Eribulin Improves Overall Survival in Women with Heavily Pretreated Metastatic Breast Cancer

Data published in the Lancet this week support the effectiveness of eribulin mesylate (Halaven)—a microtubule inhibitor—in women with advanced breast cancer that has progressed after several treatments. The FDA approved eribulin in November 2010 for metastatic breast cancer patients treated with at least two chemotherapy regimens (an anthracycline and a taxane). As EMBRACE investigator Chris Twelves, MD, said last year at the American Society of Clinical Oncology Annual Meeting, this is the first evidence that a chemotherapeutic agent can improve overall survival (OS) in a heavily pretreated population.

 

The primary endpoint of EMBRACE was a significant increase in OS, and this was met, with eribulin improving survival by 2.5 months. Median OS was 13.1 months in the eribulin arm versus 10.6 months in the physician's choice (TPC) group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66-0.99; P = .041). 

 

Following eribulin's activity in phase I and phase II studies, investigators enrolled 762 women from 19 countries for this phase III trial. All participants had locally advanced or recurrent metastatic breast cancer and had completed 2 to 5 chemotherapy regimens. In the study, 16% of women were HER2-positive and 19% had triple-negative disease, but results were not stratified according to cancer subtype.

 

Investigators randomly assigned patients at a 2-to-1 ratio to eribulin (n = 508; 1.4 mg/m² intravenously on days 1 and 8 of a 21-day cycle) or TPC (n = 254). Median treatment duration was 3.9 months in the eribulin group, with 59% of patients receiving at least 5 cycles. Most (96%) of patients in the TPC arm received chemotherapy and continued treatment for a median of 2.1 months; 9 patients took hormonal agents for a median of 1.0 month.

 

During the study, fewer deaths occurred in the eribulin arm than in the TPC group (54% vs 58%, respectively), and more patients in the eribulin arm than in the TPC arm survived 1 year (53.9% vs 43.7%, respectively). Independent review found progression-free survival (PFS) slightly better with eribulin, at a median of 3.7 months compared with 2.2 months for the TPC group (HR, 0.87; 95% CI, 0.71-1.05; P = .137) in the intent-to-treat (ITT) population. Investigator assessment found significantly improved PFS for the eribulin arm of the ITT population (HR, 0.76; 95% CI, 0.64-0.90; P = .002).

 

In this heavily pretreated population, 12% of patients given eribulin demonstrated objective response compared with only 5% of patients receiving TPC (P = .002). The median duration of response was shorter with eribulin than with TPC (4.2 mo vs 6.7 mo, respectively; P = .159), but the clinical benefit rate for the eribulin arm was higher than for the TPC arm due to eribulin's improvements in OS and response (23% vs 17%, respectively).

 

Most patients experienced 1 or more adverse events, the majority of which were grade 1 or 2. In the eribulin arm, 99% (503) of patients suffered an adverse event, which was serious in one-quarter of patients. In the TPC arm, 93% (230) of patients had an adverse event, with 26% experiencing a serious adverse event.

 

Compared with the TPC group, the eribulin arm had higher rates of grade 3/4 neutropenia (21% vs 45%, respectively), leucopenia (6% vs 14%, respectively), and peripheral neuropathy (2% vs ~9%, respectively). Patients taking eribulin who had grade 1/2 neuropathy at the start of the study were no more likely to develop grade 3/4 neutropenia than patients who started the study with no evidence of neuropathy. Hypersensitivity reactions were uncommon, reported for only 1% (4) of patients taking eribulin.

 

In each study arm, 1% of patients suffered fatal adverse events due to treatment. The 5 eribulin-related deaths were attributed to febrile neutropenia, lung infection, bronchoneumia, and dyspnea (2 cases). Treatment-related deaths in the TPC arm consisted of 1 case of febrile neutropenia and 1 case of aspergillosis.

 

After the study's conclusion, a requested updated analysis of OS rates found that 76% of patients in the eribulin arm had died compared with 80% of patients in the TPC group (HR, 0.81; 95% CI, 0.67-0.96; P = .014). Investigators said this showed eribulin's survival advantage persisted over time.

 

An ongoing study is comparing eribulin with capecitabine in women with previously treated metastatic breast cancer in an effort to assess quality of life.

 

While the authors concede that the range of agents used in the TPC group could be considered a limitation of the study, they counter that their protocol better reflects "real-life choices made by oncologists and their patients." They recommend that eribulin be considered a new standard of treatment for heavily pretreated women with metastatic breast cancer.