Evolving Role of the Epothilones

April 15, 2008

Ms. Donovan and Dr. Vahdat present a review of the literature on a novel class of agents, the epothilones, focusing in particular on the two most-investigated agents to date-patupilone and ixabepilone (Ixempra).

Ms. Donovan and Dr. Vahdat present a review of the literature on a novel class of agents, the epothilones, focusing in particular on the two most-investigated agents to date-patupilone and ixabepilone (Ixempra). Indeed, ixabepilone recently became the first epothilone to receive US Food and Drug Administration (FDA) approval for the treatment of metastatic or locally advanced breast carcinoma, either as monotherapy following the failure of an anthracycline, a taxane, and capecitabine (Xeloda), or as combination therapy with capecitabine following the failure of an anthracycline and a taxane.

Value of the Epothilones

Ixabepilone and the other epothilones represent a most useful addition to the arsenal of chemotherapeutic agents because of their antitumor activity, manageable toxicity profile, and low susceptibility to multiple mechanisms of tumor resistance, including those affecting the taxanes, as demonstrated in both the preclinical and clinical settings.[1,2] Resistance to chemotherapy represents a major obstacle to the treatment of cancer. Furthermore, although targeted therapies are becoming increasingly important in oncology, cytotoxic agents are likely to remain a valuable element in the treatment of cancer, as data show that combinining the two approaches provides the most benefit in the clinical setting.[3,4]

Looking to the future, one might wonder where this class of agents will be positioned in the paradigm of cancer treatment, besides the setting of patients with tumor resistance.

Ixabepilone Studies

Combination trials of ixabepilone with targeted agents are ongoing. A recently reported study evaluated the safety and efficacy of TIC (carboplatin, trastuzumab [Herceptin], ixabepilone) in patients with HER2-positive, treatment-naive, metastatic breast cancer. A total of 60 patients received trastuzumab intravenously on days 1, 8, 15, and 22 and ixabepilone (15 mg/ m2) plus carboplatin (area under the concentration-time curve [AUC] 2) on days 1, 8, and 15 of a 28-day cycle.[5] Among the 59 patients evaluable for response, 3 (5%) had a complete response and 23 (39%) had a partial response, for an overall response rate of 44%. This combination therapy was effective and caused acceptable rates of neuropathy and neutropenia. A National Cancer Institute–sponsored phase II study is currently underway to evaluate ixabepilone in combination with trastuzumab in patients with HER2-positive breast cancer.[6]

The combination of ixabepilone with bevacizumab (Avastin) as first-line therapy for metastatic breast cancer is currently being investigated in a phase II trial. Patients will be randomized to receive either ixabepilone at 16 mg/m2 given as a 1-hour infusion weekly for 3 weeks plus bevacizumab at 10 mg/kg every 2 weeks, or ixabepilone at 40 mg/m2 given as a 3-hour infusion every 3 weeks plus bevacizumab at 15 mg/kg every 3 weeks, or paclitaxel at 90 mg/m2 administered as a 1-hour infusion weekly for 3 weeks plus bevacizumab at 10 mg/kg every 2 weeks.[7]

The potential of ixabepilone as a cancer therapy is not limited to the metastatic setting, however. A phase II trial evaluated the pathologic response to neoadjuvant ixabepilone in women with stage IIA/IIIB breast cancer.[8] Following treatment with four doses of ixabepilone, 40 mg/m2, given as a 3-hour infusion every 21 days, patients underwent surgical resection and adjuvant anthracycline-based therapy. At the time of reporting, 164 patients had been enrolled and data were available on 96 patients. A complete pathologic response in the breast was achieved by 29 patients (19%), 17 (11%) of whom also had complete pathologic responses in axillary lymph nodes. Subanalysis of a cohort of estrogen receptor (ER)-negative, HER2-negative patients showed that 11 (26%) had a complete pathologic response in the breast and 8 (19%) also had complete pathologic responses in axillary lymph nodes. ER status, as measured by fluorescence in situ hybridization (FISH), was predictive of response to ixabepilone, with greater responses noted in ER-negative patients.

Data from this study indicate that ixabepilone has a manageable toxicity profile and may offer promising clinical benefit to patients receiving neoadjuvant treatment. The pathologic complete tumor response rate observed after four cycles of single-agent ixabepilone is comparable to that reported in studies of single-agent taxanes, and combination chemotherapy with AC (doxorubicin [Adriamycin], cyclophosphamide). Moreover, responders to neoadjuvant ixabepilone included patients with triple-negative tumors (ER/progesterone receptor (PR)/HER2–negative), a patient subpopulation with limited treatment options due to the absence of relevant targets for therapy.

Given the promising results of this neoadjuvant experience, randomized trials are currently evaluating the role of ixabepilone in the neoadjuvant and adjuvant settings. The PACS 08 study will randomize patients with ER/PR/HER2–negative early-stage breast carcinoma to receive adjuvant therapy with FEC100 (fluorouracil at 500 mg/m2, epirubicin [Ellence] at 100 mg/m2, and cyclophosphamide at 500 mg/m2) for three cycles every 3 weeks, followed by either docetaxel at 100 mg/m2 or ixabepilone at 40 mg/m2 for three cycles every 3 weeks.

An ongoing randomized phase II neoadjuvant trial is randomizing patients with ER/HER2–negative early-stage breast carcinoma to AC every 3 weeks, and then either weekly paclitaxel at 80 mg/m2 for 12 weeks, or ixabepilone at 40 mg/m2 for four cycles every 3 weeks.[9]

Patupilone Studies

Patupilone is many times more potent than paclitaxel or docetaxel (Taxotere). This agent has shown activity in breast cancer as well as several other histologies, as discussed by Donovan and Vahdat. Preclinical evidence shows that patupilone crosses the blood-brain barrier in animal models and suggests that patupilone has the potential to cross the blood-brain barrier in humans. Therefore, this epothilone is currently being evaluated for patients with brain metastases from non–small-cell lung cancer and breast cancer.[10,11]

Conclusions

The role of epothilones in cancer treatment is still evolving, and might not be confined to the setting of patients with tumor resistance. Future trials may elucidate distinct areas of applicability for this new class of agents in comparison to taxanes, for example in the subset of ER/PR/HER2–negative breast cancer patients, and in patients with brain metastases.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References
1. Lee FY, Borzilleri R, Fairchild CR, et al: BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429-37, 2001.
2. Thomas E, Tabernero J, Fornier M, et al: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 25:3399-3406, 2007.
3. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001.
4. Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666-2676, 2007.
5. Moulder SL, Wang M, Gradishar W, et al: A phase II trial of trastuzumab, weekly ixabepilone and carboplatin (TIC) in patients with HER2/neu-positive metastatic breast cancer: A trial coordinated by the Eastern Cooperative Oncology Group (E2103) (abstract 6070). Breast Cancer Res Treat 106(suppl 1), 2007.
6. National Cancer Institute: Trastuzumab and ixabepilone in treating women with HER2-positive metastatic breast cancer. ClinicalTrials.gov Identifier NCT00079326. Available at http://clinicaltrials.gov/. Accessed March 2, 2008.
7. Bristol-Myers Squibb: A trial of 2 schedules of ixabepilone plus bevacizumab and paclitaxel plus bevacizumab for breast cancer. ClinicalTrials.gov Identifier NCT00370552. Available at http://clinicaltrials.gov/. Accessed March 2, 2008.
8. Baselga G, Gianni L, Llombart A, et al: Predicting response to ixabepilone: Genomics study in patients receiving single agent ixabepilone as neoadjuvant treatment for breast cancer (BC) (abstract 305). Breast Cancer Res Treat 94(suppl 1):S31–S32, 2005.
9. Bristol-Myers Squibb: This is a neoadjuvant study of AC followed by ixabepilone or paclitaxel in early stage breast cancer that is HER-2 negative and estrogen receptors negative. ClinicalTrials.gov Identifier NCT00455533. Available at http://­clinicaltrials.gov/. Accessed March 2, 2008.
10. Novartis: Study of patupilone in patients with brain metastasis from non-small cell lung cancer. ClinicalTrials.gov Identifier NCT00219297. Available at http://­clinicaltrials.gov/. Accessed March 2, 2008.
11. National Cancer Institute: Epothilone B in treating patients with CNS metastases from breast cancer. ClinicalTrials.gov Identifier NCT00450866. Available at http://­clinicaltrials.gov/. Accessed March 2, 2008.