Emergence of the Epothilones

Epothilones, representing a newer class of naturally occurring antimicrotubule macrolides, have emerged as cytotoxic agents with significant antitumor activity against tumors that are resistant to taxanes. At least six different epothilone derivatives have entered clinical studies, including ixabepilone (Ixempra), patupilone, KOS-862, BMS-310705, KOS-1584, and ZK-EPO. Epothilones interact with microtubules in a manner distinct and functionally independent from that of taxanes.[1]. They have the advantage of not being susceptible to Pgp-mediated efflux and exhibit superior cytotoxic potency compared to taxanes, particularly in taxane-refractory tumors.[2] Additional benefits of epothilones are that they can be administered without steroid premedication and they do not cause alopecia.

Use in Breast Cancer

Of the epothilones, ixabepilone, a derivative of epothilone B and D, is the most extensively studied and the only one that is US Food and Drug Administration (FDA)-approved. This agent is indicated for use as monotherapy in metastatic breast cancer after anthracycline, taxane, and capecitabine (Xeloda) failure and in combination with capecitabine in anthracycline- and taxane-resistant advanced breast cancer.

As summarized in the review article by Donovan and Vahdat, numerous phase I/II trials have shown clinical activity of ixabepilone as monotherapy in metastatic breast cancer, with response rates as high as 57% in untreated disease, and 30% in heavily pretreated disease. Even in highly resistant breast cancers for which anthracycline, taxane, and capecitabine treatment had failed, 50% of patients receiving ixabepilone achieved stable disease, with overall response rates of 11% to 18%.

In particular, significant antitumor activity with ixabepilone was observed in triple-negative breast cancers (ie, estrogen receptor–, progesterone receptor–, and HER2 receptor–negative), which are notoriously resistant to most other agents. In a study where ixabepilone was given as neoadjuvant therapy, genomic studies found that women with hormone-receptor–negative breast cancer were more likely to respond to ixabepilone.[3] Thus, ixabepilone is a potentially effective therapy for these patients who have more limited treatment options.

Capecitabine is usually the next line of therapy for anthracycline- and/or taxane-pretreated metastatic breast cancer. Preclinical studies showing synergistic antitumor activity between capecitabine and ixabepilone eventually led to a phase III trial (the only phase III trial reported so far for an epothilone) comparing ixabepilone and capecitabine with capecitabine alone. This trial demonstrated a 25% reduced risk of disease progression and better response rates (35 vs 14%) with capecitabine and ixabepilone, given at 40 mg/m² intravenously every 21 days, compared to capecitabine alone.

The main side effects of ixabepilone, given every 3 weeks, were myelosuppresion and dose-limiting neurotoxicities in about 33% of patients, which is comparable to the rate of neurotoxicity with taxanes. Unlike taxane-related neurotoxicity, however, ixabepilone-induced neurotoxicity is generally reversible and can be reduced by schedule adjustment. Most breast cancer patients being offered ixabepilone have failed prior taxane therapy and may already have taxane-related neuropathy, so it would be difficult in the clinic to justify using ixabepilone in these patients.

Studies of epothilone D (KOS-862) in breast cancer have been reported in abstract form only. A phase I study showed that combining KOS-862 with trastuzumab (Herceptin) in patients with HER2-overexpressing chemotherapy-refractory tumors was feasible. Ongoing phase II studies in breast cancer are combining epothilones with trastuzumab, bevacizumab (Avastin), and other cytotoxic agents and will help define their place in breast cancer treatment. ZK-EPO, which was developed to overcome multidrug resistance, is also currently being tested in metastatic breast cancer.

Use in Prostate Cancer

In prostate cancer, both ixabepilone and patupilone have been fairly well studied and have been shown to significantly reduce prostate-specific antigen (PSA) levels and increase progression-free survival in hormone-refractory disease. Two randomized phase II trials have demonstrated superior PSA responses to ixabepilone and estramustine (Emcyt) compared with ixabepilone alone in chemotherapy-­naive, castrate metastatic prostate cancer. Of interest, Rosenberg et al reported that 51% of patients who had previously been treated with ixabepilone still responded to second-line taxane therapy, indicating that epothilones and taxanes are not cross-resistant and may be useful when administered in tandem.[4] Definitive phase III trials are needed to confirm these results.

Patupilone, one of the earliest epothilones to undergo clinical development, has a unique toxicity profile. Unlike the side-effect profiles of ixabepilone and other epothilones, diarrhea is the most common dose-limiting side effect of patupilone, and few patients develop neuropathy with this agent.[5]

Use in Other Cancers

Patupilone and ixabepilone have demonstrated clinical antitumor activity either alone or in combination in various cancers including ovarian, bladder, non–small-cell lung, pancreatic, and gastric carcinomas. In non–small-cell lung cancer, platinum- or taxane-pretreated patients had response rates of 6% to 14% when given patupilone or ixabepilone. Patients with platinum- and taxane-resistant ovarian cancer who were treated with patupilone had response rates as high as 25%. Interestingly, renal cell cancer, which has negligible response rates with any cytotoxic chemotherapy, yielded responses to ixabepilone in 14% of patients. Another interesting finding with epothilones is their ability to cross the blood-brain barrier in preclinical studies.[6] This has led to an ongoing trial examining the effects of these agents on brain metastases from breast cancer.

Conclusions

While the activity of epothilones in various chemotherapy-resistant cancers is encouraging, there is still no evidence that they should replace taxanes. No head-to-head comparisons have yet been conducted between taxanes and epothilones. At the least, epothilones are an alternative therapeutic option for these patients. Future trials (some already underway) will need to address the following issues: the optimal way of dosing and combining epothilones (especially with targeted agents), how epothilone efficacy and toxicities truly compare to that of taxanes, whether genomic signatures can predict treatment response, and the role of epothilones in patients who have been less heavily pretreated. With more information, we can then determine where epothilones should be positioned in our armamentarium of anticancer therapy.

Financial Disclosure: Dr. Venook has received research support from Genentech and Pfizer.

References:

References
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2. Fojo T, Menefee M: Mechanisms of multidrug resistance: The potential role of microtubule-stabilizing agents. Ann Oncol 18(suppl 5):3-8, 2007.
3. 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.
4. Rosenberg JE, Galsky MD, Rohs NC et al: A retrospective evaluation of second-line chemotherapy response in hormone-refractory prostate carcinoma: Second line after first-line epothilone-B analog ixabepilone therapy. Cancer 106:58-62, 2006.
5. Rubin EH , Rothermel J, Tesfaye F et al: Phase I, dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 23:9120-9129, 2005.
6. Fumoleau P, Coudert B, Isambert N, et al: Novel tubulin-targeting agents: Anticancer activity and pharmacologic profile of eopthilones and related analogues. Ann Oncol 18(suppl 5):9-15, 2007.