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Eribulin improves survival in HER2 negative advanced breast cancer; pooled analysis of two phase III trials

Data from a pooled analysis presented today at the 50th Annual Meeting of the American Society of Clinical Oncology ( ASCO ) have provided further evidence that Eribulin ( Halaven ) improves overall survival in women with advanced breast cancer compared with other standard therapies ( 15.2 vs 12.8 months, HR=0.85 [ 95% CI, 0.77-0.95 ]; p=0.003 ).
In particular, a significant overall survival benefit was observed in women with human epidermal growth-factor receptor-2 ( 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 triple negative breast cancer ( 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 and 301 studies.

Eribulin remains the only single agent chemotherapy proven to improve significantly overall survival in women with advanced breast cancer after either adjuvant or metastatic anthracycline and taxane treatment. These new data clearly confirm that women with advanced breast cancer benefit from Eribulin.

The pooled analysis examined data from two pivotal phase III studies of more than 1,800 women; EMBRACE ( Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice Versus Eribulin ) and study 301.
The objective of the analysis, requested by the European Medicines Agency ( EMA ), was to assess overall survival in the overall intent to treat ( ITT ) population and in subgroups based on HER2 and hormone receptor status.

On 27 May 2014, the EMA's Committee for Medicinal Products for Human Use ( CHMP ) issued a positive opinion for Eribulin for 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.

Eribulin is a non-taxane, microtubule dynamics inhibitor currently indicated for the treatment of people 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 which prevents cell division.

305/301 pooled data

The pooled analysis included data from EMBRACE 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/m2 iv on days 1 and 8 every 21 days ) or TPC ( Treatment of Physician's Choice ).
The second study in the pooled analysis ( study 301 ) has 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/m2 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.

Study 305 ( EMBRACE )

EMBRACE an open-label, randomised, global, multi-centre, parallel two-arm study designed to compare overall survival in people treated with Eribulin versus 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 has included 762 people 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 people in the TPC arm received chemotherapy.
In the total phase III EMBRACE study population, Eribulin was shown to prolong median overall survival in people heavily pre-treated metastatic breast cancer compared to people receiving TPC by 2.7 months ( 13.2 vs 10.5, HR=0.81; nominal p=0.014 ).
A pre-planned analysis of people from Region 1 of the study ( North America / Western Europe / Australia ) has shown 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, neutropenia, 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 people involved in the EMBRACE study.
Death due to serious side effects, discontinuation and serious adverse events were lower in the Eribulin arm of the study compared with the TPC arm.

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.
Participants 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/m2 ( administered intravenously over two to five minutes on days 1 and 8, every 21 days ) or Capecitabine 2.5g/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 and progression-free survival.
The study demonstrated a trend favouring improved overall survival with Eribulin compared to Capecitabine in the intention-to-treat population, although the improvement was not statistically significant. Women treated with Eribulin had a median overall survival of 15.9 months ( HR=0.879; 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; 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=0.035 ], 2 year 32.8% Eribulin vs 29.8% Capecitabine [ P=0.324 ], 3 year, 17.8% Eribulin vs 14.5% Capecitabine [ P=0.175 ] ).

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 generally not be treated with non-HER2 positive directed therapy.
In an exploratory analysis for the planned subset of HER2 negative women ( n=755 ), overall survival was 15.9 months for Eribulin vs 13.5 months for Capecitabine ( HR=0.838 ).
In the HER2 positive population ( n=169 ) overall survival was 14.3 months for Eribulin vs 17.1 months for Capecitabine ( HR=0.965 ).

Metastatic breast cancer and HER2 protein

Over 300,000 women are diagnosed with breast cancer in Europe every year, of whom about one third subsequently develop metastatic disease.
HER2 is a protein that is found on the surface of cells. This protein can be targeted with HER2 targeted therapies such as Herceptin ( Trastuzumab ), in people who overexpress HER2, but not in people with normal levels of HER2 protein ( HER2-negative ) breast cancer.
Breast cancers are routinely tested for the presence of HER2 to decide the most appropriate treatment.
Triple-negative breast cancer refers to any breast cancer that does not express the genes for oestrogen receptor, progesterone receptor and HER2. ( Xagena )

Source: Eisai, 2014