Bevacizumab Boosts Response to Capecitabine in Metastatic Disease

INDIANAPOLIS—Adding the antiangiogenesis agent bevacizumab (Avastin) to capecitabine (Xeloda) increases the objective response rate—but not progression-free survival—in women with advanced breast cancer, according to a phase III trial. This was the first randomized trial to report results with an antiangiogenic agent in patients with metastatic disease, according to lead investigator Kathy D. Miller, MD, assistant professor of medicine in the division of hematology/oncology at Indiana University School of Medicine, Indianapolis.

The trial compared capecitabine plus bevacizumab to capecitabine alone in heavily pretreated women with metastatic breast cancer. Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), a potent proangiogenic peptide. Dr. Miller said that in a phase II trial of bevacizumab alone in similarly heavily pretreated patients, 17% of the patients either responded or were stable at 22 weeks.

Patients Pretreated With Anthracycline and Taxane

All participants in the current study had been treated with both an anthracycline and a taxane, and the patients generally had received one or two previous therapies for metastatic disease. The one exception was that women who had received adjuvant therapy with an anthracycline and a taxane but had relapsed within 1 year were allowed to enter the trial as their first metastatic therapy.

Patients were required to have completed their last therapy at least 21 days before entering the trial and had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. In an attempt to limit potential toxicity, patients were excluded if they had central nervous system metastases, significant baseline proteinuria (greater than 500 mg/24 hours), or required therapeutic anticoagulation.

A total of 462 patients were enrolled. The median age was 51, and 50% of the participants were ECOG performance status 0. About 50% were estrogen receptor-positive, 42% were progesterone receptor-positive, and 27% were HER2-positive. The median time since diagnosis of metastatic disease was 1.2 years, and 76% of the patients had visceral disease.

Patients were randomized to capecitabine plus bevacizumab or capecitabine alone. Capecitabine was given in standard doses of 1,250 mg/m² twice daily for 14 days in a 21-day cycle. Bevacizumab was given as a single intravenous infusion every 3 weeks at a dose of 15 mg/kg.

The study was designed to identify the primary endpoint of progression-free survival, as determined by an independent review facility. The facility reviewed all images and clinical data, not just those of patients believed to be responding locally.

No Added Toxicity

"The addition of bevacizumab to capecitabine did not alter the incidence or severity of capecitabine toxicity," Dr. Miller said. "Overall, the treatment was quite well tolerated, with approximately 12% of patients in both treatment groups discontinuing therapy due to adverse events." Quality-of-life assessments found no differences between the two groups.

Grade 3 hypertension, requiring initiation or adjustment of antihypertensive therapy, occurred in 17.9% of patients on the combination therapy, and thromboembolic events were "quite rare," she noted, occurring in 7.4% of patients on capecitabine and bevacizumab. There was no difference between the two treatment groups in serious thromboembolic events.

The addition of bevacizumab did increase the risk of minor bleeding; 28.8% of the patients on the combination experienced bleeding vs 11.2% for those on capecitabine alone. There was no difference between the two groups in severe bleeding, which was rare, 0.4% with combination therapy and 1.4% with capecitabine alone.

Proteinuria, typically only grade 1 or 2, occurred in 22.3% of patients taking capecitabine plus bevacizumab. Congestive heart failure occurred in two (0.9%) patients on single-agent therapy vs seven (3.1%) patients on the combination.

The small number of cardiac events in the trial limits the ability to determine conclusively whether they are related to bevacizumab, Dr. Miller said. "However, as this was seen in our phase II experience as well, further studies will be needed to determine if there is an association between this toxicity and other known cardiac risk factors, such as extent of previous anthracycline exposure or left chest wall radiation."

Short-Lived Responses

The objective response rate was clearly increased in the bevacizumab-capecitabine group, Dr. Miller reported, with an overall investigator-designated objective response rate of 30.2% in the combination group vs 19.1% in the capecitabine-alone arm. (By independent review, the rates were 19.8% for the combination vs 9.1% for capecitabine alone.)

Many of these additional responses were short-lived, however, resulting in a nonstatistically significant decrease in the median duration of response in the combination group (4.96 months for the combination compared to 6.7 months for capecitabine alone). However, the proportion of long-term responders was identical in both groups. There was no difference in progression-free survival: 4.86 months for patients taking capecitabine plus bevacizumab vs 4.17 months for those on the single-agent therapy (hazard ratio, 0.98).

Potential Correlates

Subset analysis of a group of patients with more detailed pharmacokinetic sampling showed no differences in the pharmacokinetic parameters of capecitabine with the addition of bevacizumab. Dr. Miller noted that tissue arrays have been created from primary tumor samples and are being analyzed for a large number of potential correlates of angiogenic activity, tumor proliferation, and response by a pathologist who is blinded to both treatment assignment and patient response.

"The addition of bevacizumab to capecitabine in this heavily pretreated population does not result in an improvement in progression-free survival," Dr. Miller said. "However, the near doubling of the response rate with bevacizumab that had first been reported in this patient population in a phase II study is an important proof of concept of the potential value of antiangiogenic therapies in general and therapies that target VEGF specifically."

She suggested that future trials should try to take advantage of this activity in less heavily pretreated advanced patients and should specifically try to develop methods to identify patients most likely to benefit from this form of therapy. One such trial, she noted, is the ongoing ECOG 2100 trial, which is randomizing patients with newly diagnosed metastatic disease to paclitaxel alone or to paclitaxel with bevacizumab, a combination that has shown strong synergy in preclinical studies. This trial also includes a number of correlates in primary tumor samples, as well as serum and urine, to try to identify those patients most likely to benefit from VEGF-targeted treatments.