Eisai Presents New Research on Halaven® (eribulin) at the European Cancer Congress

HATFIELD, England, September 30, 2013 /PRNewswire/ --

PRESS RELEASE FOR EUROPEAN AND RUSSIAN MEDIA ONLY

Data show further evidence for eribulin in locally advanced or metastatic breast cancer

Data from five abstracts presented at the European Cancer Congress (ECC) 2013, Amsterdam, Netherlands (27 September - 1 October) provide further evidence on the profile of eribulin in the treatment of patients with locally advanced or metastatic breast cancer (MBC).^{[1],[2],[3],[4],[5],[6]}

Some of the information discussed in this release is about investigational uses for eribulin. Eribulin is indicated in Europe for the treatment of patients with locally advanced or MBC who have previously received at least two chemotherapeutic regimens. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments.^[6]

One of the five abstracts presented the first observational study results in a European setting.^[4] This retrospective study showed that the favourable efficacy and safety profile of eribulin observed in its pivotal Phase III study (EMBRACE)^[7] matched the experience in the clinic (n=104).

A second poster presented at the congress showed that patients in a recent Phase III trial (Study 301) with a 'newly detected' metastasis may have a worse prognosis than those whose disease progresses with an increase in size of pre-existing lesions.^[5] This suggests that the type of progression a person with breast cancer experiences can lead to different outcomes.^[5]  

Results from this post hoc analysis may help explain the difference in overall survival (OS) and progression free survival (PFS) observed in Study 301.^[8] This study did not meet its pre-specified co-primary endpoint for OS and PFS, but demonstrated a trend which favoured improved OS with eribulin vs capecitabine that did not reach statistical significance (median OS of 15.9 months vs 14.5 months, respectively; HR 0.88; 95% CI 0.77, 1.00; p=0.056).  No difference was observed in PFS. These analyses suggest that the results may have been driven by fewer patients in the eribulin arm with a new metastasis as opposed to progression of an existing lesion. The apparent discordance between PFS and OS may be due to this difference.^[5]

"These results suggest that the conventional PFS definition may not be adequate and that clinically meaningful differences may exist among different subsets of patients with metastatic breast cancer depending on how and where their disease progresses. The importance in this post hoc analysis of the emergence of 'new' metastases is intriguing and warrants further study," comments Dr Christopher Twelves, Professor of Clinical Cancer Pharmacology and Oncology, University of Leeds and St James' University Hospital and investigator for Study 301.

In another post hoc analysis presented at the congress, the sequencing of treatment prior to eribulin (including capecitabine, vinorelbine or capecitabine plus vinorelbine) was shown to have no additional OS benefit.^[1] The authors concluded that the only therapies that should be required prior to the use of eribulin are an anthracycline and a taxane, in either the neo/adjuvant and/or metastatic setting, unless patients were not suitable for these treatments as per the Phase III EMBRACE study protocol.^[6]

Data from a Phase I combination study of eribulin and trastuzumab in Japanese patients, also presented at the ECC, demonstrated that the two drugs in combination were well tolerated in people with advanced or recurrent HER2+ breast cancer.^[2]

The final abstract presented at the ECC congress identified the pharmacokinetic (PK) profile of eribulin using results from Phase I, II and III studies.^[3] Study investigators generated a model that can characterise eribulin's PK profile and predict eribulin exposure in cancer patients.

"Eisai remains committed to evaluating further the safety and efficacy of eribulin in women living with locally advanced or MBC. The data presented at this year's ECC demonstrate our commitment to discovering, developing and producing innovative oncology therapies that can make a difference and impact the lives of patients and their families", commented Uday Bose, Oncology Business Unit Head, Eisai Europe, the Middle East, Africa and Russia (EMEA).

The following Eisai abstracts were presented at the congress:

Abstract number Abstract name and authors First year daily clinical experience with eribulin in Spain; EUFORIA-1 study (Eribulin Use For the treatment of Abstract advanced breast cancer: Observational, Retrospective No: 1899 Analysis) PO72 Ruiz-Borrego M, García-Sáenz JA, Hornedo FJ, Calvo I, Lao J, Manso L, González A, Feijoo M, Florián J, Rodríguez-Villaneuva J New metastasis versus increase in size of pre-existing Abstract lesions as a predictor of overall survival in patients No: 1911 with metastatic breast cancer treated with eribulin or PO84 capecitabine Perez EA, O'Shaughnessy J, Twelves C, Cortes J, Awada A, Yelle L, Wanders J, Olivo M, He Y, Kaufman PA Abstract Does the prior chemotherapy treatment sequence affect the No: 1891 overall survival (OS) benefit associated with eribulin? PO64 Simons WR, Rodriguez-Villanueva J, Sheffield R, Rege J, He YP, Lin S A Phase I combination study of eribulin mesylate with Abstract trastuzumab for advanced or recurrent human epidermal No: 1898 growth factor receptor 2-positive (HER2+) breast cancer PO71 Mukai H, Shimada K, Naito Y, Matsubara N, Nakanishi T, Obaishi H, Namiki M, Narita T, Masuda M, Sasaki Y Abstract Population pharmacokinetics (PPK) of eribulin in cancer No.859 patients PO54 Majid O, Gupta A, Olivo M, Reyderman L, Hussein Z

Notes to Editors

Halaven^® (eribulin)

Eribulin is a non-taxane, microtubule dynamics inhibitor indicated for the treatment of patients with breast cancer who have previously received at least two chemotherapeutic regimens for metastatic disease and whose prior therapy should have included an anthracycline and a taxane.

Eribulin belongs to a class of antineoplastic agents, the halichondrins, which are natural products, isolated from the marine sponge Halichondria okadai. It is believed to work by inhibiting the growth phase of microtubule dynamics without affecting the shortening phase and sequesters tubulin into non-productive aggregates. Potential investigational mechanisms in mouse models may show that eribulin could have a novel inhibitory effect on tumour metastasis by suppressing the expression in epithelial-mesenchymal transition (EMT) gene sets.^{[9],[10],[11]} EMT is a phenomenon in which cells acquire characteristics that allow them to develop into tumours and is highly significant in the infiltration and metastasise of cancer.

Further investigational mechanisms in mouse models show that eribulin may also improve blood perfusion in tumour tissues meaning that it could increase the amount of oxygen available to tumours.^[12] When tumours are deprived of oxygen they are more likely to metastasise and as such eribulin may work to inhibit metastasis. Following treatment with eribulin in investigational mouse models, tumours were less aggressive and invasive.

Halaven is approved in 50 countries across the world including the European Union, USA, Russia, Switzerland, South Korea, Japan, and Singapore. Halaven has received pricing authorisation and has been launched in Canada, Denmark, Finland, France, Iceland, Italy, Norway, Sweden, Switzerland, Slovenia, and the UK. In addition, Halaven is available in Austria and Germany.

Global Phase III Study 301^[8]

Study 301 was an open-labelled, randomised, two-parallel-arm, multicentre study of Halaven (eribulin) versus capecitabine in 1,102 women with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes, either in the (neo) adjuvant setting or for locally advanced or metastatic disease. This study was outside of the licensed indication for eribulin. Patients in the study received zero to two previous chemotherapies for advanced disease.

Patients were randomised from 2006-2010, to treatment with either eribulin 1.4mg/m² (administered intravenously over two to five minutes on days 1 and 8, every 21 days) or capecitabine 1.25g/m² (administered orally twice daily in two equal doses on days 1 to 14, every 21 days).

Study 301 had a co-primary endpoint of overall survival (OS) and progression-free survival (PFS). The study demonstrated a trend favouring improved OS with eribulin compared to capecitabine, although the improvement was not statistically significant. Women treated with eribulin had a median OS of 15.9 months (HR 0.879; 95% CI: 0.770-1.003; p=0.056) versus 14.5 months with capecitabine. The trial did not meet the pre-specified endpoint for progression-free survival, with 4.1 and 4.2 months for eribulin and capecitabine respectively (HR 1.079; 95% CI: 0.932-1.250; p=0.305). Adverse events in Study 301 were consistent with the known profile of both drugs.

Study 301 had a secondary endpoint of QoL assessed using the EORTC quality of life questionnaire-C30 (QLQ)  and QLQ-BR23 questionnaires at baseline, 6 weeks, 3, 6, 12, 18 and 24 months after starting treatment or until progressive disease or treatment change, and at unscheduled visits. Longitudinal analyses were carried out using weighted generalised estimating equations adjusted for non-random attrition due to death within 12 months. Model covariates were time (visit), region, and baseline QoL. The primary endpoint for QOL was change from baseline for Global Health Status (GHS)/overall QoL, and exploratory endpoints were change from baseline for a range of functions and signs/symptoms.

Global Phase III Clinical Study 305 (EMBRACE)^[2]

EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice (TPC) Versus Eribulin E7389) was an open-label, randomised, global, multi-centre, parallel two-arm study designed to compare overall survival in patients treated with eribulin versus a Treatment of Physician's Choice (TPC) arm. TPC was 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. The study included 762 patients with metastatic breast cancer who previously had been treated with at least two and a maximum of five prior chemotherapies, including an anthracycline and a taxane. The vast majority (96%) of patients in the TPC arm received chemotherapy.

In the Phase III study population (n=762), eribulin was shown to prolong overall survival in heavily pre-treated patients with metastatic breast cancer by 2.5 months compared to patients receiving Treatment of Physicians Choice (TPC), representing a mix of real-life treatment choices (eribulin 13.1 months vs. TPC 10.6 months, HR 0.81 (95% CI 0.66, 0.99) p=0.041). Updated data from the pivotal Phase III EMBRACE trial confirmed these results, showing that patients treated with eribulin survived a median of 2.7 months longer than patients who received treatment of physician's choice (overall survival of 13.2 months versus 10.5 months, respectively, HR 0.81 (95% CI 0.067, 0.96), nominal p=0.014). A pre-planned analysis of patients from Region 1 of the study (North America/Western Europe/Australia) showed a significant overall survival benefit of eribulin over TPC of 3.0 months (p=0.009).

The most commonly reported adverse reactions among patients treated with eribulin in the EMBRACE study were fatigue (asthenia), a decrease in infection-fighting white blood cells (neutropaenia), hair loss (alopecia), numbness and tingling in arms and legs (peripheral neuropathy), nausea and constipation. Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in less than 5% of the patients involved in the EMBRACE trial. Neutropaenia only led to eribulin discontinuation for 0.6% patients. Death due to serious side effects, discontinuation and dose interruptions to treatment were lower in the eribulin arm of the trial compared with the TPC arm.

Metastatic Breast Cancer

Over 300,000 women are diagnosed with breast cancer in Europe every year, of whom about one third subsequently develop metastatic disease.^[13],[14]Metastatic disease is an advanced stage of the disease that occurs when cancer spreads beyond the breast to other parts of the body.

Eisai in Oncology

Our commitment to meaningful progress in oncology research, built on scientific expertise, is supported by a global capability to conduct discovery and preclinical research, and develop small molecules, therapeutic vaccines, and biologic and supportive care agents for cancer across multiple indications.

About Eisai

Eisai is one of the world's leading research and development (R&D) based pharmaceutical companies, that has defined its corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call human health care (hhc).

Eisai concentrates its R&D activities in three key areas:

• Oncology, including: anticancer therapies, tumour regression, tumour suppression and antibodies
• Neuroscience, including: Alzheimer's disease, epilepsy, pain and weight loss
• Vascular/Immunological reaction, including: thrombocytopenia, rheumatoid arthritis, psoriasis and inflammatory bowel disease

With operations in the USA, Asia, Europe and its domestic home market of Japan, Eisai employs more than 10,000 people worldwide. From its EMEA Knowledge Centre in Hatfield, UK, Eisai has recently expanded its business operations to include Europe, the Middle East, Africa and Russia (EMEA). Eisai EMEA has sales and marketing operations in over 20 markets, including the United Kingdom, France, Germany, Italy, Spain, Switzerland, Sweden, Ireland, Austria, Denmark, Finland, Norway, Portugal, Czech Republic, Slovakia, the Netherlands, Belgium, the Middle East and Russia.

For further information please visit our web site http://www.eisai.co.uk

 

References

1. Simons et al. Does the prior chemotherapy treatment sequence affect the overall survival (OS) benefit associated with eribulin? ECC 2013 abstract 1891  

2. Mukai et al. A Phase I combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2-positive (HER2+) breast cancer. ECC 2013 abstract 1898

3. Majid et al. Population pharmacokinetics (PPK) of eribulin in cancer patients. ECC 2013 abstract P859

4. Ruiz-Borrego M et al. First year daily clinical experience with eribulin in Spain; EUFORIA-1 study (Eribulin Use For the treatment of advanced breast cancer: Observational, Retrospective Analysis). ECC 2013 abstract 1899

5. Perez et al. New metastasis versus increase in size of pre-existing lesions as a predictor of overall survival in   patients with metastatic breast cancer treated with eribulin or capecitabine. ECC 2013 abstract 1911

6. SPC Halaven (updated April 2013). Available at: http://www.medicines.org.uk/emc/medicine/24382. Last accessed August 2013

7. Cortes J, O'Shaughnessy J, Loesch D, 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. 2011; 377: 914 -923

8. Kaufman P, Awada A, Twelves C et al. A Phase III, open-label, randomised, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Presented at 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Abstract No. S6-6

9. McCracken P.J, Ito. K, Yanagimachi M, et al. Eribulin alters vascular function in human triple-negative (TN) breast MX-1 and MDA-MB-231 tumor xenograft models as measured by DCE-MRI. AACR abstract 2013 abstract # 4502  

10. Dezso Z, Oestreicher J, Weaver A et al. Gene expression profiling (GEP) reveals Epithelial Mesenchymal Transition (EMT) genes selectively differentiating eribulin sensitive breast cancer cell lines. AACR abstract 2013 abstract # 1522

11. Agoulnik SI, Oestreicher JL, Taylor NH et al. Eribulin and Paclitaxel differentially affect gene expression profiling of blood vessel cells and in vitro angiogenesis in co-cultures of human endothelial cells with pericytes. AACR abstract 2013 abstract # 3830

12. Matsui J, Toyama O, Ino M et al. Eribulin caused re-modeling of tumor vasculature altering gene expression profiling in angiogenesis and Epithelial Mesenchymal Transition (EMT) signaling pathway of host cells within human breast cancer cell (BCC) xenografts in nude mice. AACR abstract 2013 abstract # 1413

13. Ferlay et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013; 49(6):1374-403

14. O'Shaughnessy, J. Extending Survival with Chemotherapy in Metastatic Breast Cancer. The Oncologist. 2005;  10(suppl 3):20-29

 

Date of preparation: September 2013
Job code: Halaven-UK0187