Xeloda/Avastin moderately active in advanced breast cancer

ASCO—As a first-line treatment of advanced breast cancer, the combination of bevacizumab (Avastin) and capecita-bine (Xeloda) was moderately active in the phase II XCALIBr trial, sponsored by Roche. George Sledge, MD, of Indiana University School of Medicine, reported the results at the ASCO 2007 annual meeting (abstract 1013).

The trial, which included 106 HER2-negative, previously untreated metastatic breast cancer patients, did meet its primary endpoint, which was to improve upon the 4 month time to progression seen with first-line capecitabine alone in previous studies to more than 5.6 months. However, according to Dr. Sledge, "the results were somewhat disappointing, as compared with the previous E2100 trial of bevacizumab plus paclitaxel."

Patients received capecitabine 1,000 mg/m2 twice daily on days 1 to 15 and bevacizumab 15 mg/kg on day 1, every 3 weeks until disease progression. After progression, patients received second-line therapy with bevacizumab plus either paclitaxel or vinorelbine (Navelbine).

The capecitabine/bevacizumab combination yielded a 38% overall response rate. With 12.9 months of follow-up, median time to progression was 5.7 months, and median overall survival has not yet been reached, Dr. Sledge reported.

The combination was well tolerated. Capecitabine at 1,000 mg/m2 twice daily was considerably less toxic than the 1,250 mg/m2 twice-daily dose that was studied in previous trials, he noted. The most common grade 3 adverse events were hand-foot syndrome (13%), diarrhea (8%), and hypertension (5%). There were two drug-related deaths, one due to cerebral hemorrhage and one due to sepsis.

In an exploratory analysis, investigators attempted to learn why this combination was not more effective. They found that patients with estrogen-receptor (ER)-positive tumors had significantly better outcomes than ER-negative patients (P < .0001). Response rates were 47% among ER-positive patients but only 27% among ER-negative patients; time to progression was 8.9 months vs 4.0 months, respectively. In the ER-positive subjects, overall survival has not been reached after 16.6+ months of treatment, but was limited to 7.5 months in ER-negative patients.

"Ten ER-positive patients are still on this treatment, having had a median of 19 cycles, whereas no ER-negative patients are still on this front-line treatment," Dr. Sledge commented. "This suggests that the combination of capecitabine plus bevacizumab is more active in ER-positive patients." He emphasized that the subgroup analysis is only exploratory and should not be considered in clinical decision-making.