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Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp. 792-799 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.098 Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast CancerFrom the Indiana University, Indianapolis, IN; University of California Los Angeles, Los Angeles; Kaiser Northern California, Vallejo; Genentech Inc, South San Francisco; University of California San Francisco, San Francisco, CA; US Oncology, Houston, TX; Rush-Presbyterian-St Luke's Medical Center, Chicago, IL; Duke University, Durham, NC; Memorial Sloan Kettering Cancer Center, New York, NY; Case Western University, Cleveland, OH Address reprint requests to Kathy D. Miller, MD, Indiana University Cancer Pavilion, 535 Barnhill Dr, RT-473, Indianapolis, IN 46202; e-mail: kathmill{at}iupui.edu
PURPOSE: This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. PATIENTS AND METHODS: Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility. RESULTS: From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment—Breast were comparable in both treatment groups. CONCLUSION: Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.
Metastatic breast cancer (MBC) remains a devastating disease, claiming the lives of more than 40,000 women in the United States each year.1 Though an expanding array of active agents has become available for the treatment of metastatic disease, overall survival has changed little in the last half century.2 While response rates  30% are routinely achieved in previously untreated patients, response rates decrease significantly in patients previously exposed to chemotherapy.3 Further therapeutic advances require new strategies that are based on an understanding of breast cancer biology. Invasion and metastasis of breast cancer depends on angiogenesis, the formation of new blood vessels that nourish the tumor.5,6 Extensive laboratory data suggest that angiogenesis plays an essential role in breast cancer development, invasion, and metastasis.7–10 Clinicopathologic correlations confirm this role. Breast cancer vascularity, quantified by tumor microvessel density, predicts tumor shedding at the time of surgery,11 bone marrow micrometastases,12 recurrence, and overall survival.13–15 This nascent vascular network provides a unique opportunity for therapeutic intervention. Vascular endothelial growth factor (VEGF) is among the most potent stimulators of angiogenesis. In addition to endothelial cell mitogenesis and migration, VEGF inhibits endothelial cell apoptosis and supports maintenance of the newly formed tumor vasculature. VEGF produces other biologic effects, including induction of proteinases that remodel extracellular matrix, increased vascular permeability, vasodilation, and inhibition of antigen-presenting dendritic cells.16 Bevacizumab (Avastin; Genentech, South San Francisco, CA), a humanized monoclonal antibody (mAb) directed against all isoforms of VEGF-A, inhibits growth of human tumors in animal models.17 A phase II study of bevacizumab monotherapy in 75 patients with previously treated MBC reported a 9.3% objective response rate, with 17% of patients responding or stable at 22 weeks; four patients continued therapy without progression for more than 12 months.18 Bevacizumab, alone and in combination with chemotherapy, was well tolerated, with hypertension, proteinuria, thrombosis, and bleeding being the most commonly reported toxicities.19–22 Given the efficacy and minimal toxicity in the phase II studies, this randomized phase III study was initiated to compare capecitabine monotherapy with the combination of capecitabine plus bevacizumab in patients with previously treated MBC.
Patient Eligibility Women with histologically or cytologically confirmed MBC were eligible if they had received prior therapy with both an anthracycline and a taxane, and at least one, but no more than two, prior chemotherapy regimens for metastatic disease. If relapse occurred within 12 months of completing adjuvant anthracycline and taxane therapy, patients were eligible without intervening chemotherapy. Patients with HER2-positive disease (3+ protein expression by immunohistochemistry or gene amplification by fluorescence in situ hybridization) must have progressed following trastuzumab. Additional inclusion criteria included bidimensionally measurable disease with at least one lesion measuring 2 cm; Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate renal, hepatic, and hematologic function. Patients were excluded if they had any history or radiographic evidence of CNS disease; screening head computed tomography or brain magnetic resonance image was required. Patients could not have other primary malignancy except basal cell carcinoma of the skin or in situ cervical cancer within 5 years, major surgery within 4 weeks, other antitumor therapy within 21 days, nonhealing wound or fracture, infection requiring parenteral antibiotics, or clinically significant cardiovascular disease. Therapeutic anticoagulation, regular nonsteroidal anti-inflammatory medication, and aspirin (> 325 mg/d) were prohibited, but prophylactic anticoagulants to maintain a vascular access device were permitted. Concurrent administration of bisphosphonates was allowed if initiated at least 21 days before study entry. Women of reproductive potential were required to use effective contraception. Local institutional review boards approved the protocol, and patients provided written informed consent before screening.
Treatment Plan
Patients randomized to the combination arm received bevacizumab (15 mg/kg) intravenously on day 1 of each 3-week cycle. Initially, bevacizumab was infused over 90 minutes. If no infusion-related reactions occurred, subsequent infusions were reduced to 60, then 30 minutes. Premedication was optional. Treatment was interrupted for proteinuria Patients continued therapy for a maximum of 35 cycles or until disease progression or prohibitive toxicity. Patients without progression at the completion of 35 cycles could continue the same treatment on an extension study. Patients randomized to the combination arm could continue bevacizumab, either alone or with other therapies, after initial disease progression. Patients randomly assigned to capecitabine monotherapy could not receive bevacizumab at any time.
Safety and Efficacy Assessments
Pharmacokinetics
Quality of Life
Statistical Analysis Sample size calculations assumed a two-sided log-rank test, 90% power at the 5% significance level, a hazard ratio of bevacizumab versus control of 0.667 (improvement in median PFS from 4 to 6 months), and one interim analysis at 50% information time, which required 265 events. Enrollment of 400 patients would allow analysis when 66% of patients had progressed. The study would stop at the interim analysis if the hazard ratio for PFS was less than 0.5 (1-sided P < .0001) or greater than 1, corresponding to an asymmetric stopping boundary (the efficacy interim analysis was later cancelled due to delayed availability of IRF assessments). An independent data monitoring committee reviewed all deaths, and serious and targeted adverse events (grade 3 and 4 diarrhea, grade 3 hand-foot syndrome, grade 3 and 4 bleeding, and any thrombosis) monthly until December 2001. The protocol was extended to enroll approximately 50 additional patients for PK assessment. Data cutoff for this analysis was 28 June 2002—3 months after the last patient was randomly assigned.
Random assignment was stratified for Eastern Cooperative Oncology Group performance status (0 or 1), number of prior chemotherapy regimens for metastatic disease (0 or
Patient Population A total of 462 patients were randomly assigned between November 2000 and March 2002 at 96 US centers: 230 to capecitabine alone and 232 to combination treatment. Fifteen patients randomly assigned to capecitabine alone and three patients randomized to combination treatment never received study treatment and were not included in the safety analysis. Overall, 93 (20%) of the treated patients failed to meet one or more of the eligibility criteria; major reasons for ineligibility included prior therapy within 21 days (n = 27), more than two regimens for metastatic disease (n = 19), CNS involvement (n = 10), laboratory values out of range (n = 10), no chemotherapy for metastatic disease with relapse more than 12 months from adjuvant therapy (n = 4), and no prior anthracycline or taxane (n = 3). Analysis of major end points excluding ineligible patients did not affect the outcome (data not shown); therefore, results presented include all randomized patients. Baseline demographic and tumor characteristics were well balanced between treatment groups (Table 1).
Efficacy The objective response rate (ORR) significantly improved with addition of bevacizumab, as determined by both the IRF (19.8% [95% CI, 14.7% to 25.0%] v 9.1% [95% CI, 5.4% to 12.9%]; P = .001) and the investigators (30.2% [95% CI, 24.3% to 36.1%] v 19.1% [95% CI, 14.1% to 24.2%]; P = .006). The IRF and investigator disagreed on disease progression in 105 patients (22.7%): investigator-determined progression was not confirmed by the IRF in 79 patients, most commonly when progression was determined by physical examination. In 26 patients, progression was determined by IRF review but not investigator review. The combination of capecitabine and bevacizumab did not increase PFS as determined by the IRF (hazard ratio, 0.98 [95% CI, 0.77 to 1.25]; P = .857; Figure 1A) or the investigator (data not shown). The median duration of response and the proportion of subjects with responses of more than 4 months' duration were similar in the two treatment groups (Fig 1B)
At data cutoff, 38% of patients had died. The majority of deaths (95.2%) were due to progressive disease. Two patients in the capecitabine-alone group died while on therapy: one patient suffered a cardiopulmonary arrest shortly after initiating treatment, and a second died from a presumed pulmonary embolus during cycle 2. No treatment-related deaths occurred during initial therapy in the combination arm. Median overall survival was similar in the two treatment groups (Fig 1C).
Safety
Hypertension was more common in the combination arm but was generally managed with medical therapy; no patient experienced grade 4 hypertension (Table 3). Four patients discontinued bevacizumab because of hypertension. Changes in preinfusion mean systolic and diastolic blood pressure were –2.6 and –0.7 mmHg, respectively, in the capecitabine alone group, compared with +5.5 and +4.6 mmHg in the combination group. The risk for developing hypertension correlated only with bevacizumab treatment; no relationship was observed with duration of therapy or pre-existing hypertension.
Proteinuria was more common in patients receiving combination therapy but was rarely clinically significant. Two patients discontinued treatment because of grade 3 proteinuria. One patient subsequently developed nephrotic syndrome; renal biopsy revealed collapsing glomerulopathy. She had mild renal insufficiency at baseline (creatinine clearance 41 mL/min) and had received pamidronate, a drug known to be associated with collapsing glomerulopathy,25,26 for nearly 2 years. The incidence of proteinuria in patients receiving concurrent bevacizumab and pamidronate was 33.9%, compared with 18.5% in patients receiving bevacizumab without pamidronate (P = .026). Additionally, patients on the combination arm with proteinuria were more likely to report hypertension (47.1% v 16.9%). Proteinuria was rare in patients receiving capecitabine monotherapy, and there was no increase with pamidronate treatment. Bevacizumab clearly increased minor mucosal bleeding. There were no grade 3 or 4 episodes of epistaxis in either patient group. However, a difference between treatment arms did occur for grades 1 or 2 epistaxis, with three events (1.4%) in the capecitabine treatment arm and 36 events (15.7%) in the capecitabine plus bevacizumab arm. Grade 3 or serious bleeding was rare and not different between treatment groups. Grade 4 hemorrhage was not reported. The incidence of thromboembolic events was infrequent and similar in the two treatment groups. Nine patients in the study developed grade 3 or 4 congestive heart failure or cardiomyopathy: two in the capecitabine-alone group and seven in the combination group (Table 4). Baseline left ventricular ejection fraction (LVEF) was measured in 418 patients. Mean LVEF and number of patients with baseline LVEF less than 50% (14.9% capecitabine alone v 12.2% combination) were similar in the two treatment groups. LVEF was less than 50% at baseline in three of six bevacizumab-treated patients who developed congestive heart failure or cardiomyopathy (baseline LVEF not measured in one), and in one of two control patients. Cardiac symptoms improved with medical management in all but one patient. Two of seven affected patients continued to receive bevacizumab therapy.
Seventy patients continued bevacizumab, either alone or in combination with other therapies, after initial progression. There were no new toxicities observed or safety issues that emerged in any of the patients.
PK
QOL
We report the first completed phase III trial of antiangiogenic therapy in patients with MBC. The patients enrolled had received prior anthracycline and taxane therapy; most had visceral involvement. Treatment was based on capecitabine, the only US Food and Drug Administration-approved chemotherapeutic in this refractory population. The addition of bevacizumab to capecitabine therapy was generally well tolerated, with no significant increase in capecitabine-related toxicities. Though the majority of patients required capecitabine dose modification, excellent dose-intensity was maintained. The incidence of grade 3 hand-foot syndrome in our study (approximately 25%) is higher than in previous reports (approximately 10% to 13%).4,27 This difference may be attributed to increased investigator awareness of hand-foot syndrome and the different toxicity grading scales used. We assessed toxicity according to NCI-CTC criteria, which defines skin changes with pain interfering with function as a grade 3 toxicity. In contrast, previous studies used the NCIC-CTC (National Cancer Institute of Canada CTC) scale, which defines pain interfering with function as a grade 2 toxicity. Bevacizumab-associated toxicities were well predicted by the phase II experience and rarely limited therapy.18,22,28 Hypertension requiring initiation or adjustment of prior antihypertensive therapy occurred in 18% of patients. Proteinuria developed in 22% of patients (predominantly grade 1). An apparent association between hypertension and proteinuria was noted in the combination arm: patients with proteinuria were more likely to develop hypertension (47.1% v 16.9%; P < .001) than patients who did not develop proteinuria. Thromboembolic events were infrequent and similar in the two treatment arms. Bleeding was primarily limited to minor mucosal oozing that did not require medical intervention; serious hemorrhage was rare and was not increased in bevacizumab-treated patients. An apparent increase (two v seven cases) in congestive heart failure and cardiomyopathy occurred in the bevacizumab-treatment arm, but the small number of events makes this association uncertain. All patients had prior anthracycline exposure, three of seven had received left chest wall radiation, and three had an LVEF less than 50% at study entry. In a previous phase II study, two of 75 breast cancer patients treated with bevacizumab monotherapy also developed congestive heart failure. Both had received prior anthracyclines and chest wall radiation; one had metastatic involvement of the pericardium.18 The association between the cardiac dysfunction, prior anthracycline exposure, and bevacizumab therapy is unclear. The addition of bevacizumab to capecitabine clearly increased response rates, whether assessed by the IRF or the investigators, without significantly adding to the overall toxicity of the treatment regimen. Despite improvement in ORR, the duration of the responses was short with respect to PFS, and the proportion of long-term responders was similar in the two groups. The challenge now is to better understand how to exploit this activity. While it is possible that a negative interaction occurred between bevacizumab and capecitabine, the increased ORR and absence of augmented capecitabine toxicity makes this an unlikely explanation. There are several possible explanations why the study did not meet its primary end point. This study used bevacizumab as a general therapy given on a population basis, rather than as a targeted therapy given to patients with a specific molecular phenotype. Methods to select those patients most likely to benefit from VEGF-directed therapies need to be developed. Analysis of primary tumor samples for pathologic factors correlating with response to bevacizumab is ongoing. Initial results were limited by the small number of patients contributing samples, and did not clearly identify a patient subset more likely to benefit from combined therapy.29 Full results of correlative pathology studies will be reported separately. The results of this study suggest that the optimal time to intervene with an antiangiogenic agent may be earlier in the course of disease. Angiogenic pathways become more numerous and redundant as breast cancer progresses.30 Thus, it is unlikely that inhibition of a single factor or pathway would produce a sustained clinical effect in patients with previously treated, highly refractory disease. It is also unlikely that advanced breast cancer is VEGF-independent, but increased expression of other angiogenic factors render VEGF less critical for continued tumor growth. As such, future trials should focus on patients with less advanced disease when fewer redundant angiogenic pathways exist. In a recently completed study, addition of bevacizumab to first-line chemotherapy (irinotecan, FU/leucovorin) in patients with metastatic colorectal cancer increased ORR, extended the duration of response, and prolonged PFS and overall survival.31 The increased ORR in our study and the results of the metastatic colorectal cancer trial further support the investigation of bevacizumab in patients with less refractory breast cancer. A phase III trial evaluating bevacizumab in combination with paclitaxel in chemonaive MBC patients (E2100) completed accrual in May 2004.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: James D. Reinmann, Genentech; Amy P. Sing, Genentech; Virginia Langmuir, Genentech. Consultant/Advisory Role: Kathy D. Miller, Genentech; Frankie A. Holmes, Amgen, Pfizer, Tibotec; Melody A. Cobleigh, Genentech; Amy P. Sing, Genentech; Virginia Langmuir, Genentech. Stock Ownership: James D. Reinmann, Genentech; Amy P. Sing, Genentech; Virginia Langmuir, Genentech. Honoraria: Kathy D. Miller, Genentech; Frankie A. Holmes, Amgen, Pfizer, Roche; Melody A. Cobleigh, Genentech; Maura Dickler, Genentech; Beth A. Overmoyer, AstraZeneca, Aventis; Hope S. Rugo, Genentech. Research Funding: Kathy D. Miller, Genentech; Melody A. Cobleigh, Genentech; P. Kelly Marcom, Genentech; Maura Dickler, Genentech; Hope S. Rugo, Genentech. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue.
The authors would like to acknowledge the support of Mary Jean Pramik in the preparation of this manuscript.
Supported by Genentech Inc. A full list of participating investigators and institutions can be found in the Appendix. Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 11-14, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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30. Relf M, LeJeune S, Scott PA, et al: Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57:963–969, 1997 31. Hurwitz H, Fehrenbacher L, Cartwright T, et al: Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): Results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC. Proc Am Soc Clin Oncol 22, 2003 (abstr 3646) Submitted May 18, 2004; accepted October 25, 2004. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
bevacizumab + capecitabine/
2 test; overall survival comparisons used an unstratified log-rank test. Exploratory analyses to gauge the impact of potential prognostic factors on PFS were conducted using Cox regression to estimate treatment effect within various subgroups. 
