Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study

Javier Cortes MD a, Joyce O'Shaughnessy MD b, David Loesch MD c, Joanne L Blum MD b, Linda T Vahdat MD d, Katarina Petrakova MD e, Philippe Chollet MD f, Alexey Manikas MD g, Veronique Diéras MD h, Thierry Delozier MD i, Vladimir Vladimirov MD j, Fatima Cardoso MD k, Han Koh MD l, Philippe Bougnoux MD m, Corina E Dutcus MD n, Seth Seegobin MSc o, Denis Mir MSc o, Nicole Meneses MSHS n, Jantien Wanders MD o, Prof Chris Twelves MD p

, on behalf of the EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators

Summary

Background

Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments.

Methods

In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to eribulin mesilate (1·4 mg/m2 administered intravenously during 2—5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726.

Findings

762 women were randomly allocated to treatment groups (508 eribulin, 254 TPC). Overall survival was significantly improved in women assigned to eribulin (median 13·1 months, 95% CI 11·8—14·3) compared with TPC (10·6 months, 9·3—12·5; hazard ratio 0·81, 95% CI 0·66—0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) of 503 patients.

Interpretation

Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting.