Pharmacology Update

Ixabepilone Injection (Ixempra™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved a new drug for the treatment of advanced breast cancer. Ixabepilone is a microtubule inhibitor in the class of epothilones. The drug was approved by priority review and is manufactured by Baxter Oncology GmBH in Germany and marketed by Bristol-Myers Squibb as Ixempra.™

Indications

Ixabepilone is indicated in combination with capecitabine for the treatment of metastatic or locally advanced breast cancer in patients who have failed an anthracycline and a taxane or if the cancer is taxane resistant and further anthracycline therapy is not indicated. It is also indicated as monotherapy for patients who have failed an anthracycline, taxane, and capecitabine.1

Dosage

The recommended dose is 40 mg/m2 infused intravenously over 3 hours every 3 weeks. Patients with body surface area greater than 2.2 m2 should be dosed based on 2.2 m2. Dosage reduction is necessary for patients with elevated ALT, AST, and bilirubin, moderate to severe neuropathy, hematologic toxicity (eg, neutropenia, thrombocytopenia), and concomitant administration with a strong CYP3A inhibitor. Premedication with a histamine-1 and 2 receptor antagonists is recommended. For those who have experienced a hypersensitivity reaction previously, premedication with a corticosteroid (eg, dexamethasone) is recommended.1

Ixabepilone is available as 15 mg and 45 mg vials.

Potential Advantages

Activity has been reported in patients with metastatic breast cancer resistant to an anthracycline, a taxane, and capecitabine.2,3 The combination of ixabepilone and capecitabine is more effective than capecitabine alone.4

Potential Disadvantages

Ixabepilone is metabolized by CYP3A4 thus concomitant administration with a strong inhibitor or reducer should generally be avoided. It is contraindicated in patients with severe hypersensitivity to Cremophor EL or polyoxyethylated castor oil. Major adverse events are peripheral neuropathy and bone marrow suppression necessitating dose reduction or possibly discontinuation of therapy. Ixabepilone is contraindicated in patients with AST or ALT greater than 2.5 x ULN or bilirubin greater than 1 x ULN.1

Comments

Ixabepilone is a semisynthetic analog of epothilone B. The latter is isolated from myxobacterium Sorangium cellulosum. In vitro studies showed activity against taxane-sensitive as well as taxane-resistant cell lines including those with overexpression of multidrug resistance of efflux transporter (eg, P-glycoprotein) and isoforms of beta-tubulin.5,6 It acts by stabilizing microtubule dynamics leading to cell death. FDA priority approval was based on an open label, phase III study in 752 women with measurable locally advanced or metastatic breast cancer previously treated or resistant to an anthracycline or resistant to taxane with various hormone and HER2 receptor status.1,4 Subjects were randomized to capecitabine (2,500 mg/m2 orally days 1 through 14 of a 21-day cycle or capecitabine (2000 mg/m2 orally daily) and ixabepilone (40 mg/m2 on day 1 of a 21-day cycle). The primary endpoint was progression-free survival. This was defined as time from randomization to radiologic or clinical progression (measurable skin lesion or death from any cause). Secondary endpoints were objective tumor response (ORR) based on RECIST (Response Evaluation Criteria in Solid Tumors), response duration and overall survival. Combination therapy reduced the risk of disease progression by about 30% (hazard ratio of 0.69, 95% CI; 0.58 - 0.83). ORR was 34.7% for the combination and 14.3% for capecitabine alone. Median duration of response was 6.4 months and 5.6 months respectively. Benefit of the combination appears to be independent of estrogen receptor, HER2, and estrogen-progesterone-HER2 status. Grade 3 or 4 sensory neuropathy was more common with the combination (21% vs 0%), also with fatigue (9% vs. 3%), and neutropenia (68% vs 11%), death due to toxicity (3% vs 1%). The risk of neutropenia-related death was greater in patients with liver dysfunction. About 50% of patients required dose reduction for ixabepilone or capecitabine compared to about 40% for capecitabine alone. It's too early to assess overall survival. In patients with advanced breast cancer resistant to an anthracycline a taxane, and capecitabine (n = 126), ixabepilone monotherapy produced an objective response rate of 11.5% (95% CI 6.3% -18.9%).1,3 Fifty percent of patients achieved stable disease with 14.3% of 6 months or longer. Depending on the body surface area of the patient, the cost for 5 cycles ranges from $18,440 to $27,657.

Clinical Implications

There will be an estimated 180,000 new cases of breast cancer in the United States this year with over 40,000 deaths.7 Approximately 30% of the cases are advanced or metastatic cancer. Ixabepilone provides another alternative for advanced breast cancer in patients who have failed or cannot tolerate an anthracycline, taxane or capecitabine. Its benefit appears to be across subtypes of disease including those with triple negative status (ER-receptor, progesterone-receptor, and HER2), a subtype associated with poor prognosis.8 The magnitude of benefit reported with ixabepilone and capecitabine was similar to that reported for lapatinib and capecitabine in HER2-positive patients who have progressed on a regimen containing an anthracycline, a taxane, and trastuzumab.9

References

1. Ixempra Product Information. Bristol-Myers Squibb. October 2007.

2. Thomas E, et al. J Clin Oncol. 2007;25(23): 3399-3406.

3. Perez EA, et al. J Clin Oncol. 2007;25(23):3407-3414.

4. Eva S, et al. J Clin Oncol. 2007;25(23):5210-5217.

5. Pivot X, et al. Clin Breast Cancer. 2007;7(7):543-549.

6. Lee FYF, et al. Proc Am Assoc Cancer Res. 2006;47:119 (abst 503).

7. American Cancer Society. Cancer Facts and Figures 2007. Atlanta, Ga. American Cancer Society 2007.

8. Haffty B, et al. J Clin Oncol. 2006;24:5652-5657.

9. Geyer CE, et al. N Engl J Med. 2006;355:2733-2743.