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14 June 2011
The EMBRACE study of women with heavily pre-treated metastatic or locally recurrent breast cancer (n=762) found that eribulin mesylate 1.4mg/m2 administered intravenously at days 1 and 8 of a 21-day cycle (n=508) improved median overall survival by 2.5 months compared with treatment of physician’s choice. 96% of patients in the control group received chemotherapy. The incidence of serious adverse events appeared to be similar in the two groups. The most common adverse events were asthenia or fatigue, and neutropenia.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
Eribulin▼ has recently been launched in the UK for women with locally advanced or metastatic breast cancer who have progressed after at least two previous chemotherapy regimens. It is a non-taxane, new class of agent that inhibits the growth phase of microtubules. There are few options available currently for heavily pre-treated women and therefore there may be interest from patients and physicians.
Local decision-making bodies may need to consider the managed introduction of this drug at this time, taking into account that NICE guidance is anticipated in December 2011.
What is the background to this?
Breast cancer is the most common cancer affecting women in the UK. Over 40,000 women were newly diagnosed in England and Wales during 2007. Approximately 5% of women presenting with breast cancer have advanced disease with distant metastases. The role of current treatments for advanced and metastatic breast cancer is to palliate symptoms, prolong survival and maintain a good quality of life with minimal adverse events.
Eribulin (Halaven®) has recently become available in the UK at a price of £313 per 2ml vial. It is a non-taxane agent that inhibits the growth phase of microtubules. It is licensed as monotherapy for 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. The recommended dose is 1.23mg/m2 eribulin (equivalent to 1.4mg/m2 eribulin mesylate) administered intravenously over two to five minutes on days 1 and 8 of every 21-day cycle.
NICE guidance on eribulin for advanced breast cancer is expected to be published in December 2011.
Further information on the management of breast cancer can be found on NHS Evidence and in the e-learning section of the NPC’s website.
What does this study claim?
The primary end point was overall survival in the intention-to-treat (ITT) population. There were 274 (54%) deaths in the eribulin group and 148 (58%) in the comparator group which comprised the treatment of physician’s choice (TPC) at the time the primary analysis was performed. Overall survival was improved by eribulin (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.66 to 0.99, P=0.041). Median overall survival was 13.1 months (95%CI 11.8 to 14.3) in the eribulin group and 10.6 months (95%CI 9.3 to 12.5) in the TPC group, an improvement of 2.5 months. Median progression-free survival (PFS), a secondary end point, was 3.7 months with eribulin and 2.2 months with TPC [HR 0.87 (95%CI 0.71 to 1.05), P=0.137]. The most common adverse events in both groups were asthenia or fatigue (54% with eribulin vs. 40% with TPC) and neutropenia (52% vs. 30%, respectively).
How does this relate to other studies?
NICE makes recommendations about approaches to therapy in their clinical guideline on advanced breast cancer. It notes that there is little good-quality evidence about the relative clinical and cost effectiveness of currently recommended treatments, either in combination or in sequence.
The guideline recommends first-line treatment with an anthracycline-based chemotherapy regimen. Where this is unsuitable (for example if the person has previously received anthracycline-based adjuvant therapy or has a contraindication to anthracyclines), or where the disease relapses following an anthracycline-based regimen, docetaxel monotherapy is recommended. Vinorelbine or capecitabine may be considered as subsequent lines of treatment.
Gemcitabine in combination with paclitaxel, within its licensed indication, is recommended as an option for the treatment of metastatic breast cancer only when docetaxel monotherapy or docetaxel plus capecitabine are also considered appropriate.
At present, the only data on eribulin patients previously treated with capecitabine therapy is from a sub-group of the EMBRACE trial. However, a study comparing eribulin to capecitabine for locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes is ongoing, with a date for final data collection of September 2011.
So what?
There are currently few options for women with locally advanced or metastatic breast cancer who have received two or more chemotherapy regimens. The authors of the EMBRACE study state that a literature search of phase III trials of metastatic breast cancer found that no other studies included such heavily pre-treated patients as in EMBRACE. Although it is the gold standard, the use of overall survival as the primary endpoint in such a trial is uncommon but welcome.
The use of several different chemotherapies in the TPC control group, each with their specific adverse effect profile, may have precluded detailed comparison with eribulin.
However various subgroup analyses of the data were carried out for licensing purposes by the EMA, including in taxane-refractory patients and in those patients who had received prior capecitabine therapy. There were no important differences in terms of clinical efficacy with regard to HR point estimates and CIs for any of the sub-group analyses conducted. The results from these analyses supported the primary ITT population analysis.
In addition to improving survival, goals of chemotherapy in advanced breast cancer are alleviation of cancer-related symptoms and enhanced quality of life. Unfortunately, due to the design of the EMBRACE study and possible confounding by the different treatment options used in the TPC arm, it was not possible to capture QOL data in this study. Without quality of life data it is difficult to assess how the additional 2.5 months of survival gained is balanced by the adverse effects that the patient may experience. Quality of life is being investigated in ongoing trials.
Design
Phase III, global, randomised, open-label, event-driven study. Patients and investigators were not masked to treatment allocation. Randomisation was stratified to ensure balance between treatment groups within the following levels: geographical region, previous capecitabine treatment and HER2 status before randomisation.
Patients
Women with heavily pre-treated locally recurrent or metastatic breast cancer with a life expectancy of 3 months or more were included. They had to have adequate bone marrow, renal and hepatic function. Patients with pre-existing neuropathy (greater than grade 2) were amongst those excluded.
Included patients had received a median of four previous chemotherapy regimens, including an anthracycline and a taxane and at least two regimens for locally recurrent or metastatic breast cancer. 73% of patients had received capecitabine. They had a mean age of 55 years and 74% had HER2 negative disease.
Intervention and comparison
Patients were randomised to eribulin or control in a 2:1 ratio. Eribulin (n=508) was administered as 1.4mg/m2 eribulin mesylate intravenously during two to five minutes on days 1 and 8 of a 21-day cycle. The control group (n=254) was given treatment of physician’s choice (TPC), which consisted of single-agent chemotherapy, hormonal or biological treatment; radiotherapy; or symptomatic treatment alone. Doses could be modified if grade 3 or 4 adverse events were seen. Treatment was continued until the emergence of unacceptable adverse events, disease progression, a request to stop or serious protocol non-compliance.
A total of 238 out of the 247 (96%) of women who received TPC received chemotherapy (such as vinorelbine, gemcitabine or capecitabine). The median duration of treatment was 2.1 months (range 0.03 to 21.2) for patients who received chemotherapy and 3.9 months (range 0.7 to 16.3) for those in the eribulin group. 295 of the 503 patients (59%) who received eribulin had five or more cycles (range 1 to 23).
Outcomes and results
The primary end point was overall survival in the ITT population. Eribulin was more effective than TPC: 274 deaths (54%) vs. 148 (58%) respectively. HR for overall survival 0.81 (95%CI 0.66 to 0.99), P=0.041. Median overall survival was 13.1 months (95%CI 11.8 to 14.3) in patients who had received eribulin and 10.6 months (95%CI 9.3 to 12.5) in the TPC group, an improvement of 2.5 months.
An updated analysis of overall survival (not protocol prespecified) that was requested by European and US regulatory authorities included 589 deaths (386 [76%] in the eribulin group; 203 [80%] in the TPC group). These results confirmed the significant increase in overall survival for eribulin compared with TPC in the ITT population; HR 0.81 (95% CI 0.67 to 0.96), P=0.014. Median overall survival was 13.2 months (95% CI 12.1 to 14.4) with eribulin and 10.5 months (9.2 to 12.0) with TPC.
Median PFS, a secondary end point, was assessed by independent, blinded review. This was 3.7 months (95%CI 3.3 to 3.9) for eribulin and 2.2 months (95%CI 2.1 to 3.4) for TPC [HR 0.87 (95%CI 0.71 to 1.05), P=0.137].
13% of patients receiving eribulin and 15% of those having TPC discontinued therapy due to an adverse event. Peripheral neuropathy was the most common adverse event leading to discontinuation in 5% (24/503) patients the eribulin arm. Serious adverse events were seen in 25% (126/503) of the eribulin and 26% (64/247) of the TPC groups. Common adverse events in both groups were asthenia/fatigue (54% with eribulin vs. 40% with TPC) and neutropenia (52% vs. 30%, respectively). Granulocyte colony stimulating factor was given to 18% of the eribulin and 8% of the treatment of physician’s choice group. Fatal adverse events related to treatment, including febrile neutropenia, occurred in five patients (1%) receiving eribulin and in two patients (1%) receiving their physician’s treatment of choice.
Sponsorship
This study was sponsored by Eisai.
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