Overall Survival Trend Seen with Eribulin versus Capecitabine

March 2013, Highlights

A trend toward improved overall survival (OS) with eribulin mesylate (Halaven) was demonstrated in the global phase 3 clinical trial comparing this newer agent with capecitabine (Xeloda) in patients with previously treated metastatic breast cancer.

“We did not show a statistically significant superiority of eribulin over capecitabine, which was our goal, but eribulin demonstrated a trend favoring an overall survival benefit over capecitabine, a widely accepted and used standard therapy in this setting,” said Peter A. Kaufman, MD, Associate Professor of Medicine at Dartmouth in Lebanon, NH.

“Eribulin is the only chemotherapeutic agent with a demonstrated survival benefit for patients with heavily pretreated metastatic breast cancer,” Dr Kaufman noted. The drug has a novel mechanism of action that is distinct from most other tubulin-targeted agents.

In the previous phase 3 Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389 (EMBRACE) trial, treatment with eribulin improved OS by 2.5 months versus current treatments (physician’s choice) in patients who were previously treated for metastatic disease (Cortes J, et al. Lancet. 2011;377:914-923). This study led to the US Food and Drug Administration approval of eribulin for patients with metastatic breast cancer who have received at least 2 previous chemotherapy regimens that included an anthracycline and a taxane.

The global, randomized, open-label, multicenter, phase 3 trial (Study 301) examined whether eribulin would be effective earlier in the treatment course for patients with locally advanced or metastatic disease. Eribulin was compared with capecitabine, which is widely used in all lines of therapy for metastatic breast cancer and is approved in patients whose disease is resistant to paclitaxel (Taxol) and to an anthracycline-containing regimen.

The study included 1102 patients with locally advanced or metastatic breast cancer who had received ≤3 previous chemotherapy regimens (≤2 regimens for advanced disease) and who had received previous therapy with an anthracycline and a taxane in the neoadjuvant or adjuvant setting or for locally advanced or metastatic disease. Half the population had received only 1 previous regimen for advanced disease and 28% had received only 2 previous regimens.

Almost all patients (84%-88%) had visceral disease; 66% had HER2-negative, approximately 40% had estrogen receptor (ER)-negative, and 27% had triple-negative tumors.

Patients were randomly assigned to receive eribulin 1.4 mg/m2 on days 1 and 8 every 21 days or capecitabine 1250 mg/m2 twice daily on days 1 to 14, every 21 days. Strati­fication was by geographic region and HER2 status. The coprimary end points were OS and progression-free survival (PFS).

Improved Overall Survival Trend Shown

The median OS was 15.9 months with eribulin and 14.5 months with capecitabine, for a 12% reduction in risk that trended toward, but did not meet, statistical significance (P = .056).

“There was an early separation of the curve and a trend, but it’s not statistically significant,” Dr Kaufman noted.

The OS rate was 64.4% with eribulin versus 58.0% with capecitabine at 1 year (P = .035); 32.8% versus 29.8%, respectively, at 2 years (P = .324); and 17.8% versus 14.5%, respectively, at 3 years (P = .175), he reported at an oral session and at a press briefing, where the results were highlighted.

Median PFS was 4.1 months with eribulin and 4.2 months with capecitabine (hazard ratio [HR], 1.079; P = .305).

The assessments were similar by independent and investigator reviews.

The objective response rates were 11% and 12%, respectively, by independent review and 16% and 20%, respectively, by investigator review. The clinical benefit rates were 26% and 27%, respectively, by independent review and 33% and 34%, respectively, by investigator review.

Study medication exposure was similar between the arms. The median duration of treatment was 4.1 months with eribulin and 3.9 months with capecitabine. The median numbers of treatment cycles were 6 and 5, respectively, and the relative dose intensities were 87% and 86%, respectively, Dr Kaufman reported.

Some Subgroups May Benefit More

“Prespecified exploratory analyses suggested that particular patient subgroups may derive greater therapeutic benefit with eribulin, and this may warrant further study,” Dr Kaufman said. Trends favoring eribulin over capecitabine were observed in 3 subsets of patients (Figure):

Overall Survival, by Receptor Status: Eribulin versus Capecitabine
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  • Triple-negative: HR, 0.702 (95% confidence interval [CI], 0.545-0.906); median OS, 14.4 months versus 9.4 months, respectively
  • ER-negative: HR, 0.779 (95% CI, 0.635-0.955); median OS, 14.4 months versus 10.5 months, respectively
  • HER2-negative: HR, 0.838 (95% CI, 0.715-0.983); median OS, 15.9 months versus 13.5 months, respectively.

Of note, in the triple-negative subset of 284 patients, who typically have aggressive disease, the median OS was 14.4 months with eribulin compared with 9.4 months with capecitabine, Dr Kaufman said.

The median OS was 14.4 months versus 10.5 months for ER-negative patients; and 15.9 months versus 13.5 months, respectively, for HER2-negative patients.

Adverse Event Profile

The adverse event profiles of the 2 drugs were consistent with their previously known side effects. There was a higher incidence of neutropenia with eribulin than with capecitabine, but febrile neutropenia occurred in only 2% of patients receiving eribulin (vs <1% in patients taking capecitabine), “which is low and acceptable,” Dr Kaufman said.

As expected, capecitabine was associated with more hand-foot syndrome than treatment with eribulin and slightly more diarrhea, nausea, and vomiting. The researchers are currently compiling data from the quality-of-life analysis, which should help guide future studies of eribulin in patients with metastatic breast cancer, he noted.

“Although we did not meet our primary end points, this is still the first study demonstrating the activity of eribulin in earlier lines of treatment of metastatic breast cancer,” Dr Kaufman said. “Eribulin is an active therapy in this setting, and overall it has potentially comparable activity to capecitabine, which is a widely used treatment in this patient population.”

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