Updated Phase III Data confirms the role of eribulin (Halaven? also E7389, Eisai Inc) as a potential new standard of care for women with heavily pretreated metastatic breast cancer (MBC). The trial data was published in The Lancet earlier today. The EMBRACE trial (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician’s Choice Versus Eribulin E7389) demonstrated that eribulin significantly improved overall survival (OS) compared with treatment of physician’s choice (TPC) in women with MBC previously treated with at least an anthracycline and a taxane.[1] TPC is defined as any single-agent chemotherapy, hormonal treatment or biologic therapy approved for the treatment of cancer, or palliative treatment or radiotherapy administered according to local practice.[2]

Eribulin is an injectable therapy believed to work by inhibiting cancer cell growth. The drug is afirst-in-class,chemotherapeutically active compound, anon-taxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. It is a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai.[3, 4] Eisai recently received positive opinion from The Committee for Medicinal Products for Human Use (CHMP) for the use of eribulin as a monotherapy in the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments. Eribulin has already received FDA approval in the United States.

Imprortance
Worldwide, more than one million women a year are diagnosed with breast cancer, including 421,000 women in Europe.[5],[6] Approximately 30 percent of women initially diagnosed with earlier stages of breast cancer eventually develop recurrent or metastatic disease,[7] and while around 9 out of 10 of women diagnosed with early stage breast cancer survive beyond five years, this drops to around 1 in 10 among women first diagnosed with MBC.[8] Most MBC patients have a limited survival time of approximately 18-24 months.[9]

Clinical trial
The EMBRACE trial was an open-label, randomised, multi-centre study of 762 women with MBC who were previously treated with at least two and a maximum of five prior chemotherapies (greater than or equal to 2 for advanced disease), including an anthracycline and a taxane. Patients must have been refractory to the most recent chemotherapy, documented by progression on or within six months of therapy. The study was designed to compare OS in patients treated with eribulin versus a TPC arm, reflecting a real-world clinical setting where a variety of agents are used to treat patients. The primary endpoint was OS. Secondary endpoints were objective response rate, progression-free survival, safety and duration of response.[1]

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“There is an urgent need for therapies with a proven survival benefit for women with metastatic breast cancer who have already received multiple treatments,” commented Dr. Javier Cortes, lead author and investigator for the EMBRACE study and Specialist Physician at the Oncology Department of Vall d’Hebron University Hospital, Barcelona, Spain. “In the EMBRACE study we see a clear overall survival benefit for these patients when treated with eribulin. This is a remarkable step forward in this treatment setting where previously overall survival has been considered an endpoint difficult to attain.”

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The EMBRACE study met its primary endpoint, demonstrating a statistically significant increase in OS in the intention to treat (ITT) population for eribulin compared with TPC of 2.5 months (median 13.1 and 10.6 months respectively; p=0.041; hazard ratio [HR] 0.81). EMBRACE showed eribulin to have a predictable and manageable side effect profile with the most common adverse events in both arms being fatigue (53.7% with Halaven, 39.7% with TPC) and neutropaenia, or abnormally low levels of neutrophil white blood cells (51.7% with Halaven, 29.6% with TPC).[1]

“The publication of EMBRACE in The Lancet further reinforces the importance of eribulin as a potential new treatment for patients with metastatic breast cancer,” said Uday Bose, Head of Institutional Care, Eisai Europe, Ltd. “These data open the door for a new treatment strategy in Europe, and one that will benefit patients who previously had very limited options. We are looking forward to the potential forthcoming authorisation of Halaven in Europe.”

For more information:
Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. The Lancet, Early Online Publication, 3 March 2011, doi:10.1016/S0140-6736(11)60070-6
Lin NU, Burstein HJ. EMBRACE, eribulin, and new realities of advanced breast cancer. The Lancet, Early Online Publication , 3 March 2011, doi:10.1016/S0140-6736(11)60280-8

References:
[1] Cortes J, O’Shaughnessy J, Loesch D, et al. A Phase III open-lable randomized study (EMBRACE) or eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer. The Lancet. 2011; 377: 1-10.
[2] Twelves C et al. Updated Survival Analysis of a Phase III Study (EMBRACE) of Eribulin Mesylate Versus Treatment of Physician’s Choice in Subjects with Locally Recurrent or Metastatic Breast Cancer Previously Treated with an Anthracycline and a Taxane. San Antonio Breast Cancer Symposium (SABCS) 2010; Poster P6-14-18.
[3] Kuznetsov G, Towle MJ, Cheng H, et al: Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res 2004; 64: 5760-5766
[4] Towle MJ, et al. In Vitro and In Vivo Anticancer Activities of Synthetic Macrocyclic Ketone Analogues of Halichondrin B. Cancer Res 2001; 61: 1013-1021
[5] Coughlin, S. Breast cancer as a global health concern. Cancer Epidemiology, October 2009; 33: 315-18.
[6] Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer.2010: 46(4):765-781
[7] O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 2005;10 Suppl 3:20-29
[8] Cancer Research UK, Breast Cancer Statistics Key Facts [updated April 2010], Last Accessed August 4, 2010
[9] Fernandez Y, Cueva J, Palomo AG, et al. Novel therapeutic approaches to the treatment of metastatic breast cancer. Cancer Treat Rev.2010:36(1):33-42.

Clinical trials
E7389 Versus Treatment of Physician’s Choice in Patients With Locally Recurrent or Metastatic Breast Cancer.

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