Date: 2014-11-13
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in Breast Cancer Research and Treatment
Company: Eisai (Japan)
Product: Halaven® (eribulin)
Action
mechanism: 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.
Disease: metastatic breast cancer
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The pooled analysis included data from EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician\'s Choice (TPC) Versus Eribulin) and involved women who received 2-5 lines of chemotherapy for advanced disease. In this third line setting, women were randomised 2:1 to receive eribulin (1.23 mg/ iv on days 1 and 8 every 21 days) or TPC. The second study in the pooled analysis (study 301) included women who had received 0-2 prior chemotherapies for advanced disease who were randomised 1:1 to receive either eribulin (dose schedule as per EMBRACE) or capecitabine (1.25 g/m[2] orally twice daily on days 1-14 every 21 days). The objective of this pooled analysis was to assess overall survival in the overall ITT population and in subgroups based on HER2 and hormone-receptor status. Latest
news: * On November 13, 2014, Eisai announced that the results from a pooled analysis of two Phase III Halaven® (eribulin) trials are published in Breast Cancer Research and Treatment. Findings from the pooled analysis show that eribulin improves overall survival in women compared to control. This overall survival benefit was observed in women with human epidermal growth-factor receptor-2 (HER2) negative breast cancer and triple negative breast cancer (TNBC). The pooled analysis examined data from two pivotal Phase III studies in 1,864 women; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician\'s Choice Versus Eribulin) and Study 301. The objective of the analysis, initially requested by the European Medicines Agency (EMA), was to assess overall survival in the overall intent to treat (ITT) population and in specific patient subgroups, previously treated with an anthracycline and a taxane, based on HER2 and hormone receptor status. In the pooled analysis, eribulin was found to improve significantly overall survival vs. control in the ITT population (15.2 vs 12.8 months, HR=0.85 [95% CI, 0.77, 0.95]; p=0.003). A significant overall survival benefit was observed in women with HER2 negative breast cancer (15.2 vs 12.3 months, HR=0.82 [95% CI, 0.72, 0.93]; p=0.002), a subtype that affects an estimated 85% of women with breast cancer.This overall survival benefit was also seen in people with TNBC, (12.9 vs 8.2 months, HR=0.74 [95% CI, 0.60, 0.92]; p=0.006), but not in women with HER2 positive breast cancer (13.5 vs 12.2 months, HR=0.82 [95% CI, 0.62, 1.06]; p=0.135). There were no noticeable differences in the tolerability and safety data previously shown in the EMBRACE study (Study 305) and Study 301. On 3 July 2014, The European Commission (EC) issued Marketing Authorisation Approval (MAA) for eribulin in the treatment of patients with locally advanced or metastatic breast cancer (MBC) who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments.[6] This decision was based on clinical evidence from EMBRACE (Study 305) and Study 301.
Global Phase III Study 305 (EMBRACE)
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 women treated with eribulin versus a 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 participants with MBC 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 participants in the TPC arm received chemotherapy.
In the total Phase III EMBRACE study population, eribulin was shown to prolong median overall survival in heavily pre-treated women with MBC compared to women receiving TPC by 2.7 months (13.2 vs 10.5 HR 0.81 (95% CI 0.67, 0.96) nominal p=0.014). A pre-planned analysis of participants from Region 1 of the study (North America/Western Europe/Australia) showed a significant median overall survival benefit of eribulin over TPC of 3.0 months (nominal p=0.031).
The most commonly reported adverse reactions among people treated with eribulin in the EMBRACE study were fatigue (asthenia), a decrease in infection-fighting white blood cells (neutropenia), 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 women involved in the EMBRACE trial. Neutropenia only led to eribulin discontinuation for 0.6%. 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.
Global Phase III Study 301
Study 301 was an open-labelled, randomised, two-parallel-arm, multicentre study of 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. Women in the study received zero to two previous chemotherapies for advanced disease.
The study opened in 2006 and the last patient was randomised in 2010. Patients were randomised to treatment with either eribulin 1.23mg/m[2] (administered intravenously over two to five minutes on days 1 and 8, every 21 days) or capecitabine 2.5g/m[2] (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 and progression free survival. The study demonstrated a trend favouring improved overall survival with eribulin compared to capecitabine in the ITT population, although the improvement was not statistically significant. Women treated with eribulin had a median overall survival 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).
1-,2- and 3- year overall survival rates for eribulin versus capecitabine showed an early improvement which was maintained throughout the study (1 year, 64.4% eribulin vs 58.0% capecitabine (P=0.0351), 2 year 32.8% eribulin vs 29.8% capecitabine (P=0.324), 3 year, 17.8% eribulin vs 14.5% capecitabine (P=0.175).
Unlike studies conducted today, Study 301 included all women regardless of their human epidermal growth factor receptor 2 (HER2), oestrogen receptor (ER) or progesterone receptor (PR) status. Patients are usually tested for their HER2 status as there are now effective treatments specifically for patients with the HER2 mutation. HER2 positive patients would
