VIENNA – Paclitaxel may be a better partner for bevacizumab than capecitabine for treating chemotherapy-naive women with HER2-negative breast cancer, the first efficacy results from the prospective phase III TURANDOT trial suggest.

The secondary end points of progression-free survival (11 months vs. 8.1 months, hazard ratio 1.36, P = .0052) and objective response rates (44% vs. 27%, P less than .0001) were significantly better with bevacizumab (Avastin) and paclitaxel than with bevacizumab and capecitabine (Xeloda).

The primary end point of overall survival did not show a statistically significant difference between the combinations (HR 1.04), however. Overall survival was 30.5 months with bevacizumab plus paclitaxel and 26 months with bevacizumab plus capecitabine (HR 1.04, P = .059). The respective overall survival rates were 81% versus 79% at 1 year, 68% versus 70% at 2 years, and 60% versus 55% at 3 years.

"Many agents are available for first-line treatment of HER2-negative inoperable locally advanced or metastatic breast cancer, but currently there is no gold standard," Dr. Christoph Zielinski said Sept. 29 at the European Society for Medical Oncology Congress.

Dr. Zielinski, of the Medical University of Vienna, noted that progression-free survival and overall response rates were significantly improved when bevacizumab was combined with first-line weekly paclitaxel in the E2100 trial (J. Clin. Oncol. 2009;27:4966-72) or with capecitabine in the RIBBON-1 trial (J. Clin. Oncol. 2011;29:1252-60), but there was no head-to-head comparison.

Both combinations have been registered for use in Europe, although the National Institute for Health and Clinical Excellence in the United Kingdom has rejected both on the grounds of no clear overall survival benefit and the cost-to-benefit ratio.

In the United States, the Food and Drug Administration withdrew an indication for bevacizumab in metastatic breast cancer after subsequent clinical trials failed to confirm the margin of benefit seen in E2100.

TURANDOT Offers Direct Comparison

TURANDOT (Capecitabine and Bevacizumab Randomized Against Avastin and Taxol) is the first prospective trial directly comparing bevacizumab and paclitaxel versus bevacizumab and capecitabine as first-line treatment for inoperable locally advanced or metastatic breast cancer.

The international, multicenter, double-blind trial involved 564 women (median age 59 years) who had received no prior chemotherapy in the advanced setting. Prior adjuvant or neoadjuvant chemotherapy, radiotherapy, or both were permitted only if the regimens used had been completed at least 6 months before enrollment.

Women were treated until progression or until unacceptable toxicity, with 285 receiving bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m² on days 1, 8 and 14 of a 4-week cycle. The remaining 279 women received bevacizumab 15 mg/kg on day 1 plus capecitabine 1,000 mg/m² on days 1-14 of a 3-week cycle. The primary objective was to demonstrate that the latter combination was noninferior to bevacizumab plus paclitaxel.

The safety population included 561 women, with 51% versus 64% of patients discontinuing bevacizumab treatment in the paclitaxel and capecitabine arms, respectively. A similar percentage (16% vs. 14%) discontinued bevacizumab because of adverse events, and two and four patients in each group died.

A higher percentage of patients in the bevacizumab-capecitabine arm than in the bevacizumab-paclitaxel arm discontinued chemotherapy due to disease progression (63% vs. 32%), although there were fewer discontinuations due to adverse events (15% vs. 34%). Chemotherapy had to be modified because of toxicity in 46% and 54% of cases, respectively.

Subgroup analysis of overall survival showed no difference between the two treatment arms. Final overall survival results are expected in 2014.

The time to achieve a response was significantly shorter with the paclitaxel-containing regimen (HR 0.58, P = .0002), although the time to treatment failure and duration of response was not significantly different.

Adverse events were consistent with those previously reported with the agents used, with higher rates of hematologic events and neuropathy associated with the paclitaxel-containing regimen and more diarrhea, anemia, hypertension, and hand-foot syndrome with the capecitabine-containing regimen.

"PFS and response rates corroborate results of previous phase III trials," Dr. Zielinski said, adding, "treatment selection depends on each individual’s priorities."

Paclitaxel Might Be More Active

Providing an independent comment on the trial, Dr. Javier Cortes said: "Bevacizumab-based therapy is a good first-line treatment option for patients with HER2-negative metastatic breast cancer."

Dr. Cortes, of the Vall d’Hebron Institute of Oncology in Barcelona, added: "If bevacizumab is used, paclitaxel might be more active than capecitabine.

"Differences in overall survival between paclitaxel and capecitabine when combined with bevacizumab are unlikely to be found, but it does not mean that both schedules are the same."

Roche sponsored the TURANDOT trial. Dr. Zielinski disclosed receiving honoraria from the company. Dr. Javier Cortes has received honoraria from Roche.

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