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Tumour biology, metastatic sites and taxanes sensitivity as determinants of eribulin mesylate efficacy in breast cancer: results from the ERIBEX retrospective, international, multicenter study

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      Abstract

      Background

      Our retrospective, international study aimed at evaluating the activity and safety of eribulin mesylate (EM) in pretreated metastatic breast cancer (MBC) in a routine clinical setting.

      Methods

      Patients treated with EM for a locally advanced or MBC between March 2011 and January 2014 were included in the study. Clinical and biological assessment of toxicity was performed at each visit. Tumour response was assessed every 3 cycles of treatment. A database was created to collect clinical, pathological and treatment data.

      Results

      Two hundred and fifty-eight patients were included in the study. Median age was 59 years old. Tumours were Hormone Receptor (HR)-positive (73.3 %) HER2-positive (10.2 %), and triple negative (TN, 22.5 %). 86.4 % of the patients presented with visceral metastases, mainly in the liver (67.4 %). Median previous metastatic chemotherapies number was 4 [ 19]. Previous treatments included anthracyclines and/or taxanes (100 %) and capecitabine (90.7 %). Median number of EM cycles was 5 [ 119]. The relative dose intensity was 0.917. At the time of analysis (median follow-up of 13.9 months), 42.3 % of the patients were still alive. The objective response rate was 25.2 % (95 %CI: 20–31) with a 36.1 % clinical benefit rate (CBR). Median time to progression (TTP) and overall survival were 3.97 (95 %CI: 3.25–4.3) and 11.2 (95 %CI: 9.3–12.1) months, respectively. One- and 2-year survival rates were 45.5 and 8.5 %, respectively. In multivariate analysis, HER2 positivity (HR = 0.29), the presence of lung metastases (HR = 2.49) and primary taxanes resistance (HR = 2.36) were the only three independent CBR predictive factors, while HR positivity (HR = 0.67), the presence of lung metastases (HR = 1.52) and primary taxanes resistance (HR = 1.50) were the only three TTP independent prognostic factors. Treatment was globally well tolerated. Most common grade 3–4 toxicities were neutropenia (20.9 %), peripheral neuropathy (3.9 %), anaemia (1.6 %), liver dysfunction (0.8 %) and thrombocytopenia (0.4 %). Thirteen patients (5 %) developed febrile neutropenia.

      Conclusion

      EM is an effective new option in heavily pretreated MBC, with a favourable efficacy/safety ratio in a clinical practice setting. Our results comfort the use of this new molecule and pledge for the evaluation of EM-trastuzumab combination in this setting. Tumour biology, primary taxanes sensitivity and metastatic sites could represent useful predictive and prognostic factors.

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      Most cited references 18

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

      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 ClinicalTrials.gov, 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. Eisai. Copyright © 2011 Elsevier Ltd. All rights reserved.
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        Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

        Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. Conclusion In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.
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          Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies

          Data from two phase 3 studies of eribulin were pooled in analyses initially requested by the European Medicines Agency to assess whether specific patient subgroups, previously treated with an anthracycline and a taxane, benefited from eribulin. Study 305/EMBRACE included women after two-to-five lines of chemotherapy for advanced breast cancer who were randomized to eribulin mesylate (1.4 mg/m2 on days 1 and 8 every 21 days) or treatment of physician’s choice. In Study 301, patients who had received up to two prior chemotherapy regimens for advanced disease were randomized to eribulin (as above) or capecitabine (1.25 g/m2 b.i.d. on days 1–14 every 21 days). In the pooled population, overall survival (OS), progression-free survival and response rates were analysed in the intent-to-treat population and selected subgroups. Overall, 1,062 patients were randomized to eribulin and 802 patients to control. Median OS was 15.2 months with eribulin versus 12.8 months with control (hazard ratio [HR] 0.85; 95 % CI 0.77, 0.95; P = 0.003). In all subgroups assessed, OS data favoured eribulin; significant improvements occurred in some subgroups, notably in women with human epidermal growth factor receptor 2 (HER2)-negative disease (HR 0.82; P = 0.002), although the effect in those with HER2-negative but hormone-receptor-positive disease did not reach statistical significance; benefits were also seen, among others, in those with estrogen-receptor-negative and triple-negative disease. Eribulin improves OS in various patient subgroups with advanced/metastatic breast cancer who had previously received an anthracycline and a taxane. Women with HER2-negative disease are among those who may obtain benefit from eribulin. Electronic supplementary material The online version of this article (doi:10.1007/s10549-014-3144-y) contains supplementary material, which is available to authorized users.
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            Author and article information

            Affiliations
            [ ]Département de Pharmacie Clinique, Institut régional du Cancer de Montpellier (ICM), 208, rue des Apothicaires, 34298 Montpellier Cedex 5, France
            [ ]Medical Oncology Department, Institut Claudius Regaud, IUCT- Oncopole, Toulouse, France
            [ ]Medical Oncology Department, Centre Georges-François Leclerc, Dijon, France
            [ ]Breast Center (CePO), University Hospital CHUV, Rue du Bugnon 46, 1011 Lausanne, Switzerland
            [ ]Département de Biostatistiques, Institut régional du Cancer de Montpellier (ICM), 208, rue des Apothicaires, 34298 Montpellier Cedex 5, France
            [ ]Département d’Oncologie Médicale, Institut régional du Cancer de Montpellier (ICM), 208, rue des Apothicaires, 34298 Montpellier Cedex 5, France
            [ ]Medical Oncology Department, University Hospital of Geneva, Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland
            Contributors
            Melodie.DellOva@chu-fortdefrance.fr
            DeMaio.Eleonora@iuct-oncopole.fr
            sguiu@cgfl.fr
            Lise.Roca@icm.unicancer.fr
            dalenc.florence@iuct-oncopole.fr
            Anna.DurigovaAbdouh@hcuge.ch
            Frederic.Pinguet@icm.unicancer.fr
            khedidja.Bekhtari@icm.unicancer.fr
            +33467612339 , William.jacot@icm.unicancer.fr
            stephane.pouderoux@icm.unicancer.fr
            Journal
            BMC Cancer
            BMC Cancer
            BMC Cancer
            BioMed Central (London )
            1471-2407
            8 October 2015
            8 October 2015
            2015
            : 15
            4599752 1673 10.1186/s12885-015-1673-3
            © Dell’Ova et al. 2015

            Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

            Categories
            Research Article
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            © The Author(s) 2015

            Oncology & Radiotherapy

            breast cancer, eribulin mesylate, efficacy, safety

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