Ixabepilone plus capecitabine for breast cancer patients with an early metastatic relapse after adjuvant chemotherapy: two clinical trials

BackgroundDespite recent advances in treating patients with metastatic breast cancer (MBC), outcomes remain poor. Ixabepilone is a semisynthetic analogue of epothilone B with low susceptibility to multiple mechanisms of tumor-cell resistance. This review examined the results of 2 phase III clinical trials of ixabepilone in patients with drug-resistant or heavily pretreated, locally advanced breast cancer or MBC.Patients and MethodsIn both studies, women with locally advanced breast cancer or MBC pretreated with, or resistant to, taxanes or anthracyclines were randomly assigned to ixabepilone plus capecitabine, or capecitabine alone, until disease progression or unacceptable toxicity occurred.ResultsIxabepilone plus capecitabine significantly prolonged progression-free survival (PFS) compared with capecitabine alone. The median PFS was prolonged by 1.5 months and 1.8 months in the 2 studies (hazard ratio, < 0.8 in both studies; P ≥ .001). These observations remained valid within several patient subsets: those receiving ixabepilone as first-line therapy, those with taxane-resistant disease, and those with particularly poor prognostic features. Ixabepilone plus capecitabine significantly improved overall survival (OS) compared with capecitabine in patients with symptomatic disease (12.3 vs. 9.5 months, respectively; P = .015). Peripheral neuropathy with ixabepilone was generally reversible and was effectively managed by dosage reduction in most patients. Ixabepilone did not exacerbate capecitabine-induced hand-foot syndrome or diarrhea.ConclusionThe results of these 2 large phase III trials suggest that ixabepilone plus capecitabine may improve treatment outcomes for patients with locally advanced breast cancer or MBC resistant to, or heavily pretreated with, taxanes or anthracyclines, even in those with poor prognostic features.     

Ixabepilone: clinical role in metastatic breast cancer

Ixabepilone has shown promising clinical data in metastatic breast cancer (MBC) and may be particularly valuable in patients showing progression after treatment with standard chemotherapy. This article reviews the developing clinical profile of ixabepilone in MBC. Unlike taxanes and anthracyclines, ixabepilone has low susceptibility to multiple mechanisms of tumor cell resistance and has activity against tumors resistant to taxanes and/or anthracyclines. In phase II studies, single-agent ixabepilone resulted in objective response rates ranging from 11.5% to 57% in patients who had locally advanced or metastatic breast cancer, including patients who were treated as first-line therapy or in resistant patients who had received multiple lines of previous treatment. In two large phase III studies in women who had locally advanced or MBC pretreated with or resistant to taxanes and/or anthracyclines, a combination of ixabepilone plus capecitabine was superior to capecitabine alone in terms of progression-free survival and response rates. The efficacy of ixabepilone has also been shown in subsets, including patients with poor prognosis, the first-line metastatic setting, and in triple-negative disease. Studies are underway to investigate this agent in combination with biologics. A recent three-arm study has shown the activity and tolerability of ixabepilone plus bevacizumab; however, comparative data are not yet available. The toxicity profile of ixabepilone is generally manageable and predictable. The most common adverse events associated with ixabepilone include peripheral neuropathy and neutropenia. Ixabepilone appears to offer a promising alternative chemotherapeutic agent for patients with MBC who progress on various taxanes, anthracyclines, and capecitabine.     

Optimizing ixabepilone treatment schedules in patients with advanced or metastatic breast cancer

The epothilone B analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. Ixabepilone is approved by the FDA for treatment of patients with metastatic breast cancer (MBC) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. Ixabepilone is generally well tolerated at the approved dose and administration schedule of 40 mg/m(2) every 3 weeks. The most commonly observed dose-limiting adverse events (AEs) associated with ixabepilone are myelosuppression and peripheral neuropathy. Dose modification including dose reduction and dosing schedule modification may be utilized to manage toxicities, but this must be based on careful hematologic, neurologic, and liver function monitoring. Other ixabepilone dose schedules are being evaluated to further improve the risk/benefit profile. Weekly and daily schedules of ixabepilone have shown useful efficacy and reasonable tolerability. A recent phase II trial compared the tolerability of ixabepilone dosed once weekly (16 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle) or every 3 weeks (40 mg/m(2) on Day 1 of each 21-day cycle) in patients with MBC. Preliminary data showed that both dosing schedules had an acceptable safety profile; however, more AEs were reported in patients receiving ixabepilone every 3 weeks. Ixabepilone is also being evaluated in combination with other anticancer agents (e.g., bevacizumab and lapatinib), in earlier breast cancer settings and in other indications.     

Activity of Ixabepilone in Patients with Metastatic Breast Cancer with Primary Resistance to Taxanes

Primary drug resistance, defined as disease progression as best response to treatment, presents an important problem in everyday clinical practice. Primary taxane resistance, reported in up to 55% of patients with breast cancer, plays a critical role in minimizing the efficacy of taxane-based chemotherapy for metastatic breast cancer (MBC). The epothilones are a novel class of antineoplastic agents, developed to overcome tumor-resistance mechanisms. Ixabepilone, the first drug in this class, stabilizes microtubule polymerization, and induces cell-cycle arrest and apoptosis. Ixabepilone demonstrates low susceptibility to different and multiple mechanisms of drug resistance that play a crucial role in primary taxane resistance, such as tumor overexpression of neuronal-specific β-tubulin isotype III and drug-efflux transporters. In phase II trials, ixabepilone demonstrated proven activity in patients with MBC whose tumors had primary or secondary resistance to taxanes and other agents. Ixabepilone also demonstrated activity in patients with tumor types such as renal-cell cancer and pancreatic cancer that are usually intrinsically insensitive to chemotherapy, including taxanes. To determine the activity of ixabepilone in patients with primary taxane resistance, a retrospective analysis of patient subsets from 2 clinical trials was conducted. Ixabepilone demonstrated clinical activity as monotherapy, and in combination with capecitabine, in patients with MBC who had disease progression as best response to previous taxane therapy. Response rates in patients with primary taxane resistance were comparable to responses observed in total patient populations. The clinical results support the hypothesis that ixabepilone can overcome or circumvent primary mechanisms of resistance to taxanes and other chemotherapeutic agents.     

Clinical experience with epothilones in patients with breast cancer

The search for novel chemotherapeutic agents in the treatment of breast cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the epothilones and their analogues. Epothilones stabilize microtubules in a manner similar to taxanes but are structurally distinct. Ixabepilone, an epothilone B analogue, having demonstrated high antimicrotubule activity in preclinical studies, has shown notable efficacy in phase II trials in patients with early-stage and metastatic breast cancer. Of particular note, single-agent ixabepilone is effective in tumors resistant to anthracyclines, taxanes, and capecitabine, for which there is currently no recommended therapy. Different mechanisms of action and the non-overlapping toxicities of ixabepilone with other agents provide the rationale for ixabepilone in combination as a valid therapeutic approach. Phase II results assessing ixabepilone in combination with capecitabine in anthracycline- and taxane-pretreated patients are promising. The investigation of ixabepilone in the neoadjuvant setting has also revealed potential biomarkers to predict ixabepilone response. Ixabepilone has demonstrated activity in patients with tumors that are estrogen receptor-, progesterone receptor-, and HER2-negative. The safety profile throughout the trials has been manageable, with peripheral neuropathy as one of the more notable adverse events, which has been mostly reversible. A phase III trial comparing ixabepilone plus capecitabine versus capecitabine alone demonstrated significant prolongation of median progression-free survival and reduction in relapse risk. Additionally, other members of the epothilone family, such as patupilone, ZK-EPO, BMS-310705, and KOS-862, have demonstrated efficacy against breast cancer in phase I clinical trials. Ongoing phase II/III trials continue to assess ixabepilone and other members of the epothilone family in breast cancer, particularly in combination regimens, as being valid treatment options in multidrug-resistant breast cancer.     

Role of cytotoxics in combination with targeted agents

Combining cytotoxics with targeted agents can lead to enhanced efficacy in metastatic breast cancer (MBC). Cytotoxic/targeted agent combinations approved for the treatment of MBC include trastuzumab plus paclitaxel or docetaxel for the first-line treatment in patients presenting with HER2-positive breast cancer. Furthermore, in HER2-negative disease combining bevacizumab with paclitaxel for the first-line treatment of HER2-negative patients is superior compared to monotherapy with either drug. Lapatinib plus capecitabine recently received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for conditional marketing authorisation in patients with HER2-positive breast cancer following prior therapy with anthracyclines, taxanes and trastuzumab. The novel epothilone ixabepilone is also under investigation in this setting. Preclinical studies have demonstrated synergistic activity in combination with targeted agents including trastuzumab and bevacizumab and early clinical studies have revealed encouraging response rates in combination with trastuzumab and carboplatin in patients with HER2-positive MBC. This article will review recent data on the efficacy of combining cytotoxics with targeted agents for the treatment of MBC.     

Efficacy of ixabepilone in ER/PR/HER2-negative (triple-negative) breast cancer

Patients with ER/PR/HER2-negative (triple negative) breast cancer are not candidates for hormonal therapy or HER2-targeted agents. Ongoing research is aimed at identifying and understanding the benefit of established and emerging therapies in this disease setting. Triple-negative patients may achieve early responses to anthracyclines and taxanes, but novel strategies are also eagerly sought. The epothilone B analog ixabepilone acts to stabilize microtubules and demonstrates antitumor activity in recent breast cancer studies. Herein, we have analyzed efficacy and safety data of ixabepilone specifically for the treatment of women with triple-negative disease. A retrospective analysis was completed using activity and toxicity data in the triple-negative subsets from 5 phase II studies. In addition, a prospective pooled analysis of triple-negative patients from 2 phase III trials is also reviewed. Of 2,261 patients evaluated in these trials, 556 (24.5%) had triple-negative tumors. In the neoadjuvant setting, ixabepilone produced a pathologic complete response rate in the breast of 26% in triple-negative patients (vs. 15% in the non-triple-negative population). In patients with metastatic breast cancer whose pretreatment status ranged from no prior therapy to progression on several classes of agents, overall response rates (ORR) in the phase II ixabepilone monotherapy trials ranged from 6 to 55%, comparable to rates seen in patients with non-triple-negative tumors. The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23% in triple-negative patients. A similar ORR (31%) was observed for a preplanned pooled analysis of triple-negative patients in the phase III trials of ixabepilone plus capecitabine. The median progression-free survival (PFS) was significantly longer for triple-negative patients treated with ixabepilone plus capecitabine (4.2 months) compared with treatment with capecitabine alone (1.7 months). No increase in toxicity was noted in the triple-negative subgroup compared with other patients. Ixabepilone shows notable antitumor activity in patients with triple-negative breast cancer when used in a variety of settings. The addition of ixabepilone to capecitabine results in an approximately twofold increase in median PFS for triple-negative patients versus capecitabine alone and responses to ixabepilone in triple-negative disease are comparable to those seen in patients with non-triple-negative tumors.     

Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors

Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane‐resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U.S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy‐sensitive and chemotherapy‐resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single‐agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline‐ and taxane‐resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy‐naïve and taxane‐resistant hormone‐refractory prostate cancer and platinum‐resistant non‐small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone.     

Ixabepilone for the treatment of taxane-refractory breast cancer

The ephothilones are a novel class of agents that bind to beta-tubulin, promote microtubule stabilization and cause cell-cycle arrest in G2/M phase. Ixabepilone (Ixempra) is an epothilone B that has demonstrated preclinical activity against a variety of tumor types and has recently been US FDA approved (application for registration ongoing in Europe) as a single agent for the treatment of taxane-refractory metastatic breast cancer, or in combination with capecitabine for patients with advanced breast cancer refractory to anthracyclines and taxanes. This review will provide an overview of the clinical development of ixabepilone, and emphasize the drug's utility for the treatment of advanced breast cancer.     

Preclinical discovery of ixabepilone, a highly active antineoplastic agent

The epothilones and their analogs constitute a novel class of antineoplastic agents, produced by the myxobacterium Sorangium cellulosum. These antimicrotubule agents act in a similar manner to taxanes, stabilizing microtubules and resulting in arrested tumor cell division and apoptosis. Unlike taxanes, however, epothilones and their analogs are macrolide antibiotics, with a distinct tubulin binding mode and reduced susceptibility to a range of common tumor resistance mechanisms that limit the effectiveness of taxanes and anthracyclines. While natural epothilones A and B show potent antineoplastic activity in vitro, these effects were not seen in preclinical in vivo models due to their poor metabolic stability and unfavorable pharmacokinetics. A range of epothilone analogs was synthesized, therefore, with the aim of identifying those with more favorable characteristics. Here, we describe the preclinical characterization and selection of ixabepilone, a semi-synthetic epothilone B analog, among many other epothilone analogs. Ixabepilone demonstrated superior preclinical characteristics, including high metabolic stability, low plasma protein binding and low susceptibility to multidrug resistance protein-mediated efflux, all of which were predictive of potent in vivo cell-killing activity. Ixabepilone also demonstrated in vivo antitumor activity in a range of human tumor models, several of which displayed resistance to commonly used agents such as anthracyclines and taxanes. These favorable preclinical characteristics have since translated to the clinic. Ixabepilone has shown promising phase II clinical efficacy and acceptable tolerability in a wide range of cancers, including heavily pretreated and drug-resistant tumors. Based on these results, a randomized phase III trial was conducted in anthracycline-pretreated or resistant and taxane-resistant metastatic breast cancer to evaluate ixabepilone in combination with capecitabine. Ixabepilone combination therapy showed significantly superior progression-free survival and tumor responses over capecitabine alone.     

Ixabepilone, first in a new class of antineoplastic agents: the natural epothilones and their analogues

Although targeted therapies are becoming increasingly important in oncology, cytotoxic agents are likely to remain a valuable element in the treatment paradigm of cancer. However, resistance to chemotherapy is a major obstacle to the successful treatment of cancer. Therefore, there is a need for novel antineoplastic agents that are able to overcome mechanisms of tumor resistance. Drugs that target microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapies is limited by difficulties with formulation, administration, and resistance induced by P-glycoprotein. The epothilones and their analogues are a novel class of antimicrotubule agents that has demonstrated antitumor activity in the setting of resistance. These antimicrotubule agents are structurally unrelated to the taxanes, with a distinct beta-tubulin-binding mode. Ixabepilone is a rationally designed, semisynthetic analogue of natural epothilone B, which displays reduced susceptibility to a range of common tumor resistance mechanisms. Promising phase II activity and a manageable safety profile with ixabepilone have been seen in a wide range of tumor types, including heavily pretreated/resistant and early-stage breast cancer. Moreover, encouraging phase III results with ixabepilone and capecitabine for patients with breast cancer have recently been presented. Clinical trials are also planned for ixabepilone in combination with targeted agents, such as trastuzumab and bevacizumab. Ixabepilone is likely to be the first available drug in its class, with the potential to bring clinical benefit to patients with a wide range of malignancies.     

Systematic review of ixabepilone for treating metastatic breast cancer

Background

Ixabepilone is now a Food and Drug Administration-approved therapeutic option for patients with metastatic breast cancer (MBC) whose disease has progressed despite prior anthracycline and taxane therapy. We conducted a systematic review and meta-analysis to systematically evaluate the efficacy and safety of ixabepilone for treating metastatic breast cancer.

Methods

A systematic review and meta-analysis were conducted. Randomized controlled studies applying ixabepilone for treating MBC were included. The primary outcome was Overall Survival (OS). The authors of primary articles were contacted and methodological quality was evaluated. Subgroups were drawn based on intervention measures; heterogeneity and bias were discussed.

Results

Eight studies with 5247 patients were included. Compared with a weekly schedule, a triweekly schedule of ixabepilone was better at improving overall response rate (ORR), while there were no differences in improving OS and progression-free survival (PFS). Ixabepilone plus capecitabine was superior to capecitabine monotherapy in improving OS, PFS and ORR. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. There was no difference in the improvement of ORR, clinical benefit rate (CBR) and disease control rate (DCR) between ixabepilone and eribulin.

Conclusions

Current evidence suggests that a triweekly schedule of ixabepilone is more effective than weekly dosing in improving ORR. Use of ixabepilone in combination with capecitabine possesses superior clinical efficacy to the use of capecitabine alone. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. The efficacy and safety between ixabepilone and eribulin were identical.

     

Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study

Taxanes are a standard first-line option for metastatic breast cancer (MBC), but their utility may be limited by primary or acquired resistance. New microtubule-targeting agents have been developed to overcome taxane resistance and provide additional options for improving patient outcomes. This article reviews these alternative microtubule-targeting agents and their potential clinical benefits for MBC patients. Relevant clinical data were compiled through searches within PubMed and congress abstract databases. Ixabepilone, a novel microtubule-stabilizing drug approved by the US Food and Drug Administration (FDA), has proven efficacy across multiple lines of therapy, including patients with taxane-resistant/refractory disease. In phase III trials, ixabepilone plus capecitabine significantly improved progression-free survival compared with capecitabine alone in anthracycline/taxane-pretreated patients. Eribulin has recently been approved by the FDA and by the European Medicines Agency for the treatment of patients with MBC who have received at least two prior chemotherapy regimens for late-stage disease. In a phase III trial, eribulin extended overall survival compared with the physician's treatment choice in heavily pretreated MBC patients. In addition, several investigational microtubule-targeting agents may have therapeutic potential in MBC. The development of new microtubule-targeting agents helps to address the need for additional effective regimens for patients progressing after standard treatment with anthracycline- and taxane-containing regimens.     

Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer

We report the first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for human epidermal growth factor receptor (HER)-2-positive locally recurrent (LR) or metastatic breast cancer (MBC). Patients were aged ≥18 years with confirmed breast adenocarcinoma, measurable LR/MBC and documented HER-2-positive disease. Patients received bevacizumab (15 mg/kg on day 1) plus trastuzumab (8 mg/kg on day 1 of cycle 1, 6 mg/kg on day 1 of each subsequent cycle) plus capecitabine (1,000 mg/m2 twice daily, days 1-14) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Eighty-eight patients were enrolled; 40 (46%) are still on study treatment. The median follow-up was 8.8 months (range, 0.9-17.1 months). The overall response rate, the primary endpoint, was 73% (95% confidence interval [CI], 62%-82%), comprising 7% complete and 66% partial responses. The median progression-free survival interval was 14.4 months (95% CI, 10.4 months to not reached [NR]), with 35 events. The median time to progression was 14.5 months (95% CI, 10.5 months to NR), with 33 events. Treatment was well tolerated; main side effects were grade 3 hand-foot syndrome (22%), grade ≥3 diarrhea (9%), and grade ≥3 hypertension (7%). Overall, 44% of patients experienced grade ≥3 treatment-related adverse events and 13 patients discontinued capecitabine because of toxicity, but continued with bevacizumab and trastuzumab. Heart failure was seen in two patients. The combination of bevacizumab, trastuzumab, and capecitabine was clinically active as first-line therapy for patients with HER-2-positive MBC, with an acceptable safety profile and no unexpected toxicities.     

Proactive Management of Adverse Events Maintains the Clinical Benefit of Ixabepilone

Ixabepilone is a novel microtubule‐stabilizing agent with clinical efficacy in advanced breast cancer, including patients whose disease has progressed on prior anthracyclines and taxanes. The safety profile of single‐agent ixabepilone and combination ixabepilone plus capecitabine therapy is reviewed, outlining the steps to effectively manage and prevent common adverse events. Ixabepilone is generally well tolerated, and importantly, its toxicity profile does not overlap with that of capecitabine. Peripheral sensory neuropathy and neutropenia are the most common toxicities associated with ixabepilone; both can be effectively managed by monitoring patients and then, depending on severity, instituting a treatment delay until recovery and reducing the ixabepilone dose for subsequent treatment cycles. Ixabepilone dose reductions are recommended for most grade 3 events, excluding transient fatigue, arthralgia, and myalgia, whereas treatment discontinuation is recommended for persistent grade 3 neuropathy or any grade 4 nonhematological toxicity. Because ixabepilone exposure is greater in patients with hepatic impairment and those receiving concomitant strong cytochrome P‐450 CYP3A4 inhibitors, dose adjustments and restrictions are recommended according to the degree of hepatic impairment, whether ixabepilone is administered alone or in combination with capecitabine, and whether a strong CYP3A4 inhibitor is being coadministered. Patients should be premedicated with oral H₁ and H₂ antihistamines to prevent hypersensitivity reactions. Unlike taxanes, corticosteroid premedication is not required unless a hypersensitivity reaction occurred during a previous cycle or during treatment with another Cremophor‐containing agent. By effectively managing adverse events and taking steps to minimize them, clinicians can ensure that patients derive the maximum benefit from ixabepilone therapy.     

Sorafenib in breast cancer treatment: A systematic review and overview of clinical trials

AIM: To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer. METHODS: An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms “sorafenib” and “breast cancer”. Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer. RESULTS: Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes, bevacizumab and ixabepilone showed inadequate efficacy, while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising. CONCLUSION: At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.     

Global experience with ixabepilone in breast cancer

Ixabepilone approval in a number of countries across the world as monotherapy and in combination with capecitabine has led to widespread uptake in the later-line breast cancer setting. However, individualized data for ixabepilone in different ethnic groups are limited. Overall, data from small numbers of ethnic subgroups including Hispanic, Japanese and Chinese patients have revealed no clinically significant variation in the disposition, efficacy or tolerability of ixabepilone from that established in pivotal trials. Global use of ixabepilone, while usually along the lines of standard practice, may vary because of local regulatory decisions, clinical practice guidelines and cost considerations. Further information on the global patterns of use of ixabepilone will assist in optimizing the use of this novel therapy.     

Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms

Tumor resistance to chemotherapeutic agents ultimately leads to treatment failure in the majority of cancer patients. The identification of new agents that are less susceptible to mechanisms of tumor resistance could, therefore, bring significant clinical benefits to patients with advanced cancer. One new drug class of great interest in this respect is the epothilones and their analogues, which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone is an analogue of natural epothilone B with activity against a wide range of tumor types, including drug-resistant tumors. This is consistent with the preclinical activity of ixabepilone against human cancer cell lines resistant to taxanes and other agents. Taxane resistance in these cells may be acquired or primary and results from several mechanisms, such as overexpression of multidrug-resistance proteins and the betaIII-tubulin isoform. Ixabepilone has demonstrated efficacy as monotherapy or in combination with capecitabine in anthracycline- and taxane-pretreated/resistant metastatic breast cancer (MBC), and has recently been approved for use in resistant/refractory MBC. Other epothilones, such as patupilone, KOS-1584, and ZK-EPO, are also being evaluated in drug-resistant cancers. Ixabepilone represents a new treatment option for MBC patients with cancers resistant to available chemotherapeutic agents.     

Phase I/II study of ixabepilone plus capecitabine in anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer

PURPOSE: The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline-pretreated/ resistant and taxane-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21- day cycle). RESULTS: No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption. CONCLUSION: Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline-pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.     

Capecitabine and vinorelbine in metastatic breast cancer

BackgroundAs anthracyclines and taxanes are frequently used in the adjuvant and first-line metastatic settings, capecitabine and vinorelbine are frequently used as monotherapy and in combination for metastatic breast cancer (MBC). In the absence of comparative, phase III data, retrospective analyses and cross-trial comparisons provide the only indication of the relative efficacy of these options.MethodsWe reviewed studies evaluating the 2 agents alone or in combination in MBC.ResultsWe identified 6 capecitabine and 2 vinorelbine phase III trials, numerous phase II monotherapy studies and 35 phase I/II studies exploring capecitabine–vinorelbine combination therapy (1 with trastuzumab in HER2-positive MBC).ConclusionFor monotherapy, the limited, retrospective comparative evidence supported by consistent prospective data suggests that capecitabine is more effective than vinorelbine. Comorbidities, organ function tolerability, tumour biology and patient characteristics should also inform treatment choice. If combination therapy is deemed clinically appropriate, intravenous vinorelbine with capecitabine may be considered, potentially improving efficacy compared with monotherapy, but at the cost of increased toxicity. Randomised evaluation versus capecitabine monotherapy is ongoing. In contrast, cross-trial comparison suggests that addition of oral vinorelbine to capecitabine adds haematological toxicity without apparently improving efficacy in pretreated MBC. Data from small, single-arm, phase II studies in the first-line setting are more encouraging. In summary, the strongest clinical data support capecitabine monotherapy in the majority of patients. In certain populations, a capecitabine–vinorelbine combination may be appropriate but requires further validation in randomised trials.