Primary Endpoint Not Met for Eribulin vs Capecitabine in Breast Cancer 


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While a global phase III trial failed to meet its primary endpoint in showing an overall or progression-free survival benefit for eribulin (Halavan) in metastatic breast cancer, a trend toward greater efficacy than capecitabine (Xeloda) was observed, researchers reported at the 2012 San Antonio Breast Cancer Symposium.1 Eribulin is a nontaxane microtubule dynamics inhibitor.

Novel Mechanism

“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,” said Peter A. Kaufman, MD, Associate Professor of Medicine at Dartmouth-Hitchcock Norris Cotton Cancer Center in Lebanon, New Hampshire.

Dr. Kaufman noted that eribulin is the only chemotherapeutic agent that has demonstrated a significant survival benefit in heavily pretreated metastatic breast cancer patients. The drug’s novel mechanism of action is distinct from most other tubulin-targeted agents.

The earlier EMBRACE trial did show a 2.5-month survival benefit over standard treatment as selected by the treating physician, leading to the FDA’s approval of the drug in November 2010, for patients with metastatic disease who have received at least two prior chemotherapy regimens with anthracyclines and taxanes.

Current Study

Study 301 examined whether eribulin would be effective for patients less heavily pretreated, with a standardized control arm, capecitabine. Half of the 1,102 patients had received only one prior regimen for advanced disease. Patients were randomly assigned to receive eribulin mesylate at 1.4 mg/m2 on days 1 and 8 every 21 days or capecitabine at 1,250 mg/m2 twice daily on days 1 to 14, every 21 days. The coprimary endpoints were overall survival and progression-free survival.

Dr. Kaufman reported that median overall survival was 15.9 months with eribulin and 14.5 months with capecitabine, for a 12% reduction in risk that was not statistically significant (P = .056). The statistical plan for the study determined the P values for superiority to be ≤ .0372 for overall survival and ≤ .01 for progression-free survival.

Overall survival rates per year were 64.4% with eribulin vs 58.0% with capecitabine at 1 year (P = .035); 32.8% vs 29.8%, respectively, at 2 years (P = .324); and 17.8% vs 14.5%, respectively, at 3 years (P = .175).

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

Median progression-free survival was 4.1 months with eribulin and 4.2 months with capecitabine (P = .305), with no difference between independent and investigator reviews. The clinical benefit rates and drug exposure were similar for the two drugs by both review processes.

Subset Analyses

Prespecified exploratory analyses suggested that particular patient subgroups may derive greater therapeutic benefit with eribulin. Trends favoring eribulin were observed in patients with triple-negative disease, estrogen receptor–negative disease, and HER2-negative disease, but further studies would be required to confirm any benefit in these subgroups.

The adverse event profiles of the two drugs were consistent with their previously known side effects. Compared with capecitabine recipients, patients in the eribulin group had a higher incidence of neutropenia (54% vs 16%), but febrile neutropenia was “acceptably low” among eribulin recipients (2% vs < 1%). In contrast, hand-foot syndrome occurred far more frequently in the capecitabine group (45% vs < 1%).

The researchers are currently compiling data from the quality-of-life analysis, which should help guide future studies of eribulin in metastatic breast cancer, Dr. Kaufman said.

“Although we did not meet our primary endpoints, 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.” 

Disclosure: Dr. Kaufman has received a research grant and acted as a consultant for Eisai.

Reference

1. Kaufman PA, Awada A, Twelves C, et al:  A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. 2012 San Antonio Breast Cancer Symposium. Abstract S6-6. Presented December 7, 2012.


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