Ixabepilone In Combination With Capecitabine Extends Progression-Free Survival In Metastatic Breast Cancer By 40% Compared To Capecitabine Alone

Main Category: Breast Cancer
Also Included In: Cancer / Oncology;  Clinical Trials / Drug Trials
Article Date: 28 Sep 2007 - 16:00 PDT

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The results of a large Phase III clinical trial show that women with metastatic breast cancer that has rapidly progressed after prior treatment with chemotherapy, experience 40 percent longer progression-free survival (4.2 to 5.8 months) with an investigational combination chemotherapy than with the current standard treatment.1 The Bristol-Myers Squibb clinical study evaluated ixabepilone - potentially the first in a new class of cancer drugs called the epothilones - in combination with capecitabine; and met its primary endpoint of progression-free survival. In the study, improvements were observed in the late-stage treatment setting as well as in a sub-set analysis of 55 patients in the first-line setting.1

The data, reported during an oral presentation at the European Cancer Conference (ECCO 14), are the first Phase III results for the epothilone class to be presented in Europe. With 752 patients randomised, it is also the largest study of women with rapidly progressing metastatic breast cancer that has previously been treated with standard chemotherapies, such as anthracyclines and taxanes.

"Although more women are being treated successfully for breast cancer, metastatic breast cancer remains a major challenge," said Professor Jacek Jassem, Professor of Clinical Oncology, Head, Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland and study investigator. "Women who have metastatic breast cancer that is resistant to chemotherapy often have limited treatment options. Epothilones work differently than other classes of chemotherapy and are less susceptible to known tumour resistance mechanisms. Therefore, we believe this new class, and ixabepilone in particular, may be an effective treatment option for some metastatic breast cancer patients."

Metastatic breast cancer is the number one cause of cancer death worldwide in women under the age of 55.2 Its prevalence is increasing in Europe due to an ageing population, with no sign of slowing.3 Although chemotherapy is critical to breast cancer care, many tumours are resistant to treatment and continue to grow.4,5 The study results were supported at ECCO by a separate summary of Phase II and III data, which demonstrated ixabepilone's activity across multiple breast cancer settings, including in the earlier settings.6

"The initial focus of ixabepilone development is patients with resistant metastatic breast cancer, an area of high medical need as these patients currently have limited options. The data indicate that ixabepilone can be an effective new option for such patients," said David Lee, vice president, Global Clinical Development, Bristol-Myers   Squibb. "We are also encouraged to see ixabepilone activity in earlier settings of breast cancer, and Bristol-Myers Squibb is committed to further studying the potential of ixabepilone."

The epothilones are a new class of chemotherapy7 with a mode of action that allows them to bind to their target and destroy cancer cells, even if those cells have become resistant to other chemotherapies.8,9,10,11 Bristol-Myers Squibb is investigating epothilones in a number of cancers, including ixabepilone for breast cancer.

A marketing authorisation application for ixabepilone has not yet been submitted to the European Medicines Agency but a New Drug Application is being evaluated by the U.S. Food and Drug Administration.

Study results in detail:

1. Phase III - Oral Presentation

In this multinational, Phase III trial, 752 women with metastatic breast cancer, whose tumours are resistant to anthracyclines and taxanes, were randomised to treatment with ixabepilone in combination with capecitabine or capecitabine treatment alone. Resistance was defined as disease progression within three to four months following anthracycline/taxane treatment in the metastatic setting and six to 12 months following adjuvant anthracycline/taxane therapy.

Ixabepilone and capecitabine combined demonstrated superior efficacy to capecitabine alone in women with metastatic breast cancer that has rapidly progressed after prior treatment. The results were statistically significant and showed:1

- Patients who received ixabepilone and capecitabine combined experienced a 40% improvement in progression-free survival (5.8 vs. 4.2 months) (p=0.0003)

- More than twice as many patients achieved an objective tumour response with ixabepilone and capecitabine

combined (35% vs. 14%) (p<0.0001) - With ixabepilone in combination with capecitabine, the most common treatment-related adverse events were low grade (grade 1 or 2), generally reversible, and consistent with the safety profile of the individual chemotherapies. Neuropathy (defined as pain, numbness, tingling, swelling, or muscle weakness in various parts of the body) was more frequent in the combination arm, but reversible and manageable with dose reductions in most cases. The incidence and characteristics of more severe neuropathy (grade 3 or 4 neuropathy, 23%) was similar to that seen with paclitaxel.

In a prospectively-defined subset analysis, ixabepilone and capecitabine was compared to capecitabine alone for the 55 patients in the trial who received the study drugs as their first treatment for metastatic breast cancer. All 55 patients had been previously treated with anthracycline/taxane therapy in the adjuvant or neo-adjuvant setting and had relapsed rapidly from such therapy.

In this sub-set analysis, ixabepilone and capecitabine combined in a first-line metastatic treatment setting demonstrated greater progression-free survival than capecitabine alone. The results showed:1

- Patients who received ixabepilone and capecitabine combined experienced 7.0 months progression-free survival vs. 2.1 months (p=0.0109)

- Patients achieved a favorable tumour response with ixabepilone and capecitabine combined (44% vs. 10%) (p=0.0054)

- Safety results were similar in the subgroup to the larger study population.

Median overall survival data from this phase III trial are expected to become available in 2008.

2. Phase II & III - Poster Presentation

In Phase II and III clinical development, ixabepilone has been studied in various breast cancer settings, both as monotherapy and in combination with capecitabine. These data, detailed collectively, show the anti-tumour activity of ixabepilone increases with earlier use.6

Specifically, objective tumour response results from Phase II studies show that:

- In an early breast cancer setting where ixabepilone was used as neo-adjuvant therapy, the pathological complete response rate was 18% with ixabepilone

- In a first-line metastatic breast cancer setting, patients who had relapsed following anthracyclines for early breast cancer, achieved an objective tumour response of 42% (partial response)

- Patients with metastatic breast cancer that had failed multiple therapies also demonstrated a significant tumour response (12% partial response).

In a large Phase III study (detailed above) more than twice as many women with metastatic breast cancer achieved an objective tumour response with ixabepilone and capecitabine combined (35%) compared with capecitabine alone (14%).

Progression-free survival

- Progression-free survival refers to the time that a patient remains alive, without the disease getting worse.

Bristol-Myers Squibb Oncology in Europe

- Bristol-Myers Squibb has been at the forefront of the fight against cancer for more than 40 years. The company's breakthrough cancer products today represent cornerstone treatments, including cisplatin, TAXOL (paclitaxel), and carboplatin.

- In Europe, the company recently introduced SPRYCEL® (dasatinib) for the treatment of two different types of leukaemia, and has one of the strongest oncology pipelines in the industry.

Bristol-Myers Squibb

Bristol-Myers Squibb is a global pharmaceutical and related healthcare products company whose mission is to extend and enhance human life.

References

1. Jassem J, Thomas E, Gomez H, et al. Phase III study of ixabepilone plus capecitabine in patients with metastatic breast cancer (MBC) progressing after anthracyclinse and taxanes: subgroup analysis of patients receiving ixabepilone in the first- line setting. Oral presentation at the 14th European Cancer Conference (ECCO), 23-27 September 2007.

2. Ferlay J, et al. Globocan 2002: Cancer incidence, mortality and prevalence worldwide Version 2.0 (IARC, Cancerbase No. 5) Lyon, France, IARC Press, 2004.

3. European Commission RAPID Database. New EU Guidelines on Breast Cancer Screening and Diagnosis. MEMO/06/161. 7 April 2006. Last accessed 14 April 2007: Please click here.

4. Peedell C. Concise Clinical Oncology. 2005, Elsevier. p68.

5. Ng CP, Bonavida B. A new challenge for successful immunotherapy by tumors that are resistant to apoptosis: two complementary signals to overcome cross-resistance. Adv Cancer Research. 2002;85:145-74.

6. Fumoleau P, Llombard-Cussac A, Roche H, et al. Clinical activity of the novel epothilone B analog, ixabepilone, across the breast cancer disease continuum. Poster presentation at 14th European Cancer Conference (ECCO), 23-27 September 2007.

7. Nettles JH, Li H, Cornett B, et al. The binding mode of epothilone A on alpha, beta-tubulin by electron crystallography. Science. 2004;305: 866-869.

8. Altmann K-H, Pfeiffer B, Arseniyadis S et al. The Chemistry and Biology of Epothilones - The Wheel Keeps Turning. ChemMedChem. March 2007; Epub ahead of print.

9. Hofle G, Reichenbach H. Anticancer Agents From Natural Products. 2005. 413-450.

10. Fojo AT, Menefee M. Microtubule targeting agents: basic mechanisms of multi-drug resistance (MDR). Semin Oncol. 2005;32 (Suppl 7):S3-S8.

11. Borzilleri RM, Vite GD. Epothilones: new tubulin polymerization agents in preclinical and clinical development. Drugs of the Future. 2002;27:1149-1163.

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