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

Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
The Lancet (Impact Factor: 45.22). 03/2011; 377(9769):914-23. DOI: 10.1016/S0140-6736(11)60070-6
Source: PubMed

ABSTRACT 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.
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/m(2) 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, number NCT00388726.
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.
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.

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    • "This toxicity was also seen in previous trials evaluating 1 . 4 mg m À 2 of eribulin monotherapy in the same setting ( Cortes et al , 2011 ; Aogi et al , 2012 "
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    ABSTRACT: Background: We evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, recommended dose for phase II (P2RD), and preliminary anticancer activity of a combination eribulin and S-1 therapeutic in metastatic breast cancer patients pretreated with anthracycline and taxane. Method: Patients aged 20-74 years were recruited. In level 1, patients received S-1 (65 mg m(-2)) from day 1 to 14, and eribulin (1.1 mg m(-2)) on day 1 and 8 in a 21-day cycle. In level 2, eribulin was increased to 1.4 mg m(-2). In level 3, S-1 was increased to 80 mg m(-2). Results: Twelve patients were enrolled into three cohorts. Planned dose escalation was completed, with one case exhibiting dose-limiting toxicity (grade 3 hypokalaemia) at level 3, without reaching the MTD. The P2RD was determined to be level 2 (eribulin 1.4 mg m(-2) and S-1 65 mg m(-2)). The most common grade 3 or 4 toxicity was neutropenia (83.3%), followed by febrile neutropenia (25.0%). Five of eleven patients (41.7%) with measurable disease had a partial response. Pharmacokinetics were characterised by dose-dependent elimination and nonlinear exposure. Conclusion: Dose level 3 was not tolerated owing to febrile neutropenia development. Thus, intermediate dose level 2 was recommended for further evaluation. Preliminary antitumour activity warrants further investigation in this setting.
    British Journal of Cancer 02/2015; 112(5). DOI:10.1038/bjc.2015.10 · 4.84 Impact Factor
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    • "In a randomized clinical phase III study (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389, EMBRACE) involving patients with heavily pre-treated locally recurrent or metastatic breast cancer, eribulin was compared with the treatment of physician's choice (TPC). Patients who received eribulin exhibited a significant improvement in median overall survival compared with TPC (Cortes et al. 2011). Recently, sub-group analysis from phase III clinical trial demonstrated that women with TNBC had significant response to treatment with eribulin versus capecitabine, with a median overall survival of 14.4 months with eribulin, compared with 9.4 months with capecitabine (Kaufman et al. 2012). "
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    ABSTRACT: Triple-negative breast cancer (TNBC) is associated with a higher incidence of recurrence and distant metastasis and a poor prognosis, whereas effective treatment strategies remain to be established. Finding an effective treatment for TNBC has become imperative. We examined the effect of the combination of S-1 (or 5-FU in an in vitro study) and eribulin in TNBC cell lines. The in vitro effect of the combination was examined in four TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549 and MX-1) using a combination index and isobolograms. In addition, we assessed the effect of the combination in an MDA-MB-231 tumor xenograft model. A synergistic effect was observed in three TNBC cell lines (MDA-MB-231, MDA-MB-468, and MX-1), and in an in vivo study, the combination of S-1 and eribulin resulted in significantly higher antitumor effects compared with S-1 or eribulin alone. 5-FU induced epithelial-mesenchymal transition (EMT) change in the TNCB cell line, as supported by the decreased expression of epithelial marker and the increased expression of mesenchymal markers. Meanwhile, TGF-beta induced EMT changes in a TNBC cell line and decreased the sensitivity to 5-FU. This result suggests that 5-FU-induced EMT changes reduce the sensitivity to 5-FU. In contrast, eribulin induced a mesenchymal-epithelial transition (MET) in a TNBC cell line. The EMT phenotype induced by 5-FU was also canceled by eribulin. We demonstrate that the combination of S-1 (5-FU) and eribulin exerts a synergistic effect for TNBC cell lines through MET-induction by eribulin. Therefore, this combination therapy may be a potential treatment option for TNBC.
    SpringerPlus 08/2014; 3:417. DOI:10.1186/2193-1801-3-417
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    • "In patients with grade 3/4 neuropathy who continued treatment, neuropathy improved to grade 2 or lower in later cycles after delays and dose reductions. The incidence of grade 3/4 neuropathy was similar in patients with pre-existing grade 1 or 2 neuropathy (13%) as in those without pre-existing neuropathy (8%) [101]. "
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    ABSTRACT: Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose limiting side effect of commonly used chemotherapeutic agents like taxanes, vinca-alkaloids, platinum compounds, bortezomib and thalidomide. Supposed pathogenetic mechanisms of CIPN are axonopathy through dying back axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved. The exact pathophysiology however is not clear and different underlying mechanisms have been proposed for different classes of anti-cancer drugs. Sensory symptoms, like pain, numbness and tingling are most common, but motor weakness, autonomic dysfunction and even cranial nerve involvement may occur. CIPN can be painful and/or disabling, causing significant loss of functional abilities and decreasing quality of life. This can lead to dose reductions, discontinuation of treatment and may thus, ultimately, affect survival. Risk factors for CIPN include dose per cycle, cumulative dose, treatment schedule, duration of infusion, administration of other chemotherapeutics, comorbidity and pre-existing peripheral neuropathy. The exploration of polymorphisms in genes associated with incidence or severity of neuropathy might result in identifying individuals being at higher risk of neurotoxicity. An update on genes possibly associated with CIPN is given. CIPN may be reversible or be more or less permanent. Many preventive and treatment strategies have been explored, without significant efficacy up till now. In this review we describe the different drug-related characteristics of CIPN, pharmacogenomic studies, neurophysiological findings, treatment and outcome, and neuroprotective strategies.
    Cancer Treatment Reviews 08/2014; 40(7). DOI:10.1016/j.ctrv.2014.04.004 · 7.59 Impact Factor
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