. Cobleigh, Antonio C. Wolff, Peter D. Eisenberg, Mary Lehman, Charles M. Baum

	ACKNOWLEDGMENTS

 
We thank medical writers at ACUMED (Tytherington, United Kingdom) for assistance in drafting this manuscript.

	NOTES

 
published online ahead of print at www.jco.org on March 17, 2008.

Supported by Pfizer Inc.

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

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Submitted October 3, 2007; accepted January 15, 2008.

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