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Breast Cancer
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Phase III Trial of Sunitinib in Combination With Capecitabine Versus Capecitabine Monotherapy for the Treatment of Patients With Pretreated Metastatic Breast Cancer
Abstract
Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC.
Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months).
A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm.
Despite advances in endocrine treatment and conventional cytotoxic chemotherapy, metastatic breast cancer (MBC) remains, with few exceptions, an incurable disease, and effective new treatments are needed. For cancer that has progressed after prior taxane and anthracycline therapy, salvage chemotherapy produces a modest benefit. A widely used drug in this setting is capecitabine.1 Single-agent capecitabine treatment of anthracycline- and paclitaxel-resistant disease has been associated with a median overall survival (OS) of 13.5 months.2
Increased understanding of the molecular basis of neoplasia has resulted in the focus of cancer therapeutics shifting from nonspecific cytotoxic chemotherapy toward molecularly targeted therapies. Research by Folkman3 and others demonstrated the crucial importance of neoangiogenesis in cancer development.4 Signal-transduction pathways involving vascular endothelial growth factor and platelet-derived growth factor, two molecules involved in tumor neoangiogenesis, are susceptible to therapeutic molecular inhibition, and a number of inhibitors have been studied in the clinic. One of these, the monoclonal antibody bevacizumab, received conditional approval for use in MBC in 2008 based on the results of a phase III study that demonstrated a statistically and clinically significant increase in progression-free survival (PFS) in combination with paclitaxel.5 Another such drug is sunitinib malate (Sutent; Pfizer, New York, NY), an oral inhibitor of multiple receptor tyrosine kinases that include vascular endothelial growth factor receptors, platelet-derived growth factor receptors, KIT, and colony-stimulating factor 1 receptor.6–8 Sunitinib is currently approved for the treatment of advanced renal cell carcinoma, imatinib-resistant or -intolerant GI stromal tumor, and metastatic pancreatic neuroendocrine tumor.
Many sunitinib targets have been implicated in BC pathogenesis, microvascular support, and metastatic progression.9–12 In a mouse model of BC metastatic to bone, single-agent sunitinib was also found to inhibit osteolytic tumor progression.8 Single-agent activity has been demonstrated in preclinical BC models6,8 as well as clinically; an objective response rate (ORR) of 11% was achieved in a phase II clinical trial in patients with heavily pretreated MBC who received sunitinib 50 mg per day on a 4-week-on, 2-week-off treatment schedule.13 In this trial, tumor regrowth during the off-treatment period was observed in some patients after initial shrinkage while receiving treatment. An alternative schedule—37.5 mg on a continuous daily dosing (CDD) schedule—was found to be feasible in renal cell carcinoma, GI stromal tumor, and pancreatic neuroendocrine tumor14–17 and was used in subsequent sunitinib trials in MBC.
A rationale exists for studying the combination of sunitinib and fluoropyrimidines in BC. Sunitinib addition to fluorouracil in an MX-1 human BC xenograft model enhanced the antitumor activity of the chemotherapeutic agent and significantly inhibited tumor growth. The synergistic antitumor effect with combined therapy also conferred a survival benefit in animal models.18 The combination of sunitinib and capecitabine was studied in a phase I trial that identified a maximum-tolerated sunitinib dose of 37.5 mg on the CDD schedule, with capecitabine 2,000 mg/m2, days 1 to 14 every 3 weeks.19 On the basis of these preclinical and clinical data, we performed a prospective, open-label, phase III, multicenter, randomized trial in which the combination of sunitinib 37.5 mg per day and capecitabine 2,000 mg/m2 was compared with single-agent capecitabine 2,500 mg/m2 as treatment for MBC after prior therapy with anthracyclines and taxanes.
Eligible patients were age ≥ 18 years with a histologically or cytologically confirmed diagnosis of unresectable, locally advanced, or metastatic breast carcinoma; an Eastern Cooperative Oncology Group performance status of 0 or 1; and evidence of adequate organ function. Either measurable or evaluable bone-only disease was permitted. Patients must have had prior anthracycline and taxane treatment in the early- or advanced-disease setting, with either relapse within 1 year of neoadjuvant/adjuvant treatment or one to two prior chemotherapy regimens in the advanced-disease setting. Prior hormonal therapy was permitted if concurrent or sequential to adjuvant chemotherapy (hormone receptor–positive patients with bone-only disease must have experienced progression during or after hormone therapy). Human epidermal growth factor receptor 2–positive disease was permitted if previously treated with trastuzumab (continuation of trastuzumab therapy beyond progression was not standard practice when the trial was designed). Exclusion criteria included prior treatment with ≥ three chemotherapy regimens in the advanced-disease setting, prior treatment with capecitabine or sunitinib, known dihydropyrimidine dehydrogenase deficiency, CNS metastases, cardiovascular disease within 6 months of study start, or uncontrolled hypertension.
The study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable local regulatory requirements and laws. Approval from the institutional review board or independent ethics committee of each participating center was required; written informed consent was obtained from all patients before screening.
In this multicenter, prospective open-label study, patients were randomly assigned 1:1 to receive sunitinib plus capecitabine or capecitabine alone. Random assignment was performed using an interactive voice-response system, with stratification based on the number of metastatic sites (≤ two v > two), receptor status (triple negative [ie, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 negative] v all others), and number of prior chemotherapy regimens (one v > one). The primary end point was PFS (defined as time from random assignment to first documented tumor progression or death during study as a result of any cause, whichever occurred first) based on independent blinded radiologic review. Secondary end points included PFS (investigator assessment), ORR, duration of response, OS, and safety.
In the combination arm, patients received capecitabine orally at a starting dose of 2,000 mg/m2 (1,000 mg/m2 twice daily) on days 1 to 14 of a 3-week cycle plus sunitinib orally at a starting dose of 37.5 mg once daily. In the monotherapy arm, patients received capecitabine at a starting dose of 2,500 mg/m2 (1,250 mg/m2 twice daily) on days 1 to 14 of a 3-week cycle. Treatment was continued until disease progression, unacceptable toxicity, or consent withdrawal. If capecitabine was discontinued for reasons other than progression in the combination arm, patients could continue receiving sunitinib until progression or beyond at the investigator's discretion if clinical benefit was evident.
In the monotherapy arm, at the time of documented progression, patients were eligible to cross over to single-agent sunitinib 37.5 mg per day. This cross-over population was included in the analysis of OS but not in the analysis of other end points (ie, PFS [because cross-over occurred postprogression], or ORR or safety [because both were based on the study medication to which patients were randomly assigned]).
Patients were monitored for toxicity. The sunitinib dose could be reduced to 25 mg per day or increased to 50 mg per day, based on individual tolerability. Capecitabine dose adjustments were performed according to the approved label.1
Tumors were imaged using computed tomography or magnetic resonance imaging at baseline and at 6-week intervals from random assignment until documented disease progression. Additional scans were performed whenever disease progression was suspected or to confirm an objective response (partial or complete response). Confirmatory imaging was performed ≥ 4 weeks after initial documentation of response and at withdrawal from the study (if > 6 weeks since last assessment). Tumor response (based on RECIST20) was evaluated by the investigators and retrospectively by an independent radiology laboratory. Bone scans are described in the Appendix (online only).
Safety was assessed by physical examination and analysis of adverse events (AEs), hematology, blood chemistry, and vital signs at regular intervals. AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Given the known effects of sunitinib treatment on thyroid function, QT intervals, and left ventricular ejection fractions,21 these functions were monitored during the study as described in the Appendix (online only).
The median PFS for patients receiving capecitabine was assumed to be 4 months,22 and a 50% improvement in median PFS to 6 months in the sunitinib plus capecitabine combination arm was taken to be clinically significant. At least 294 events (as determined by blinded radiologic review) were required to have 90% power to detect a statistically significant difference in PFS between the treatment groups; for this, 430 patients were required (215 per treatment arm). Interim analyses were planned when 30% and 60% of PFS events had occurred to allow early stopping because of futility or efficacy or safety concerns.
The intention-to-treat population was the primary population for the evaluation of efficacy and patient characteristics. The as-treated population, which included all patients who received at least one dose of study medication, was the primary population for the evaluation of treatment administration and compliance and safety.
Descriptive statistics were used to summarize patient characteristics and treatment administration and compliance. Time-to-event end points were summarized using the Kaplan-Meier method, and between-treatment comparisons for PFS and OS were conducted using one-sided stratified and unstratified log-rank tests (α = 0.025). Subgroup analyses were performed to explore the potential influences of prespecified baseline patient characteristics (number of metastatic sites, hormone receptor status, number of prior chemotherapy regimens, Eastern Cooperative Oncology Group performance status, age, prior hormone therapy, and ethnic origin) on the primary PFS end point; Cox proportional hazards analysis was used to calculate hazard ratios (HRs). No interaction tests were performed.
A total of 442 patients from 105 centers in 18 countries were randomly assigned to receive either sunitinib plus capecitabine or capecitabine alone (n = 221 each) between February 2007 and February 2009. In the combination and monotherapy arms, 217 and 215 patients received treatment, respectively (Fig 1). In the monotherapy arm, 77 patients (35%) crossed over to sunitinib. At data cutoff (December 2009), a total of 212 and 123 patients had discontinued the study. The median duration of follow-up was 14.3 months (95% CI, 13.4 to 15.2). Demographic and baseline disease characteristics were generally well balanced between the treatment arms (Table 1).
Fig 1. CONSORT diagram.
|
| Characteristic | Sunitinib Plus Capecitabine (n = 221) | Capecitabine (n = 221) | ||
|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | |
| Age, years | ||||
| Median | 52 | 54 | ||
| Range | 27-79 | 31-77 | ||
| ECOG PS | ||||
| 0 | 130 | 59 | 126 | 57 |
| 1 | 89 | 40 | 93 | 42 |
| ≥ 2 | 2 | 1 | 2 | 1 |
| Primary diagnosis at study entry | ||||
| Metastatic | 212 | 96 | 203 | 92 |
| Locally advanced | 9 | 4 | 18 | 8 |
| No. of metastatic sites | ||||
| ≤ 2 | 111 | 50 | 111 | 50 |
| > 2 | 110 | 50 | 110 | 50 |
| Histology | ||||
| Ductal | 182 | 82 | 177 | 80 |
| Lobular | 24 | 11 | 26 | 12 |
| Other | 15 | 7 | 18 | 8 |
| Receptor status | ||||
| ER positive | 146 | 66 | 150 | 68 |
| PR positive | 110 | 50 | 119 | 54 |
| HER2 positive | 28 | 13 | 25 | 11 |
| Triple negative | 59 | 27 | 59 | 27 |
| No. of prior chemotherapy regimens | ||||
| 1 | 99 | 45 | 100 | 45 |
| > 1 | 122 | 55 | 121 | 55 |
| Prior chemotherapy regimens | ||||
| Neoadjuvant/adjuvant only | 50 | 23 | 46 | 21 |
| One for advanced breast cancer | 140 | 63 | 138 | 62 |
| ≥ Two for advanced breast cancer | 30 | 14 | 34 | 15 |
| Others* | 1 | <1 | 3 | 1 |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.
*Not including those mentioned.
The median daily dose of sunitinib administered during the study was 37.5 mg, which closely approximated the planned dose (Table 2). Median daily doses of capecitabine were somewhat lower than planned (1,727 and 2,286 mg/m2 v planned doses of 2,000 and 2,500 mg/m2 in combination and monotherapy arms, respectively). The median relative capecitabine dose-intensity was slightly lower in the combination arm (84% v 89%).
|
| Variable | Sunitinib Plus Capecitabine (n = 217) | Capecitabine (n = 215) | |
|---|---|---|---|
| Sunitinib | Capecitabine | ||
| Daily dose administered | |||
| Median | 37.5 mg | 1,727 mg/m2 | 2,286 mg/m2 |
| Range | 12.5 to 41 mg | 807 to 2,212 mg/m2 | 884 to 2,600 mg/m2 |
| Relative dose-intensity, % | |||
| Median | 88 | 84 | 89 |
| Range | 30 to 100 | 32 to 111 | 21 to 104 |
| Duration of treatment, days | |||
| Median | 114 | 121 | 143 |
| 95% CI | 87 to 132 | 98 to 136 | 120 to 169 |
| No. of cycles started | |||
| Median | 5 | 5 | 6 |
| Range | 1 to 29 | 1 to 36 | 1 to 47 |
| Dosing interruptions | |||
| No. of patients | 132 | 61 | 35 |
| % | 61 | 28 | 16 |
| Cycle delays | |||
| No. of patients | NA* | 143 | 118 |
| % | 66 | 55 | |
| Dose reductions | |||
| No. of patients | 95 | 155 | 140 |
| % | 44 | 71 | 65 |
Abbreviation: NA, not applicable.
*Sunitinib administered on continuous daily dosing schedule.
No significant difference in PFS based on independent radiologic review was observed between the two treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (HR, 1.22; 95% CI, 0.95 to 1.58; one-sided log-rank P = .941; Table 3; Fig 2A). Similar results were obtained based on investigator assessment (Fig 2B). No clinically defined subpopulation was found to have a statistically significant improvement in PFS in the combination arm (Fig 3).
|
| Variable | Sunitinib + Capecitabine (n = 221) | Capecitabine (n = 221) | HRa | 95% CI | P | ||
|---|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | ||||
| PFS | |||||||
| Independent radiologic review | |||||||
| Events | 132 | 60 | 116 | 52 | |||
| Median, months | 5.5 | 5.9 | |||||
| 95% CI | 4.5 to 6.0 | 5.4 to 7.6 | |||||
| Stratified analysisb | 1.22 | 0.95 to 1.58 | .941c | ||||
| Investigator assessment | |||||||
| Events | 160 | 72 | 152 | 69 | |||
| Median, months | 5.4 | 5.5 | |||||
| 95% CI | 4.4 to 5.8 | 4.3 to 6.8 | |||||
| Stratified analysisb | 1.11 | 0.88 to 1.39 | .812c | ||||
| OS | |||||||
| Events | 117 | 53 | 108 | 49 | |||
| Median, months | 16.4 | 16.5 | |||||
| 95% CI | 13.6 to 8.4 | 14.2 to 18.6 | |||||
| Stratified analysisb | 0.99 | 0.76 to 1.30 | .484c | ||||
| Tumor responsed | |||||||
| Independent radiologic review | |||||||
| CRe | 0 | 0 | |||||
| PRe | 40 | 19 | 36 | 18 | |||
| SDe | 112 | 54 | 119 | 59 | |||
| SD ≥ 26 weeks | 28 | 14 | 29 | 14 | |||
| ORR, % | 19 | 18 | |||||
| 95% exact CIf | 14 to 26 | 13 to 24 | |||||
| Stratified analysisb | 1.04g | 0.61 to 1.79h | .490i | ||||
| Duration of response | |||||||
| Median, months | 9.0 | 8.8 | |||||
| 95% CI | 5.7 to 20.7 | 5.7 to 13.8 | |||||
| Investigator assessment | |||||||
| CRe | 0 | 2 | 1 | ||||
| PRe | 56 | 27 | 43 | 21 | |||
| SDe | 94 | 46 | 101 | 50 | |||
| SD ≥ 26 weeks | 26 | 13 | 28 | 14 | |||
| ORR, % | 27 | 22 | |||||
| 95% exact CIf | 21 to 34 | 17 to 29 | |||||
| Stratified analysisb | 1.27g | 0.78 to 2.07h | .189i | ||||
| Duration of response | |||||||
| Median, monthsf | 5.7 | 7.6 | |||||
| 95% CI | 4.3 to 6.9 | 6.5 to 9.9 | |||||
Abbreviations: CR, complete response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease.
aHR or odds ratio > 1 favors capecitabine monotherapy arm.
bStratified by random assignment stratification factors.
cOne-sided log-rank test.
dIn patients with measurable disease (sunitinib plus capecitabine, n = 206; capecitabine, n = 201).
eBest response based on RECIST.
fBased on Kaplan-Meier estimates.
gOdds ratio.
h95% exact CI.
iOne-sided exact test.
Fig 2. Kaplan-Meier estimates of progression-free survival based on (A) independent radiologic review or (B) investigator assessments and of (C) overall survival. CAP, capecitabine; HR, hazard ratio; SU, sunitinib.
Fig 3. Subgroup analysis of progression-free survival by treatment and prespecified baseline factors based on (A) independent radiologic review or (B) investigator assessments. CAP, capecitabine, ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; SU, sunitinib.
OS was virtually identical in the two treatment arms, with medians of 16.4 and 16.5 months (HR, 0.99; 95% CI, 0.76 to 1.30; one-sided log-rank P = .484; Fig 2C). ORRs were similar between the treatment arms in patients with measurable disease based on independent radiologic review (19% v 18%; odds ratio, 1.04; 95% CI, 0.61 to 1.79; one-sided exact P = .490; Table 3), as was median duration of response (9.0 v 8.8 months).
The most common AEs of any cause are listed in Table 4. Hematologic AEs were more frequent and more severe with the sunitinib plus capecitabine combination than with capecitabine monotherapy. The frequencies of grade 3 or 4 neutropenia and thrombocytopenia were 31% and 17% in the combination arm and 4% and 0% in the monotherapy arm, respectively.
|
| Adverse event | Sunitinib Plus Capecitabine (n = 217) | Capecitabine (n = 215) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Any Grade | Grade 3 | Grade 4 | Any Grade | Grade 3 | Grade 4 | |||||||
| No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | |
| Any adverse event | 216 | 100 | 129 | 59 | 37 | 17 | 211 | 98 | 102 | 47 | 9 | 4 |
| Diarrhea | 125 | 58 | 17 | 8 | 2 | 1 | 97 | 45 | 19 | 9 | 3 | 1 |
| Nausea | 122 | 56 | 9 | 4 | 1 | < 1 | 90 | 42 | 2 | 1 | 0 | |
| Hand-foot syndrome | 117 | 54 | 35 | 16 | 0 | 132 | 61 | 52 | 24 | 0 | ||
| Neutropenia | 105 | 48 | 66 | 30 | 3 | 1 | 39 | 18 | 8 | 4 | 1 | < 1 |
| Thrombocytopenia | 104 | 48 | 29 | 13 | 8 | 4 | 14 | 7 | 0 | 0 | ||
| Vomiting | 92 | 42 | 14 | 6 | 1 | < 1 | 54 | 25 | 7 | 3 | 1 | < 1 |
| Asthenia | 78 | 36 | 26 | 12 | 1 | < 1 | 49 | 23 | 6 | 3 | 0 | |
| Decreased appetite | 66 | 30 | 5 | 2 | 0 | 44 | 20 | 1 | < 1 | 0 | ||
| Fatigue | 66 | 30 | 21 | 10 | 1 | < 1 | 54 | 25 | 6 | 3 | 1 | < 1 |
| Stomatitis | 61 | 28 | 7 | 3 | 0 | 26 | 12 | 4 | 2 | 0 | ||
| Dysgeusia | 58 | 27 | 0 | 0 | 18 | 8 | 0 | 0 | ||||
| Headache | 57 | 26 | 2 | 1 | 0 | 31 | 14 | 0 | 0 | |||
| Anemia | 54 | 25 | 9 | 4 | 6 | 3 | 36 | 17 | 9 | 4 | 1 | < 1 |
| Mucosal inflammation | 51 | 24 | 6 | 3 | 0 | 25 | 12 | 2 | 1 | 0 | ||
| Leukopenia | 50 | 23 | 8 | 4 | 1 | < 1 | 18 | 8 | 1 | < 1 | 1 | < 1 |
| Upper abdominal pain | 50 | 23 | 3 | 1 | 1 | < 1 | 30 | 14 | 0 | 0 | ||
| Hypertension | 47 | 22 | 5 | 2 | 0 | 8 | 4 | 2 | 1 | 0 | ||
| Constipation | 41 | 19 | 1 | < 1 | 0 | 43 | 20 | 0 | 0 | |||
| Abdominal pain | 39 | 18 | 5 | 2 | 0 | 30 | 14 | 4 | 2 | 0 | ||
| Dyspepsia | 38 | 18 | 0 | 0 | 13 | 6 | 0 | 0 | ||||
| Dyspnea | 33 | 15 | 5 | 2 | 1 | < 1 | 27 | 13 | 5 | 2 | 0 | |
| Epistaxis | 31 | 14 | 0 | 0 | 10 | 5 | 0 | 0 | ||||
| Cough | 30 | 14 | 1 | < 1 | 0 | 28 | 13 | 3 | 1 | 0 | ||
| Back pain | 26 | 12 | 6 | 3 | 0 | 22 | 10 | 1 | < 1 | 0 | ||
| Arthralgia | 25 | 12 | 1 | < 1 | 0 | 24 | 11 | 2 | 1 | 0 | ||
| Pain in extremity | 25 | 12 | 1 | < 1 | 0 | 33 | 15 | 3 | 1 | 0 | ||
| Hypothyroidism | 23 | 11 | 1 | < 1 | 0 | 2 | 1 | 0 | 0 | |||
| Lacrimation increased | 23 | 11 | 0 | 0 | 23 | 11 | 0 | 0 | ||||
| Pyrexia | 22 | 10 | 0 | 0 | 20 | 9 | 0 | 0 | ||||
| Rash | 19 | 9 | 1 | < 1 | 0 | 22 | 10 | 0 | 0 | |||
Nonhematologic AEs were also more frequent and more commonly of higher grade in the combination arm than in the monotherapy arm, with the exception of hand-foot syndrome, which was more common in the capecitabine arm. The most frequently reported grade 3 or 4 nonhematologic AEs in the combination arm were hand-foot syndrome (16%), asthenia (12%), and fatigue (10%). Hypertension was also reported more frequently in the combination arm (22% v 4%), as was hypothyroidism (11% v 1%); both were mostly low grade in severity. In the capecitabine arm, the most frequently reported grade 3 or 4 nonhematologic AEs were hand-foot syndrome (24%), diarrhea (10%), and vomiting (4%).
Dosing modifications (dosing delays or interruptions or dose reductions) resulting from AEs were more frequent in the combination than the monotherapy arm (88% v 66%), as were treatment discontinuations (49% v 18%). With the combination, neutropenia, thrombocytopenia, and hand-foot syndrome were the most common AEs implicated in dosing modifications (37%, 26%, and 25%, respectively) and treatment discontinuations (9%, 6%, and 5%, respectively). With monotherapy, hand-foot syndrome (35%), diarrhea (14%), and neutropenia (11%) were the most common reasons for dosing modifications, and hand-foot syndrome (3%), diarrhea (1%), and chest pain (1%) led most commonly to capecitabine discontinuation.
There were 23 deaths during the study: 14 in the combination arm and nine in the capecitabine arm (before cross-over). Two patients in the combination arm died as a result of unknown causes, and one patient in the capecitabine arm died as a result of enteritis. The remaining 12 patients in the combination arm and eight in the capecitabine arm died as a result of disease progression.
This study did not meet its primary end point, because sunitinib in combination with capecitabine did not improve PFS relative to capecitabine alone. In addition, there was no improvement in either OS or ORR relative to capecitabine alone.
It should be noted that the outcome in the control arm in this trial was somewhat better than anticipated. The 5.9-month median PFS achieved in this study with capecitabine monotherapy was higher than that observed in five previous phase III studies in patients with previously treated MBC, all of which reported a PFS of 4.1 to 4.2 months.22–26
The frequencies of both hematologic and nonhematologic AEs (with the exception of hand-foot syndrome) were higher with sunitinib plus capecitabine than with capecitabine alone but were consistent with those previously reported for the individual agents in trials in advanced BC.22,27 Grade 3 and 4 AEs, dosing modifications, and treatment discontinuations occurred more frequently in the combination arm.
The inability of sunitinib to enhance the efficacy of capecitabine in this phase III trial is consistent with the results of three other randomized phase III trials in patients with chemotherapy-naive or pretreated MBC, in which results obtained with sunitinib alone or in combination were disappointing.22,28,29 Additionally, in our study, sunitinib did not improve PFS in the subgroup of patients with triple-negative BC (Fig 3), despite promising results with these patients in the earlier phase II study (objective responses in three of 20 patients).13 Results of a more recent phase II study also confirmed that sunitinib monotherapy failed to improve clinical outcomes compared with standard-of-care chemotherapy in patients with triple-negative BC.27
The clinical development program evaluating the efficacy of sunitinib in MBC was established after the report of promising single-agent sunitinib activity in the phase II trial in extensively pretreated patients with MBC13 and the success of bevacizumab combined with chemotherapy in this setting.5 On this basis, a broad development program was implemented to test sunitinib both as a single agent and in chemotherapy-combination regimens typically used in the first-line (taxanes and taxane plus bevacizumab) and later-line settings (capecitabine). After phase Ib studies of the combination regimens, pivotal trials were designed with independent data monitoring committees for safety review and early-stopping rules for futility and efficacy. These studies were based largely on the vascular normalization concept for antiangiogenic therapies proposed by Jain,30 in which pruning of the tumor vasculature, along with a direct antitumor effect, was hypothesized to lead to superior antitumor efficacy compared with chemotherapy alone.
This hypothesis was not supported by the results of the four sunitinib phase III studies in MBC. There are a variety of potential explanations for these outcomes. From the biologic point of view, more recent preclinical results have suggested that antiangiogenic agents may overprune the tumor vasculature, leading to tumor hypoxia and genetic drift to a more aggressive or invasive phenotype.31–33 However, at least one of these predictions has not been borne out in the clinical setting; little difference in metastatic spread was observed between sunitinib and comparator treatment groups in two studies in which this was assessed (one sunitinib phase III study evaluating combination with docetaxel28 and the phase II study in triple-negative BC [Pfizer, data on file]).
Optimal dosing and sequencing of sunitinib with cytotoxic agents have yet to be determined, and this may have affected the results of the sunitinib studies. In combination studies, the optimal biologic dose of a combination of agents (compared with maximum-tolerated dose [MTD] of individual agents) is extremely difficult to define and may not have been reached. Sunitinib was administered at 37.5 mg on the CDD schedule in our study, in contrast to 50 mg per day on the 4-week-on, 2-week-off schedule used in the earlier phase II study in MBC.13 Frequent smaller doses of cytotoxic chemotherapy below the MTD may be more efficacious than standard dosing at MTD levels, and the difficulty of determining the appropriate doses of antiangiogenics combined with chemotherapy dosed in this metronomic manner have been noted.34,35 Finally, in the absence of a reliable biomarker of antiangiogenic activity, pharmacokinetic-pharmacodynamic correlations could not be established, making the selection of optimal doses for treating breast tumors difficult.
On the other hand, the toxicity profile of sunitinib at 37.5 mg per day was unfavorable in combination with chemotherapy, and this may well have affected the outcome of our study as well as other sunitinib phase III studies in MBC. Other potential reasons for these outcomes include the heavily pretreated, heterogeneous patient population studied and the incorrect assumption that MBC is heavily dependent on signaling pathways inhibited by sunitinib. It is unknown to what extent each of these factors contributed to the lack of efficacy in the sunitinib arm in this and other studies.
Moving forward, it is apparent that defining the optimal biologic dose of antiangiogenic agents alone and in combination with chemotherapy is a critical need in oncology drug development. Unfortunately, in the absence of a valid, robust biomarker for angiogenesis inhibition and/or efficacy, this necessary component of antiangiogenic drug development will remain problematic for some time.
In conclusion, the combination of sunitinib and capecitabine failed to improve PFS compared with capecitabine alone when administered to patients with MBC who had received prior therapy with anthracyclines and taxanes and exhibited an unfavorable toxicity profile. The sunitinib plus capecitabine regimen evaluated in this study is not recommended for treatment of this patient population.
Supported by Pfizer, which also funded medical writing support.
Presented in part at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Clinical trial information: NCT00435409.
Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(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: Vanessa Tassell, Pfizer (C); Xin Huang, Pfizer (C); Jolanda Paolini, Pfizer (C); Kenneth A. Kern, Pfizer (C) Consultant or Advisory Role: John P. Crown, Pfizer (C); Véronique Diéras, Pfizer (C), Novartis (C), Roche (C); Thomas Bachelot, Roche (C); Peter A. Fasching, Novartis (C); Richard Greil, Roche (C); Francesco Cognetti, Roche (C), Pfizer (C); Rolf Kreienberg, AstraZeneca (C), Pfizer (C), Novartis (C) Stock Ownership: Vanessa Tassell, Pfizer; Xin Huang, Pfizer; Jolanda Paolini, Pfizer; Kenneth A. Kern, Pfizer Honoraria: John P. Crown, Pfizer; Hans Wildiers, Pfizer; Peter A. Fasching, Novartis; Richard Greil, Roche; Francesco Cognetti, Roche Research Funding: John P. Crown, Pfizer; Thomas Bachelot, Roche; Hans Wildiers, Pfizer; Peter A. Fasching, Novartis; Richard Greil, Roche; George Fountzilas, Roche Expert Testimony: None Patents: None Other Remuneration: John P. Crown, Pfizer
Conception and design: Rolf Kreienberg, Wilson H. Miller Jr, Vanessa Tassell, Xin Huang, Jolanda Paolini, Kenneth A. Kern
Provision of study materials or patients: John P. Crown, Véronique Diéras, Elzbieta Staroslawska, Denise A. Yardley, Thomas Bachelot, Neville Davidson, Hans Wildiers, Peter A. Fasching, Olivier Capitain, Manuel Ramos, Richard Greil, Francesco Cognetti, George Fountzilas, Maria Blasinska-Morawiec, Cornelia Liedtke, Rolf Kreienberg, Wilson H. Miller Jr, Gilles Romieu
Collection and assembly of data: John P. Crown, Thomas Bachelot, Neville Davidson, Peter A. Fasching, Olivier Capitain, Manuel Ramos, Richard Greil, George Fountzilas, Maria Blasinska-Morawiec, Cornelia Liedtke, Wilson H. Miller Jr, Vanessa Tassell, Xin Huang, Gilles Romieu
Data analysis and interpretation: John P. Crown, Véronique Diéras, Elzbieta Staroslawska, Denise A. Yardley, Hans Wildiers, Peter A. Fasching, Richard Greil, Francesco Cognetti, Vanessa Tassell, Xin Huang, Jolanda Paolini
Manuscript writing: All authors
Final approval of manuscript: All authors
| 1. | XELODA (capecitabine) prescribing information, 2006 Roche http://www.gene.com/gene/products/information/xeloda/pdf/pi.pdf Google Scholar |
| 2. | LJ Oostendorp, PF Stalmeier, AR Donders , etal: Efficacy and safety of palliative chemotherapy for patients with advanced breast cancer pretreated with anthracyclines and taxanes: A systematic review Lancet Oncol 12: 1053– 1061,2011 Crossref, Medline, Google Scholar |
| 3. | J Folkman: Tumor angiogenesis: Therapeutic complications N Engl J Med 285: 1182– 1186,1971 Crossref, Medline, Google Scholar |
| 4. | D Hanahan, RA Weinberg: The hallmarks of cancer Cell 100: 57– 70,2000 Crossref, Medline, Google Scholar |
| 5. | K Miller, M Wang, J Gralow , etal: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer N Engl J Med 357: 2666– 2676,2007 Crossref, Medline, Google Scholar |
| 6. | DB Mendel, AD Laird, X Xin , etal: 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 Medline, Google Scholar |
| 7. | TJ Abrams, LB Lee, LJ Murray , etal: SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer Mol Cancer Ther 2: 471– 478,2003 Medline, Google Scholar |
| 8. | LJ Murray, TJ Abrams, KR Long , etal: SU11248 inhibits tumor growth and CSF-1R dependent osteolysis in an experimental breast cancer bone metastasis model Clin Exp Metastasis 20: 757– 766,2003 Crossref, Medline, Google Scholar |
| 9. | S Banerjee, M Dowsett, A Ashworth , etal: Mechanisms of disease: Angiogenesis and the management of breast cancer Nat Clin Pract Oncol 4: 536– 550,2007 Crossref, Medline, Google Scholar |
| 10. | J Paulsson, T Sjöblom, P Micke , etal: Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer Am J Pathol 175: 334– 341,2009 Crossref, Medline, Google Scholar |
| 11. | H Tsuda, D Morita, M Kimura , etal: Correlation of KIT and EGFR overexpression with invasive ductal breast carcinoma of the solid-tubular subtype, nuclear grade 3, and mesenchymal or myoepithelial differentiation Cancer Sci 96: 48– 53,2005 Crossref, Medline, Google Scholar |
| 12. | S Goswami, E Sahai, JB Wyckoff , etal: Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop Cancer Res 65: 5278– 5283,2005 Crossref, Medline, Google Scholar |
| 13. | HJ Burstein, AD Elias, HS Rugo , etal: 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 J Clin Oncol 26: 1810– 1816,2008 Link, Google Scholar |
| 14. | B Escudier, J Roigas, S Gillessen , etal: Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma J Clin Oncol 27: 4068– 4075,2009 Link, Google Scholar |
| 15. | CH Barrios, D Hernandez-Barajas, MP Brown , etal: Phase II trial of continuous once-daily dosing of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma Cancer 118: 1252– 1259,2012 Crossref, Medline, Google Scholar |
| 16. | S George, JY Blay, PG Casali , etal: Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure Eur J Cancer 45: 1959– 1968,2009 Crossref, Medline, Google Scholar |
| 17. | E Raymond, L Dahan, JL Raoul , etal: Sunitinib malate for the treatment of pancreatic neuroendocrine tumors N Engl J Med 364: 501– 513,2011 Crossref, Medline, Google Scholar |
| 18. | TJ Abrams, LJ Murray, E Pesenti , etal: 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 Medline, Google Scholar |
| 19. | CJ Sweeney, EG Chiorean, CF Verschraegen , etal: A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors J Clin Oncol 28: 4513– 4520,2010 Link, Google Scholar |
| 20. | P Therasse, SG Arbuck, EA Eisenhauer , etal: New guidelines to evaluate the response to treatment in solid tumors: European Organisation 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 Crossref, Medline, Google Scholar |
| 21. | Sutent (sunitinib malate) prescribing information, 2012 Pfizer http://www.pfizer.com/files/products/uspi_sutent.pdf Google Scholar |
| 22. | CH Barrios, MC Liu, SC Lee , etal: Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer Breast Cancer Res Treat 121: 121– 131,2010 Crossref, Medline, Google Scholar |
| 23. | KD Miller, LI Chap, FA Holmes , etal: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer J Clin Oncol 23: 792– 799,2005 Link, Google Scholar |
| 24. | ES Thomas, HL Gomez, RK Li , etal: Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment J Clin Oncol 25: 5210– 5217,2007 Link, Google Scholar |
| 25. | AM Brufsky, S Hurvitz, E Perez , etal: RIBBON-2: A randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer J Clin Oncol 29: 4286– 4293,2011 Link, Google Scholar |
| 26. | JA Sparano, E Vrdoljak, O Rixe , etal: Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane J Clin Oncol 28: 3256– 3263,2010 Link, Google Scholar |
| 27. | G Curigliano, X Pivot, J Cortes , etal: A randomized phase II study of sunitinib vs standard of care for patients with previously treated advanced triple-negative breast cancer Presented at the 33rd San Antonio Breast Cancer Symposium December 8-10, 2010 San Antonio, TX (poster P6-12-02) Google Scholar |
| 28. | J Bergh, IM Bondarenko, MR Lichinitser , etal: First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: Results of a prospective, randomized phase III study J Clin Oncol 30: 921– 929,2012 Link, Google Scholar |
| 29. | NJ Robert, MN Saleh, D Paul , etal: Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: A phase III, randomized, open-label trial Clin Breast Cancer 11: 82– 92,2011 Crossref, Medline, Google Scholar |
| 30. | RK Jain: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy Science 307: 58– 62,2005 Crossref, Medline, Google Scholar |
| 31. | JM Ebos, CR Lee, W Cruz-Munoz , etal: Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis Cancer Cell 15: 232– 239,2009 Crossref, Medline, Google Scholar |
| 32. | M Pàez-Ribes, E Allen, J Hudock , etal: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis Cancer Cell 15: 220– 231,2009 Crossref, Medline, Google Scholar |
| 33. | S Loges, M Mazzone, P Hohensinner , etal: Silencing or fueling metastasis with VEGF inhibitors: Antiangiogenesis revisited Cancer Cell 15: 167– 170,2009 Crossref, Medline, Google Scholar |
| 34. | G Klement, S Baruchel, J Rak , etal: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity J Clin Invest 105: R15– R24,2000 Crossref, Medline, Google Scholar |
| 35. | D Hanahan, G Bergers, E Bergsland: Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice J Clin Invest 105: 1045– 1047,2000 Crossref, Medline, Google Scholar |
Acknowledgment
We thank the participating patients and their families as well as the network of investigators, research nurses, study coordinators, and operations staff. Thanks are due to Robert Parideans (Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium) for providing constructive comments on the manuscript. Medical writing support was provided by Wendy Sacks at ACUMED (New York, NY).
Bone scans were performed at baseline, every 12 weeks, and when clinically indicated. Patients with bone-only disease also had a bone scan at 6 weeks after random assignment to distinguish tumor flares from new metastatic bone lesions. QTc intervals were monitored using 12-lead echocardiograms in triplicate at screening, on day 14 of treatment cycle one, as clinically indicated, when sunitinib was discontinued, when capecitabine was discontinued, or as required per local regulations. Left ventricular ejection fraction was assessed using two-dimensional echocardiogram or multigated acquisition scanning at screening, day 1 of cycle two, every 3 months during treatment, as clinically indicated, when sunitinib was discontinued, and when capecitabine was discontinued. Thyroid-stimulating hormone levels were measured at screening and as clinically indicated thereafter.
