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Bevacizumab-capecitabine may favor ER-positive women

Adding the antiangiogenesis agent bevacizumab to capecitabine prolonged time to progression for 106 women who received the combination as first-line therapy for metastatic breast cancer in a multicenter phase II trial.

The advantage was small, but an unplanned subset analysis surprised investigators with the observation that estrogen receptor-positive (ER+) women were about twice as likely to benefit as were those with estrogen receptor-negative (ER-) disease.

At a median follow-up of 12.9 months, overall time to progression was 5.7 months in the initial intent-to-treat analysis. The interval stretched to 8.9 months for 57 ER+ women in the subset analysis, but was only 4 months for 49 ER- women.

Although median overall survival had not yet been reached at the time of the report, it was projected to be more than 16 months for the group as a whole and more than 16.6 months for ER+ women, but only 7.5 months for ER- women.

The objective response rate based on complete and partial responses followed a similar pattern: 38% for the full cohort, 47% for ER+ women, but were 27% for those who were ER-. The differences were statistically significant (P = .0001).

At the time that the study was presented, 10 ER+ women, but none of the ER- women, were still receiving first-line treatment.

"This study suggests the combination is more active in estrogen receptor-positive patients than in estrogen receptor-negative patients, albeit with the caveat that this is an unplanned subset analysis," the lead author, Dr. George W. Sledge, told the audience.

Dr. Sledge, Ballve Professor of Medicine and Pathology at Indiana University, Indianapolis, said the researchers found the disparity when they tried to figure out why the combination did not yield a longer time to progression. The trial barely met its primary end point of 5.6 months, which was better than the 4 months reported for capecitabine (Xeloda) monotherapy at the time the trial was designed. Nonetheless, it was not as long as had been anticipated, and Dr. Sledge characterized the results overall as "somewhat disappointing."

Dr. Stephen R.D. Johnston agreed in a discussion of the study that the findings merited further investigation. "The end point was met by a matter of 3 days, but ... the difference in estrogen receptors is clearly hypothesis generating and of interest," said Dr. Johnston of the Royal Marsden NHS Foundation Trust in Chelsea, England. "The better effect seen in estrogen receptor-positive patients is hitherto unexplained."

Hoffmann-La Roche, maker of capecitabine, sponsored the trial.

Most of the women in the trial were white, with a median age of 56.8 years (range, 36-82 years). All had HER2-negative disease. Although most had received prior neoadjuvant or adjuvant therapy, none had had antiangiogenic or fluoropyrimidine therapy, and none had received adjuvant treatment within the previous 6 months.

Patients received 1,000 mg/m² of capecitabine twice daily for the first 2 weeks of a 3-week cycle and 15 mg/kg of intravenous bevacizumab (Avastin) on the first day of each cycle. Treatment continued until progression, at which point patients were to start second-line therapy with bevacizumab.

Dr. Sledge described the combination as well tolerated, with toxicity in line with expectations for capecitabine (diarrhea, stomatitis, and hand-foot-and-mouth syndrome) and bevacizumab (hypertension). Still to come are reports on analyses of serum samples and on second-line therapy in patients who progressed.

"Analysis of serum levels of VEGF [vascular endothelial growth factor] will be crucial to our understanding of what we have observed," Dr. Johnston commented, alluding to bevacizumab's mechanism of action as an inhibitor of VEGF. "It is not beyond the realm of possibility that VEGF levels are higher in ER-positive women," he said.

Sledge G. et al. Safety and efficacy of capecitabine (C) plus bevacizumab (B) as first-line in metastatic breast cancer. Abstract 1013.

Commentary

The study by Sledge et al. follows a randomized trial that compared capecitabine to capecitabine and bevacizumab in patients who had received prior therapy for metastatic disease. This earlier trial suggested bevacizumab added little benefit in this population. The subsequent Eastern Cooperative Oncology Group (ECOG) E2100 study in patients with no prior therapy for metastatic disease demonstrated, however, that the addition of bevacizumab to paclitaxel resulted in a higher response rate and progression-free survival than did paclitaxel alone. As a result XCALBR was designed to readdress the efficacy of bevacizumab and capecitabine. The results reported by Sledge et al. suggest the combination of capecitabine and bevacizumab results in a modest improvement in the expected response rate and progression-free survival over what might be expected with single-agent capecitabine as reported in previous studies. The most intriguing aspect of the study is the apparent marked increase in response rate and progression-free survival for the subset of patients with estrogen receptor-positive disease. There is no ready explanation for this observation, but it will be studied further with laboratory correlative studies yet to be reported. — William J. Gradishar, M.D.