Phase III Trial Shows No Survival Benefit for Eribulin vs Capecitabine in Advanced Breast Cancer Previously Treated With Anthracycline and Taxane
Eribulin (Halaven) currently is indicated in the United States for treatment of patients with metastatic breast cancer who previously received at least two chemotherapy regimens for metastatic disease and an anthracycline and a taxane in either the adjuvant or metastatic setting. Approval was based on a phase III trial showing a survival advantage for eribulin vs single-agent treatment of physician’s choice. In a phase III trial reported in the Journal of Clinical Oncology, Kaufman et al found no overall survival advantage for eribulin vs capecitabine as first- through third-line treatment for locally advanced or metastatic disease.
Study Details
In this open-label trial, 1,102 women with locally advanced or metastatic breast cancer who had received up to three chemotherapy regimens and up to two prior chemotherapy regimens for advanced and/or metastatic disease, and prior therapy with an anthracycline and a taxane, were randomly assigned between September 2006 and September 2009 to receive intravenous eribulin at 1.4 mg/m2 on days 1 and 8 (n = 554) or oral capecitabine at 1.25 g/m2 twice daily on days 1 to 14 (n = 548) every 21 days. The coprimary endpoints were overall survival and progression-free survival.
The eribulin and capecitabine groups were generally balanced for age (median, 54 and 53 years), race (90% white in both), geographic region (eastern Europe for 55% and 56%, Latin America for 19% in both), Eastern Cooperative Oncology Group performance status (0 for 45% and 42%, 1 for 53% and 55%), number of prior chemotherapy regimens (one in 27% and 28%, two in 58% and 57%, three in 15% and 14%), number of regimens for advanced/metastatic disease (zero in 21% and 19%, one in 51% and 54%, two in 28% and 27%), refractoriness to taxane/anthracycline (45% and 47% to taxane, 24% and 25% to anthracycline, 16% and 19% to both), HER2 status (16% and 15% positive, 68% and 69% negative, 17% and 16% not assessed), estrogen receptor status (positive in 47% and 51%, negative in 42% and 39%, not assessed in 11% and 10%), progesterone receptor status (positive in 41% and 43%, negative in 47% and 45%, not assessed in 12% in both), triple-negative disease (27% and 25%), visceral disease sites (84% and 88%), and most common metastatic sites (bone in 54% and 56%, lung in 50% and 51%, lymph nodes in 48% and 50%, liver in 45% and 50%).
Overall, 20%, 52%, and 27% received study therapy as first-line, second-line, and third-line treatment for advanced disease.
Overall and Progression-Free Survival
Median overall survival was 15.9 months (95% confidence interval [CI] = 15.2–17.6 months) in the eribulin group vs 14.5 months (95% CI = 13.1–16.0 months) in the capecitabine group (hazard ratio [HR] = 0.88, 95% CI = 0.77–1.00, P = .056). Median progression-free survival was 4.1 months (95% CI = 3.5–4.3 months) vs 4.2 months (95% CI = 3.9–4.8 months; HR = 1.08, 95% CI = 0.93–1.25, P = .30) for eribulin vs capecitabine, respecitively. Objective response rate on independent review was 11.0% in the eribulin group vs 11.5% in the capecitabine group (P = .85).
A prespecified exploratory analysis suggested an overall survival benefit for eribulin in HER2-negative patients; however, there was no significant interaction between treatment effect and HER2 status.
Adverse Events
The most common (> 20%) adverse events of any grade were neutropenia (54%), alopecia (35%), leukopenia (31%), global peripheral neuropathy (27%), and nausea (22%) in the eribulin group and hand-foot syndrome (45%), diarrhea (29%), and nausea (24%) in the capecitabine group. The most common (≥ 5%) grade 3 or 4 adverse events were neutropenia (46%), leukopenia (15%), and global peripheral neuropathy (7%) in the eribulin group and diarrhea (5%) and hand-foot syndrome (15%) in the capecitabine group. Febrile neutropenia occurred in 2.0% vs 0.9%. Colony-stimulating factor treatment was required in 15% vs 4%.
Adverse events led to discontinuation, reduction, and delay in treatment in 8% vs 10%, 32% vs 32%, and 32% vs 36% for eribulin vs capecitabine, respectively. The most common causes of treatment discontinuation were neutropenia (1.7%) in the eribulin group and hand-foot syndrome (2.2%) and dyspnea (1.1%) in the capecitabine group.
Serious adverse events occurred in 18% vs 21% of patients receiving eribulin vs capecitabine, respectively. Fatal adverse events occurred within 30 days of the last study dose in 4.8% of eribulin patients and 6.6% of capecitabine patients. These events were considered treatment-related in five eribulin patients (sepsis, pericardial effusion, sudden death, toxic hepatitis, and renal failure) and four capecitabine patients (sepsis, pneumonia, cardiogenic shock, and pancytopenia).
Global health status/overall quality of life was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (version 3.0) and breast module Quality of Life Questionnaire BR23. Both groups had improvement in average scores during the study, with no between-group differences being observed.
The investigators concluded: “[T]his trial did not demonstrate superiority of eribulin versus capecitabine for either [overall survival] or [progression-free survival]. The effects on [quality of life] in this population of patients with [metastatic breast cancer] and the [adverse event] profiles of eribulin and capecitabine were consistent with their known [adverse events].”
Peter A. Kaufman, MD, of Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Eisai. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
