Epothilones: Clinical Update and Future Directions

ABSTRACT: Epothilones are cytotoxic compounds that function in a similar fashion to paclitaxel and show promise for the treatment of a variety of cancers by inducing microtubule bundling and apoptotic cell death. However, their mechanism of microtubule binding is different from that of paclitaxel, which makes epothilones an attractive drug class for patients with taxane-resistant malignancies. As taxane resistance remains a significant barrier in the treatment of a variety of cancers, it is important to understand epothilones and their indications. Several epothilone compounds, including ixabepilone (BMS-247550, aza-­epothilone B, Ixempra), patupilone (EPO906, epothilone B), KOS-862 (desoxyepothilone B, epothilone D), BMS-310705, ZK-EPO (ZK-219477), and KOS-1584, have been tested for the treatment of a variety of solid tumor types. Recently, ixabepilone became the first epothilone to be approved by the US Food and Drug Administration, for the treatment of metastatic or locally advanced breast cancer as monotherapy or in combination with capecitabine (Xeloda) after other treatments have failed. This article reviews recent findings from clinical trials of epothilones and discusses future directions for the use of these agents in cancer therapy, with a focus on the two most-studied epothilones to date: ixabepilone and patupilone.

Epothilones are a novel class of cytotoxic compounds that function similarly to taxanes. This drug class may offer a clinical benefit in the treatment of a variety of cancers by inducing mitotic arrest and apoptotic cell death.[1,2] The specific binding of epothilones, however, is different from that of taxanes, which makes epothilones an attractive drug class for treating patients with taxane-resistant malignancies. Because taxane resistance remains a significant barrier to the treatment of a variety of tumor types,[3,4] it is important to understand epothilones and their indications.

Interest in the potential use of epothilones as anticancer agents began when submicromolar concentrations were demonstrated to induce microtubule polymerization and stabilization.[1] Several epothilone compounds, including ixabepilone (BMS-247550, aza-epothilone B, Ixempra), patupilone (EPO906, epothilone B), KOS-862 (desoxy­epothilone B, epothilone D), BMS-310705, ZK-EPO (ZK-219477), and KOS-1584, have been investigated to treat a variety of solid tumors. This article reviews recent findings from clinical trials of epothilones and discusses future directions for their use in cancer therapy, with a focus on the two most-studied epothilones to date: ixabepilone and patupilone.

Chemical Structure and Mechanism of Action

FIGURE 1

Chemical Structure of a Taxane, Ixabepilone, and Patupilone

Epothilones contain a 16-membered macrolide ring with a methylthiazole side chain and have a comparable general structure to that of taxanes ­(Figure 1). Six natural ­epothilones have been identified to date (A through F). In order to increase stability and cytotoxicity, structural modifications have been made to the naturally occurring epothilone compounds. Ixabep­ilone (Figure 1) is derived by substituting the lactone ring on natural epothilone B (patupilone, Figure 1) with a lactam ring, which reduces its susceptibility to carboxyl­esterase metabolism.[5] BMS-310705 is also a derivative of natural ­epothilone B; the addition of an amino group at the C(21) position confers increased stability and increased water solubility.[6]

TABLE 1

Epothilone Schedules

Like many anticancer agents, epothilones function by disrupting the activity of microtubules. Microtubules are excellent anticancer drug targets because they are imperative for many cellular processes associated with cell growth and proliferation, including organelle transport, mitotic spindle formation, cell signaling, and cell structure stability.[7]

Epothilone Clinical Trials

Treatment schedules for the epothilone trials discussed in this article are presented in Table 1.[8-52]

Ixabepilone

Ixabepilone, a semisynthetic intravenous epothilone derived from natural epothilone B, was the first epothilone to be tested in humans, and recently became the first epothilone to receive US Food and Drug Administration (FDA) approval. The drug is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer following the failure of an anthracycline, a taxane, and capecitabine (Xeloda), and as combination therapy with capecitabine following the failure of an anthracycline and a taxane.

TABLE 2

Ixabepilone Safety and Efficacy

Collectively, phase I and II data suggest that ixabepilone demonstrates the most favorable antitumor activity against metastatic breast and prostate cancer. However, positive results have been reported from clinical trials across a variety of tumor types ­(Table 2).[8-35,53] Treatment schedules included ixabepilone at 6 to 50 mg/ m² infused every 3 to 4 weeks (Table 1). The recommended dose of ixabepilone is 40 mg/m² infused over 3 hours every 3 weeks. The most notable grade 3 or 4 adverse events (AEs) associated with ixabepilone are neutropenia and/or neuropathy (Table 2).

• Ixabepilone Phase II Trials: Breast Cancer-The majority of phase II clinical data for ixabepilone have been collected from studies of patients with metastatic breast cancer. In one phase II trial, 37 patients with metastatic breast cancer or locally advanced breast cancer received ixabepilone.[13] The objective response rate was 22%, with a complete response (CR) achieved by one patient and partial responses (PRs) reported in seven patients. Thirteen patients (35%) had stable disease. Two patients discontinued their participation in the trial because of sensory neuropathy, and 12 patients required dose reduction because of neuropathy, diarrhea, fatigue, or neutropenia. Grade 3/4 toxicities included neutropenia (35%), febrile neutropenia (14%), and fatigue (14%).

In another phase II trial, 12 patients with metastatic breast cancer received ixabepilone. Patients who tolerated the first cycle were administered ixabepilone at 10 mg/m²/d in subsequent cycles.[53] All patients had been previously exposed to taxanes. Ten patients had stable disease for at least 6 weeks. Notable toxicities included grade 4 leukopenia (n = 1), grade 3 neutropenia (n = 2), grade 2 neuropathy (n = 3), and grade 2 transaminase elevation (n = 2).

In a phase I/II trial, the overall response rate in 50 evaluable patients with metastatic breast cancer who received ixabepilone was 30%.[21] Four of the responders were triple-negative for the estrogen receptor (ER), progesterone receptor (PR), and HER2. In a similar phase II trial, 66 patients with taxane-resistant metastatic breast cancer were treated with ixabepilone; 12% achieved a PR and 42% achieved stable disease.[23] Of patients in the 40-mg/m² cohort (n = 49), 33% and 10% of patients experienced grade 3 and grade 4 AEs, respectively. Prominent AEs included grade 3 gastrointestinal (GI) disturbances (20%), constitutional symptoms (27%), and fatigue (27%). Six patients (12%) experienced grade 3 sensory neuropathy; no patients experienced grade 4 sensory neuropathy. Among partial responders in the 40-mg/m² cohort, 83% had not previously responded to taxane therapy.

In another phase II trial of 23 metastatic breast cancer patients previously untreated with taxanes, 57% achieved a PR and 26% had stable disease following treatment with ixabepilone.[14] The median duration of response was 5.6 months. Prominent grade 3/4 AEs included fatigue (grade 3, 13%) and neutropenia (grade 3, 9%; grade 4, 13%). No patients experienced grade 3/4 autonomic or sensory neuropathy, and 1 patient experienced grade 3 motor neuropathy.

In one of the largest metastatic breast cancer ixabepilone trials to date (113 evaluable patients),[24] 50% of patients with tumors that were highly resistant to standard chemotherapy (anthracycline, taxane, and capecita­bine) achieved stable disease, and 14.3% of patients achieved stable disease lasting at least 6 months following treatment with ixabepilone. Overall response rates as assessed by an independent radiology facility and by the study investigators were 11.5% and 18.3%, respectively. Prominent grade 3/4 AEs among all patients (n = 126) included leukopenia (grade 3, 36%; grade 4, 13%), neutropenia (grade 3, 31%; grade 4, 23%), peripheral sensory neuropathy (grade 3, 13%; grade 4, 1%), and fatigue/asthenia (grade 3, 13%; grade 4, 1%).

One phase II trial assessed the efficacy and safety of ixabepilone at 40 mg/m² infused over 3 hours every 3 weeks (n = 65) and ixabepilone at 50 mg/m² infused over 1 (n = 19) or 3 (n = 9) hours every 3 weeks in patients with metastatic breast cancer who were previously treated with anthracycline chemotherapy.[25] Patients in the 50 mg/m² 1- and 3-hour infusion cohorts achieved significant clinical activity (overall response rates = 58% and 22%, respectively). However, incidence rates of severe neuropathy in these cohorts (47% and 33%, respectively) and GI toxicities using a similar treatment regimen in a parallel phase I study[11] prompted researchers to adopt a 40-mg/m² 1-hour infusion treatment regimen.

Patients in the ixabepilone 40-mg/ m² cohort achieved an overall response rate of 41.5%, with an 8.2-month median duration of response. Twenty-three patients (35%) achieved stable disease. The incidence rate of severe neuropathy in the 40 mg/m² cohort was 23%. Other notable grade 3/4 AEs included neutropenia (grade 3, 27%; grade 4, 31%) and leukopenia (grade 3, 42%; grade 4, 8%). Gastrointestinal AEs (all grades) included nausea (54%), stomatitis/pharyngitis (32%), and diarrhea (29%). However, no more than three patients (5%) experienced any one grade 3 GI-related AE, and only one patient experienced a grade 4 GI-related AE (vomiting).

• Ixabepilone Phase II Trials: Prostate Cancer-Prostate cancer has been specifically targeted in several phase II ixabepilone trials. In a trial conducted by Galsky and colleagues, 92 chemotherapy-naive patients with progressive castrate metastatic prostate cancer received ixabepilone with or without 280 mg of oral estramustine phosphate (Emcyt) given three times a day on days 1 to 5 of each ixabepilone cycle.[31] Declines in prostate-specific antigen (PSA) ≥ 50% were observed in 69% of patients treated with ixabepilone alone and in 48% of patients treated with ixabepilone plus estramustine. Partial responses were observed in 48% of patients treated with ixabepilone alone and in 32% of patients treated with ixabepilone plus estramustine. Grade 3/4 toxicities reported in patients treated with ixabepilone alone included neutropenia (22%) and neuropathy (13%). In patients treated with ixabepilone plus estramustine, grade 3/4 toxicities included neutropenia (29%), febrile neutropenia (9%), and fatigue (9%).

Another phase II trial assessed the safety and efficacy of ixabepilone in 48 chemotherapy-naive patients with hormone-refractory prostate cancer.[29] Of 42 eligible patients, 14 (33%) had confirmed PSA responses. No confirmed objective responses were reported. However, 1 patient had an unconfirmed CR, 2 patients had an unconfirmed PR, and 11 patients had stable disease. Grade 4 toxicities were neutropenia (7%) and leukopenia (2%); grade 3 toxicities included neurologic toxicity (19%), and hematologic toxicity (17%).

A recent noncomparative randomized phase II trial evaluated the safety and efficacy of ixabepilone (n = 41) or mitoxantrone with prednisone (MP, n = 41) as second-line therapy in patients with taxane-resistant hormone-refractory prostate cancer.[32] Declines in PSA ≥ 50% were observed in each treatment group (ixabepilone, 17%; MP, 20%). One patient in the ixabepilone group and two in the MP group achieved a PR. One toxic death due to neutropenic sepsis occurred in the ixabepilone group. The most prominent grade 3/4 toxicity was neutropenia (ixabepilone, 54%; MP, 63%).

• Ixabepilone Phase II Trials: Other Tumor Types-Partial responses and/or stable disease have been reported in several phase II trials that tested the activity and safety of ixabepilone in a variety of tumor types other than metastatic breast cancer or prostate cancer, including advanced colorectal cancer,[26] advanced soft-tissue sarcoma,[9] metastatic or recurrent pancreatic adenocarcinoma,[28] metastatic gastric cancer,[8] non−small-cell lung cancer (NSCLC),[15] and urothelial carcinoma.[34] Notable AEs reported in these trials included neuropathy and neutropenia.

Results from trials that tested the activity and safety of ixabepilone in treating cisplatin-refractory germ cell tumors[27] and metastatic renal cell carcinoma[33] concluded that ixabepilone was not efficacious in these cancer types.

• Ixabepilone Phase III Trial-The only reported phase III ixabepilone data to date are from patients with metastatic breast cancer who were previously treated with or who were resistant to an anthracycline and who were also resistant to taxanes.[20] Patients were administered ixabepilone plus capecitabine (n = 375) or capecitabine alone (n = 377). The primary endpoint of the trial was progression-free survival, which was longer for the ixabepilone/capecita­bine treatment group compared with patients receiving capecitabine alone, as assessed by an independent review committee (5.8 vs 4.2 months, respectively; P = .0003) and the investigators (5.3 vs 3.8 months, respectively; P = .0011). The overall response rate was also improved for the ixabepilone-plus-capecitabine group compared with the capecitabine-alone group, as assessed by an independent review committee (35% vs 14%, respectively; P < .001).

Prominent grade 3/4 AEs included neutropenia (68% for the combination vs 11% for capecitabine alone), leukopenia (57% vs 6%), and peripheral neuropathy (23% vs 0%), which was cumulative and reversible. Overall, these data suggested that ixabepilone-plus-capecitabine treatment provided superior efficacy to capecitabine treatment alone with a manageable safety profile in patients with metastatic breast cancer who were heavily pretreated with anthracyclines and taxanes.

Patupilone

Patupilone has shown promise as an anticancer agent and has been evaluated for safety and efficacy in several clinical trials (Table 3).[36-52] Patupilone is administered intravenously in a polyethylene glycol 300 solution at doses ranging from 2 to 13 mg/m², usually every 1 to 4 weeks (Table 1). The most prominent grade 3/4 AE associated with patupilone is diarrhea.

TABLE 3

Patupilone, BMS-310705, KOS-862, ZK-EPO, and KOS-1584 Safety and Efficacy

In a phase I trial that evaluated the safety and maximum tolerated dose of patupilone in patients with advanced solid tumors, 91 patients received patupilone.[36] A PR was achieved in 3 patients, and 31 patients had stable disease. The maximum tolerated dose for both treatment regimens was 2.5 mg/m². Notable toxicities included diarrhea (53%), nausea (44%), fatigue (31%), and vomiting (31%).

In a recent phase I trial conducted by Sanchez and colleagues, 50 patients with NSCLC were infused with patupilone.[41] Five patients achieved a PR, and 16 patients had stable disease. Four patients experienced dose-limiting toxicity, one with grade 3 asthenia and three with grade 3 diarrhea.

In a phase IB trial, patupilone combined with carboplatin was well tolerated for the treatment of advanced solid tumors.[40] The maximum tolerated dose of patupilone was determined to be 4.8 mg/m² for the combination with carboplatin at an area under the curve of 6 mg/mL/min. Of 17 evaluable patients, 1 achieved a CR and 10 achieved a PR.

In a phase IIA trial, 22 patients with gastric adenocarcinoma were administered patupilone.[37] Two patients achieved a PR and 6 patients had stable disease. The overall response/disease stabilization rate was 36.4%. Grade 3 AEs included diarrhea (n = 4), vomiting (n = 3), nausea (n = 1), and fatigue (n = 1). Four grade 4 AEs were reported, one each of nausea, vomiting, gastric outlet obstruction, and dehydration.

One phase II study evaluated patupilone treatment in patients with advanced hepatocellular carcinoma.[38] Among 24 evaluable patients, serious grade 4 AEs included hyponatremia (8%), cardiac arrest (4%), GI hemorrhage (4%), and diarrhea (4%). The most common serious grade 3 AE was diarrhea (12%). Eleven patients had stable disease, and one patient achieved a PR. Overall, patupilone was described as having modest antitumor activity in patients with hepatocellular carcinoma.

In another phase II study, the activity of patupilone was assessed in 13 patients with NSCLC.[39] The only grade 4 AE was colitis (n = 1); grade 3 AEs included diarrhea (n = 2) and neutropenia (n = 1). Five patients (38%) responded to treatment, and three patients (23%) had early disease progression.

Other Epothilones

Limited data concerning KOS-862, ZK-EPO, BMS-310705, and KOS-1584 have been reported in the peer-reviewed literature to date. Many preliminary reports (Table 3), using a variety of treatment schedules (Table 1), have appeared in abstract form. Collectively, these epothilones show significant potential for the treatment of a variety of cancers. However, further research is necessary to more definitively determine their safety and efficacy.

Conclusions

The epothilones represent an exciting drug class with the potential to significantly advance cancer therapy, particularly for patients with taxane-resistant malignancies. The exact mechanism underlying taxane resistance is unknown. However, ATP-dependent efflux pumps (eg, P-glycoprotein) and mutations in the taxane-binding site on beta-tubulin may play a role.[3,54,55]

Epothilone side-effect profiles vary depending on the specific compound and dosing schedule. The major grade 3 or 4 AEs associated with epothilones include transient and manageable neuropathy (ixabepilone, BMS-310705, ZK-EPO, and KOS-862) and diarrhea (patupilone). A recent review of the biomedical literature indicated that the incidence rates of grade 3/4 sensory and motor neuropathy in patients treated with epothilones were similar to those in patients with breast cancer who were treated with taxanes (with taxanes, sensory neuropathy rates = 0%–33%, motor neuropathy rates = 0%–14%; with epothilones, sensory neuropathy rates = 0%–30%, peripheral neuropathy rates = 0%–6%).[56]

Ixabepilone and patupilone are the most studied epothilones to date, and these agents show promise for the treatment of a variety of cancers. The recent approval of ixabepilone offers a much needed additional treatment option for heavily pretreated breast cancer patients with locally advanced or metastatic disease. Several recent phase II trials have demonstrated that ixabepilone has activity in untreated and heavily pretreated metastatic breast cancer, with reported overall response rates as high as 57%[14] and 30%,[21] respectively. Partial responses and stable disease have also been reported in patients with tumors that were triple-negative for ER/PR/HER2 or taxane-resistant.[21,23,24] Data from prostate cancer patients treated with ixabepilone have also been compelling; PSA responses ranging from 17% to 69%[29,31,32] have been demonstrated in some studies, and a 48% PR rate was reported in one trial.[31] Of particular importance, ixabepilone can overcome chemotherapy-induced resistance in some patients and has demonstrated a manageable safety profile similar to that of other chemotherapeutic agents.

Ongoing phase III epothilone trials will more definitively elucidate the efficacy and safety of epothilones in specific malignancies and in combination therapy. One phase III trial demonstrated that combination ixabepilone/capecitabine treatment was more efficacious than capecitabine treatment alone in patients who were previously treated with or who were resistant to anthracyclines and taxanes.[20] Another phase III trial is examining patupilone vs doxorubicin in patients with ovarian, primary fallopian, or peritoneal cancer.[57]

As taxane resistance continues to be a significant hurdle to the treatment of a variety of tumor types, the epothilones have the potential to become an important weapon in the fight against cancer. Ixabepilone is currently the only FDA-approved epothilone and may become the standard of care for heavily pretreated or resistant breast cancer patients with advanced or metastatic disease. The potential of other epothilones for treating a variety of cancers will be more clearly elucidated in the near future.

Financial Disclosure:This work was supported by Bristol-Myers Squibb Co.

References:

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