The United Kingdom’s National Institute for Health and Clinical Excellence (NICE) today published its final appraisal determination (FAD) on eribulin (Halaven?, Eisai), a non-taxane, microtubule dynamics inhibitor. While eribulin, launched on 20 April 2011,is commercially available in the UK, in England and Wales, the final NICE appraisal does not recommend NHS funding. [1]

Eribulin is a new treatment approved for the treatment of patients with locally advanced or metastatic breast cancer whose disease has progressed after at least two chemotherapeutic regimens for advanced disease.[2] Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments.

Metastatic breast cancer
Breast cancer is now the most common cancer in the UK and the lifetime risk of being diagnosed with breast cancer is 1 in 8 for women in the UK.[3] In 2008, almost 47,700 women were diagnosed with breast cancer, around 130 women a day.[4] Metastatic breast cancer is an advanced stage of the disease that occurs when cancer spreads beyond the breast to other parts of the body. Approximately five percent of women with breast cancer will have metastatic disease at the time of diagnosis[4] and 35% will develop metastatic disease at some point after the initial diagnosis.[5] Only 13% of women presenting with metastatic breast cancer will survive beyond five years.[5]

Unmet need
There is a clear unmet need for new treatment options for women with heavily pre-treated metastatic breast cancer whose disease has continued to progress despite receiving several lines of chemotherapy. Clinical trials have shown that eribulin is the first single agent chemotherapy to demonstrate a prolongation of overall survival in late lines of therapy in metastatic breast cancer.[6] It has an expected and manageable safety profile which is in line with other single agent drug treatments for advanced breast cancer.[6] Despite the need for new treatment options and the proven benefits of eribulin in improving overall survival, NICE has issued a negative recommendation for the use of eribulin on the NHS.

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Improved overall survival
Professor Chris Twelves, Deputy Director, Cancer Research UK Clinical Centre in Leeds commented; “Eribulin has challenged the notion that improved overall survival is an unrealistic outcome for women with heavily pre-treated advanced breast cancer. The EMBRACE trial not only demonstrated that eribulin provides an improvement in median overall survival compared to single agent treatments, but that this survival benefit is not outweighed by any unexpected or unmanageable side effects, an important aspect for any treatment in this setting.”

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Costs of treatment
Nick Burgin, European Director of Market Access for Eisai confirmed that the company does not understand the final NICE recommendation. “…[The] final NICE appraisal… denies women access to a treatment that is proven to prolong life and provides an opportunity for the NHS to improve cancer outcomes in metastatic breast cancer patients. … We feel that patients should not be unable to access a life-prolonging drug like eribulin on the basis of an arbitrary threshold of cost per quality adjusted life year (QALY) used by NICE…”

Quality-adjusted life year
The quality-adjusted life year is a measure of disease burden, including both the quality and the quantity of life lived used in assessing the value for money of a medical intervention or drug. The QALY method helps NICE “calculate” the number of years of life that would be added by such intervention or drug. After calculating QALY to compare how much someone’s life can be extended and improved – cost effectiveness are considered. This is based on how much a treatment of drug costs per QALY. In the United Kingdom, drugs and treatment options considered on a case-by-case basis. However, as a general rule, NICE does not consider a drug of intervention cost effective if the costs are more than ?20,000-30,000 per QALY. In these cases, the final appraisal determination will be negative.

Restricting access
Eribulin is already available and reimbursed in a number of countries throughout Europe and this negative NICE decision further demonstrates the inequality of access to cancer treatments for patients in the United Kingdom compared to other countries. The NICE decision restricts NHS access to eribulin in England and Wales, but fortunately the new drug can be accessed in England through the Cancer Drugs Fund where it has been approved in four of the 10 regions.

The Cancer Drug Fund, which began operating in April 2011 with an annual budget of ?200 million, has been established to make funds available to cancer patients to get cancer drugs that haven?t been approved by NICE and aren?t generally available within the NHS in England. Cancer Drug Fund will continue to do so until the end of March 2014. From 2014 the Britsh Government plans to introduce a new way of setting prices for cancer drugs which aims to make more drugs routinely available in the NHS.

Most of the cancer drugs made available by the fund have not been evalualted by NICE, may not work well enough or are considered not cost effective. The aim of the fund is to make it easier for patients get these new cancer drugs and to offer them as much treatment as possible. However, while the Cancer Druf Funds offers funding for eribulin in 4 Strategic Health Authorities (SHAs) in England, it denies access to those living outside these regions or in other parts of the United Kingdom, including Scotland, Wales and Northern Ireland, where the Cancer Drugs Fund system does not yet exist.

Clinical trial results
EMBRACE 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 (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 (97%) of patients in the TPC arm received chemotherapy.[2]

Results of the Phase III study showed that patients treated with eribulin survived on average 2.7 months longer than patients who received ‘treatment of physician’s choice’ (TPC) (eribulin 13.2 months vs. TPC 10.5 months, nominal p=0.014).[2] TPC represents active treatment options currently used by doctors in real world clinical practice.

A further pre-planned analysis of region 1 (North America/Australia/Western Europe) of the Phase III EMBRACE clinical trial was also carried out. The results showed a significant overall survival benefit of eribulin over TPC of 3.0 months (nominal p=0.031).[3]Ten UK trial centres were included within region 1 and this further analysis was carried out as the patients in this region were felt to best represent how patients in the UK are generally managed.

[1] National Institute for Health and Clinical Excellence. Final appraisal determination. Eribulin for the treatment of locally advanced or metastatic breast cancer. November 2011
[2] Summary of Product Characteristics Halaven (Last updated March 2011).
[3] Cancer Research UK. Cancer Statistics – Key Facts. Last accessed 1 April 2011.
[4] Cancer Research UK. Statistics and outlook for breast cancer. Last accessed 1 April 2011.
[5] Synovate track the usage of anti-cancer drugs, through a representative panel of cancer specialists completing forms directly from patient medical records in each country, including the UK. Eisai data on file.
[6]. 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 III open-label randomised study. The Lancet. 2011; 377: 914 -923.

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