Elsevier

The Lancet

Volume 377, Issue 9769, 12–18 March 2011, Pages 914-923
The Lancet

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

https://doi.org/10.1016/S0140-6736(11)60070-6Get rights and content

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.

Funding

Eisai.

Introduction

A great need exists for treatments that improve overall survival for women with advanced or recurrent metastatic breast cancer, particularly those with heavily pretreated disease. Many patients either do not respond or become refractory to agents such as anthracyclines and taxanes.1, 2 There is then no single standard of care for such women, and at the time of this study the only cytotoxics approved as monotherapy in this setting were capecitabine and ixabepilone (for patients also resistant to capecitabine; approved in the USA and some other countries on the basis of phase 2 data). Neither capecitabine nor ixabepilone has, however, been investigated in adequately powered single-agent studies assessing survival benefit.

Eribulin mesilate (E7389) is a non-taxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastic drugs. It is a structurally modified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin has a novel mode of action that is distinct from those of other tubulin-targeting agents,3, 4, 5, 6, 7 inhibiting the microtubule growth phase without affecting the shortening phase, and causing tubulin sequestration into non-productive aggregates. In preclinical studies, eribulin induced less neuropathy than did paclitaxel8 and retained activity in cell lines that were resistant to paclitaxel through β-tubulin mutations.9 Eribulin could therefore be effective in patients with disease that is resistant to other tubulin-targeting agents.

In phase 110, 11, 12 and phase 2 studies13, 14 eribulin was active, with a predictable side-effect profile, in patients with extensively pretreated locally advanced or metastatic breast cancer. Patients in both phase 2 studies (n=10313 and n=29914) had received a median of four previous chemotherapy regimens; objective response rates were 11·5% (ten of 87 patients in the per-protocol population; 95% CI 5·7–20·1) and 9·3% (25 of 269 in the eligible population; 95% CI 6·1–13·4), and median overall survival was 9·0 and 10·4 months, respectively.

In this phase 3 study, we aimed to compare overall survival of women with heavily pretreated metastatic breast cancer receiving eribulin or real-life treatment choices. A distinctive comparator group, treatment of physician's choice (TPC), represented a mix of agents (both approved and non-approved for metastatic breast cancer) to mirror clinical practice at the time in this setting.

Section snippets

Study design and patients

The EMBRACE trial (study E7389-G000-305) was a phase 3, global, multicentre, randomised, open-label study of eribulin versus TPC in women with heavily pretreated locally recurrent or metastatic breast cancer. Key inclusion criteria were: age 18 years or older; histologically or cytologically confirmed breast cancer with measurable or evaluable disease; between two and five previous chemotherapy regimens, including an anthracycline and a taxane, and two or more regimens for locally recurrent or

Results

From Nov 16, 2006, to Nov 17, 2008, 762 patients from 135 centres in 19 countries were randomly allocated to treatment groups (508 eribulin, 254 TPC; figure 1). No TPC patient received supportive care alone; most (238 [96%] of 247) received chemotherapy, which was most often vinorelbine, gemcitabine, or capecitabine (figure 1). Baseline demographic characteristics were well balanced across treatment groups (table 1). Patients were heavily pretreated (median four previous chemotherapy regimens);

Discussion

This global phase 3 study establishes a potential new standard treatment for women with heavily pretreated metastatic breast cancer, for whom there was previously no chemotherapy treatment with proven survival benefit (table 4; panel). The study met its primary endpoint of significant improvement in overall survival with eribulin versus real-life treatment choices at the time (2006–08) for women with metastatic breast cancer who had received a median of four previous chemotherapy regimens. To

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