Ixabepilone in Metastatic Breast Cancer

Metastatic Breast Cancer

Breast cancer is the most prevalent malignancy among Australian women, accounting for 28% of all newly diagnosed cancers in women in 2006. Due to an increase in the number of available new treatments and early detection, the five year survival for women after diagnosis increased from 72.6% in the period of 1980 to 1987 to 88.3% between 2000 and 2006.

Metastatic breast cancer is defined by tumour spread beyond the breast, chest wall and regional lymph nodes to other organs or tissues in the body such as the brain, liver, lungs or bones. Most women with metastatic breast cancer have been initially diagnosed with early breast cancer, treated with curative intent, and then later experience metastatic recurrence.

Treatment

The aims of treatment in women with metastatic breast cancer include control of the spread of the tumour, reduction in cancer related symptoms and complications, improved quality of life, function, and prolongation of life. Therapy can’t be considered curative when the cancer has metastasised, however for women who respond well to treatment, it can be managed for an extended period of time.

Treatment of metastatic breast cancer is based on tumour biology and clinical history, hence characterisation of tumour status is important for patients; a detailed assessment of past treatments, timing and duration, and the patient’s response during each treatment also need to be taken into account.

A large number of chemotherapy agents and combinations are effective in the treatment of metastatic breast cancer. Anthracycline and taxanes are generally considered to be the most effective. This has led to their incorporation into adjuvant chemotherapy regimens used in early breast cancer where the intention is to cure, thus many women with metastatic cancer will already have been treated with anthracyclines and/or taxanes, decreasing their usefulness in the metastatic setting, due to either resistance (inherent or acquired) or because the maximum safe cumulative dose of anthracycline is reached.

Resistance may be caused by the ability of cancer cells to alter membrane transport (decrease drug uptake into cell and increase ejection of drug from cell), alter the drug’s target enzyme, enhance DNA repair, activate pro-survival pathways, and inactivate cell death pathways.

In clinical trials, to be able to show efficacy in metastatic breast cancer, a drug needs to demonstrate an improvement in one or more of the endpoints: response rate, time to tumour progression and overall survival.

Ixabepilone

Ixabepilone is a semi-synthetic analogue of epothilone B, a natural macrolide derived from the myxobacterium Sorangium cellulosum. It blocks tubulin polymerisation in a manner similar to taxanes, inhibiting the normal process of microtubule network leading to inhibition of mitosis and cell division, it however binds to a different site of the tubulin molecule which may account for sensitivity in taxane resistant cell lines.

Three key studies have investigated the efficacy of ixabepilone as monotherapy or in combination with capecitabine in patients with metastatic breast cancer who were pre-treated with, or resistant to, anthracyclines, taxanes, or capecitabine. Capecitabine is commonly used in the anthracycline and/or taxane pre-treated population.

A non-comparative, multicentre, multinational, phase II trial investigated the safety and efficacy of ixabepilone as monotherapy in 126 women with metastatic breast cancer resistant to anthracyclines, taxanes and capecitabine.⁴ Ixabepilone 40 mg/m² was administered as a 3 hour intravenous infusion on day 1 of a 3-week cycle. Ixabepilone demonstrated efficacy and a manageable safety profile.

Fifty percent of patients achieved stable disease. Median progression free survival and duration of response was 3.1 and 5.7 months respectively. Median overall survival was 8.6 months. Noticeable treatment related events included peripheral sensory neuropathy, fatigue/asthenia, myalgia, and mucositis.

Two phase III trials investigated ixabepilone in patients with previously treated breast cancer. Study one⁵ investigated 725 patients with resistance to anthracycline and taxane therapy.

Study two⁶ had 1,221 patients pre-treated with anthracycline and taxane. These studies compared ixabepilone 40mg/m² every 3 weeks plus capecitabine 1000mg/m² twice daily for 14 days (days 1 to 14) compared with capecitabine 1250mg/m² twice a day for 14 days of a 21 day cycle.

Both studies demonstrated significant improvement in progression free survival with the addition of ixabepilone to capecitabine. The median progression free survival with ixabepilone plus capecitabine versus capecitabine alone was 5.8 versus 4.2 months in study one and 6.24 versus 4.4 months in study two.

Ixabepilone plus capecitabine was well tolerated with a manageable toxicity profile. The most common adverse events observed were neutropenia which occurred in 68% of patients receiving ixabepilone plus capecitabine compared to 11% in patients receiving capecitabine alone, and peripheral neuropathy (22% vs 0%).

In October 2007, the FDA approved ixabepilone for the treatment of metastatic or locally advanced breast cancer in patients after failure of anthracycline and a taxane in combination with capecitabine or as monotherapy after failure of an anthracycline, a taxane and capecitabine.

While not yet considered for approval in Australia, ixabepilone may improve the range of available cytotoxic drugs in the treatment of metastatic breast cancer thus improving patient outcomes.