Abstract
Eribulin mesylate is a synthetic analog of halichondrin B (a polyether macrolide isolated from a marine sponge). It is a nontaxane microtubule dynamics inhibitor with a novel mechanism of action. It is the first drug that has demonstrated an improvement in overall survival as a single agent compared with the physician's choice of currently available treatments in locally advanced or metastatic breast cancer, previously treated with anthracyclines and taxanes. It has shown a good manageable tolerability profile. This drug has been approved by the US FDA and by the EMA for patients with locally advanced or metastatic breast cancer who have received at least two chemotherapeutic regimens for advanced/metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments. The aim of this article is to describe the mechanism of action, pharmacokinetics, pharmacodynamics and the most relevant clinical trials in the development of this drug.
Breast cancer causes more than 480,000 annual deaths, representing 14% of deaths from malignant tumors. One out of every eight women will develop breast cancer and a third of the cases will present disseminated disease [1].
Metastatic breast cancer (MBC) is, nowadays, an incurable disease, and the 5-year survival rate is 26% in the USA [101]. Palliative treatment with radiotherapy, chemotherapy, and hormonal and biologic therapy can, however, reduce tumor symptoms and/or prolong life.
Anthracyclines and taxanes are the two main classes of chemotherapy in breast cancer. They are highly effective and both are used in the adjuvant and metastatic setting, although, resistance and toxicity limit their use. Even though there is no generally accepted standard of care in advanced breast cancer, current chemotherapy options for third-line or later treatment include capecitabine, new formulations of older drugs, such as nanoparticle albumin-bound paclitaxel, gemcitabine and antimicrotubule agents other than taxanes such as vinorelbine.
Antimicrotubule agents are widely used in the treatment of early and advanced breast cancer.
Microtubules are cellular organelles that play diverse roles within the cell, such as maintenance of cell structure, intracellular transport, chromosomal segregation and mitosis. They are highly dynamic polymers composed of α- and β-tubulin heterodimers. Their polymerization occurs by a nucleation–elongation mechanism. During the early stages of mitosis, they increase in length by attachment of more tubulin dimers to one end and, when they find an unattached chromosome, they lose dimers and shrink again [2].
The importance of microtubules in cell division makes them an important target for anticancer drugs. Antimitotic drugs can interact with tubulin and microtubules in a large number of distinct ways to disrupt microtubule polymerization and dynamics. Microtubule-targeted chemotherapeutic drugs inhibit cell proliferation by acting on the polymerization/depolymerization dynamics of mitotic spindle microtubules, inducing G2/M-phase cell-cycle arrest that eventually leads to cell death by apoptosis.
Classically, drugs that target microtubules were divided into stabilizers and destablizers. Now, this classification does not account for all the mechanisms of action. Microtubule desta-bilizers, such as vinca alkaloids, interact with the central portion of the β-tubulin subunit and this prevents polymerization into microtubules. Microtubule stabilizers, such as taxanes, bind to tubulin, stabilize the microtubule and inhibit its disassembly, ultimately leading to cell death by apoptosis [3].
Eribulin mesylate is a nontaxane new antimicrotubule agent that acts by another mechanism of action different from taxanes; it inhibits microtubule dynamics by specifically binding to microtubule ends, rather than along their lengths. Eribulin inhibits microtubule polymerization without effects on depolymerization. It also sequesters tubulin into nonfunctional aggregates. By inhibiting mitotic spindle formation, eribulin causes irreversible mitotic block, which leads to cell-cycle arrest in the G2/M phase and apoptosis [4].
Encouraging preclinical findings focus the development of eribulin on breast cancer. Three Phase I clinical trial, addressing safety and the maximum tolerated dose of the drug, and two consecutive Phase II clinical trials have evaluated the activity of eribulin on breast cancer, and led to a pivotal Phase III clinical trial, EMBRACE, which positioned the drug in its current indication.
EMBRACE was a multicenter study, demonstrating that eribulin mesylate significantly improves overall survival compared with currently available treatments in highly pretreated MBC patients with an acceptable tolerability profile.
In relation to this Phase III clinical trial, the EMA and the US FDA approved eribulin monotherapy for the treatment of patients with locally advanced breast cancer or MBC who have progressed after at least two chemotherapeutic regimens for advanced disease. Prior treatment should have included an anthracycline and taxane, unless patients were not suitable for these treatments.
Overview of the market
The treatment of patients with MBC that has progressed despite previous anthracycline and taxane-based therapy is a challenge for oncologists. Several agents have been evaluated in this setting, either alone or in combination with other cytotoxic agents.
Although there is no widely accepted standard of care, current treatment options for second-and third-line or later treatment (depending on previous treatment received), include the vinca alkaloids, capecitabine and new formulations of older drugs, such as nanoparticle albumin-bound paclitaxel.
Capecitabine has been studied in taxane and anthracycline-pretreated patients. In the Phase II pivotal trial, women with paclitaxel-refractory MBC were treated with oral capecitabine at a dose of 1255 mg/m2 twice daily. The mean number of prior chemotherapeutic regimens was 2.5. All patients had received prior paclitaxel, 91% had received prior anthracyclines and 82% had received a prior 5-fluorouracil-containing therapy. The overall response rate was 20%, the median duration of response was 8.3 months and the median time to disease progression was 3.2 months. Median survival was 12.2 months [5]. Capecitabine was also evaluated in a number of confirmatory studies with heavily pretreated patients, confirming the high activity in taxane-pretreated patients.
Another single agent that has been studied in several trials in this setting is vinorelbine. In a Phase II clinical trial that enrolled patients previously treated with anthracyclines and taxanes, objective response rates were observed in 25% of the patients. The median time to failure was 6 months for responding patients and disease stabilization was achieved in 23% of the patients for a median duration of 5 months. The median survival duration for the whole population was 6 months [6].
Nab-paclitaxel (Abraxane®, Celgene Corporation, NJ, USA) is a novel, nanometer-sized albumin-bound paclitaxel particle. It is the first of a new class of anticancer agents that incorporates albumin particle technology. It is a drug free of solvents, designed to avoid their adverse effects. In a Phase III clinical trial, in which nab-paclitaxel was compared with paclitaxel, nab-paclitaxel demonstrated significantly higher response rates (33 vs 19%) and a significantly longer time to tumor progression (23 vs 16.9 weeks). There was a lower incidence of grade 4 neutropenia with nab-paclitaxel [7]. It has been approved for the treatment of MBC in patients who have failed with first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated.
Introduction to the compound & its chemistry
Eribulin mesylate is a nontaxane, structurally simplified, synthetic analog of the marine natural product halichondrin B, a large polyether macrolide (Figure 1) derived from the Japanese marine sponge Halichondria okadai. It consists of the macrocyclic ketone analog of the biologically active C1–C38 moiety of halichondrin B [8].
Eribulin.
Eribulin inhibits microtubule dynamics via a novel mechanism of action, which is thought to involve binding to a unique binding site on tubulin, resulting in the suppression of microtubule polymerization, without effects on depolymerization, together with sequestration of tubulin into nonfunctional aggregates. By inhibiting mitotic spindle formation, eribulin causes irreversible mitotic block (which ultimately leads to cell-cycle arrest in the G2/M phase) and apoptosis [9].
Eribulin has demonstrated potent antiproliferative activity against a broad range of human cancer cell lines including breast, prostate, leukemia, melanoma and colorectal cancer. Furthermore, eribulin treatment was associated with tumor regression in a variety of well-established human tumor xenograft models, including those derived from breast, ovarian, melanoma and colon tumor [8].
Pharmacodynamics In vitro studies
The antiproliferative effects of eribulin mesylate were studied in vitro in different cultured human cell lines and compared with vinblastine and paclitaxel. Eribulin mesylate inhibited growth at a wide range of established human cancer cell lines via a tubulin-based antimitotic mechanism, leading to G2/M block. The in vitro potency was higher than that of vinblastine or paclitaxel: eribulin (average IC50 value: 1.8 ± 1.1 nM); vinblastine (average IC50 value: 3.2 ± 0.70 nM); and paclitaxel (average IC50 value: 7.3 ± 1.9 nM) [8].
Although growth of several human cancer cell lines was inhibited at subnanomolar concentrations, eribulin did not show cytotoxic effects with concentrations up to 1 uM against dormant IMR-90 fibroblasts, indicating that growth inhibition by low or subnanomolar levels of eribulin is specific for proliferating cells and not secondary to nonspecific cytotoxicity [8].
The activity of eribulin against taxol-resistant cancer cells was studied in vitro, showing activity in cells that are taxane-resistant based on distinct mutations in β-tubulin. The activity of eribulin was comparable with that of vinblastine with no significant resistance [10].
In vivo studies
With regard to in vivo studies, eribulin mesylate in the 0.05–1 mg/kg dose range was shown to have anticancer activity against a variety of human cancer xenograft models grown subcutaneously in athymic mice [8].
Furthermore, eribulin demonstrated a significantly wider in vivo therapeutic window compared with paclitaxel. This wide therapeutic window is particularly important, as it leads to the possibility to increase doses, leading to more complete eradication of residual tumor cells and contributing to substantial in vivo efficacy [8].
Eribulin was studied in combination with other drugs in human breast and human lung cancer xenograft models. The combination with capecitabine, erlotinib or gemcitabine showed enhanced activity, but this was not shown in the combination with doxorubicin or pemetrexed [11].
Safety of eribulin was studied in in vivo, evaluating the cardiovascular, respiratory, CNS and PNS.
Eribulin mesylate was administered as an intravenous infusion at 0.04 mg/kg for 60 min to conscious beagle dogs (on days 1, 8 and 15 in males and days 3, 10 and 17 in females). Results showed a transiently decreased systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate, and increased the QT and RR intervals in both male and female dogs. However, when QT was corrected, there was no change in QTcF or QTcQ. The highest tested dose (0.04 mg/kg) resulted in an exposure that was lower than that in the clinical setting [102].
No significant effect on the respiratory function or CNS was identified in the specific tests.
Inhibitors of tubulin polymerization and microtubule dynamics often affect the PNS. The neurotoxicity potential of eribulin was investigated. Doses of 0.5, 0.75, 1.0, 1.25 and 1.75 mg/kg were administered to BALB/c mice on a Q2D × 3 (× 2 weeks) schedule and the neurotoxic effects of eribulin mesylate were compared with that of paclitaxel. Eribulin mesylate induced no significant reduction in nerve conduction velocity or peak nerve amplitude in caudal and digital nerves, which were significantly decreased upon treatment with paclitaxel. Some mild morphological changes consistent with axonopathy were evident in the sciatic nerve and the dorsal root ganglia of eribulin-treated mice, but only at the 0.75 × maximum tolerated dose and higher [12].
Pharmacokinetics
The pharmacokinetic profile of eribulin was comparable at similar doses across three Phase I studies.
The first Phase I study was conducted with a 1-h intravenous infusion on days 1, 8 and 15 of a 28-day cycle (Table 1). The pharmacokinetics were linear and dose proportional over the dosing range of 0.25–1.4 mg/m2. Eribulin exhibited consistent pharmacokinetic parameter estimates between the first and third intravenous doses administered on days 1 and 15 at each dose level (Table 2). The plasma concentration–time profile exhibited a rapid distribution phase with a mean distribution half-life of approximately 0.43 h followed by a slower elimination phase with a half-life of 38.7 h (Figure 1C). Overall urinary excretion of eribulin was minimal with 5–6% of administered dose eliminated in urine over a 72-h period after a single dose. The maximum tolerated dose in this study was 1 mg/m2 [13].
Phase I clinical trials.
DLT: Dose-limiting toxicity.
Pharmacokinetic parameters of eribulin following a single 1h intravenous dose on day 1.
The mean values are shown with the percentage of coefficient of variation in brackets.
AUC0−∞ Area under the concentration–time curve; CL: Systemic clearance; NA: Not applicable; t1/2: Elimination half-life; Vss: Volume of distribution concentration.
In another Phase I clinical trial, eribulin mesylate was administered as a 1-h infusion every 21 days with a maximum tolerated dose of 2 mg/m2. It also showed a pharmacokinetic profile characterized by an extensive volume of distribution, a slow-to-moderate clearance and a slow elimination, with only a small fraction of the drug (~7%) excreted unchanged in the urine. Eribulin exhibited a plasma terminal half-life of approximately 2 days. Plasma area under the concentration–time curve and Cmaxincreased approximately linearly over the dosage range studied [14].
In a further Phase I clinical trial conducted in Japanese patients, eribulin mesylate was administered intravenously over 5 min on days 1 and 8 every 21 days. It recommended a dose of 1.4 mg/m2 for Phase II studies (Table 2) [15].
There was also another Phase I study carried out on patients with liver impairment, in which eribulin was generally safe and well tolerated. Hepatic impairment decreased clearance and prolonged elimination half-life. Therefore, the exposure is increased in hepatic impairment (1.75- and 2.48-fold in mild and moderate impairment, respectively) [16].
In one Phase II clinical trials patients were initially treated with eribulin at 1.4 mg/m2 on days 1, 8 and 15 of a 28-day cycle. Since many patients experienced dose interruption due to neutropenia on day 15, the schedule was changed to days 1 and 8 of a 21-day cycle [17,18]. The dosing regimen of the pivotal study was 1.4 mg/m2on day 1 and 8 of a 21-day cycle [19].
Metabolism
Eribuline is metabolized at a very low degree and no metabolites have been identified in plasma in vivo.
Eribulin is mainly eliminated through biliary excretion of unchanged drug.
The antiproliferative effects of eribulin mesylate were studied on both nonpermeability P-gpexpressing and P-gp-overexpressing human cancer cells where eribulin mesylate was shown to be a substrate for the P-gp drug efflux pump, and thus showed reduced in vitro potency against human cancer cells expressing high levels of P-gp. The IC50 of eribulin on Pgp-mediated digoxin transport activity was estimated to be greater than 10 μmol/l, indicating that eribulin is a weak P-gp inhibitor. The transport of digoxin is reduced in the presence of ≥1 μmol/l eribulin. Therefore, eribulin should not be used concomitantly with inhibitors of P-gp [20].
Concomitant treatment with enzyme inducing drugs such as carbamazepine, phenytoin and St John's wort (Hypericum perforatum) is not recommended, as these drugs are likely to give rise to markedly reduced plasma concentrations of eribulin.
No drug–drug interactions are expected with CYP3A4 inhibitors unless they are potent inhibitors of P-gp. Eribulin exposure was studied in an open-label, pharmacokinetic, two sequence, two-way crossover trial, showing that it was unaffected by ketoconazole (area under the concentration and Cmax), a CYP3A4 inhibitor [21].
Eribulin may inhibit the important drug metabolizing enzyme CYP3A4. This is indicated by in vitro data and no in vivo data are available. Concomitant use with drugs that are mainly metabolized by CYP3A4 should be made with caution and it is recommended that the patient is closely monitored for adverse effects due to increased plasma concentrations of the concomitantly used drug [22]. Eribulin does not inhibit the CYP enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 at relevant clinical concentrations [23].
Clinical efficacy Phase II clinical trials
Two Phase II clinical trials have been performed to assess eribulin efficacy in patients with MBC.
In the first trial, 103 patients were treated with eribulin mesylate (1.4 mg/m2) as a 2-5-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Owing to neutropenia on day 15, an alternative regimen on days 1 and 8 of a 21-day cycle was administered. The median number of prior chemotherapy regimens was four (range: 1–11). Eribulin achieved an independently reviewed objective response rate of 11.5% (95% CI: 5.7–20.1) and a clinical benefit rate (partial response plus stable disease ≥6 months) of 17.2. The median duration of response was 171 days, the median progression-free survival was 79 days and the median overall survival was 275 days [18].
In a further Phase II clinical trial, 391 patients received eribulin mesylate 1.4 mg/m2 on days 1 and 8 of a 21-day cycle. The median number of prior chemotherapy regimens was four. The objective response rate by independent review was 9.3% (95% CI: 6.1-13.4) and the investigator-reported objective response rate was 14.1%. The median duration of response was 4.1 months and progression-free survival was 2.6 months. Median overall survival was 10.4 months [17].
These two Phase II clinical trials demonstrated antitumor activity of eribulin in heavily pretreated patients with MBC.
Phase III clinical trial
Following the response rates observed in Phase II clinical trials, without severe adverse events, a Phase III clinical trial led to the approval of eribulin in the USA.
EMBRACE was conducted in order to elucidate the role of eribulin compared with the rest of the existing therapeutic options in advanced breast cancer once taxanes and anthracyclines had failed. In a multicenter, open-label, randomized study, eribulin was compared with the treatment chosen by the investigator in a pragmatic way. The primary end point was overall survival in the intention-to-treat (ITT) population. The enrolled patients must have received between two and five previous chemotherapy regimens at least two of which had been for advanced disease, including an anthracycline and a taxane unless contraindicated.
Patients received eribulin mesylate (1.4 mg/m2administered intravenously during 2–5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC; defined as any singleagent chemotherapy or hormonal or biological treatment approved for the treatment of cancer, radiotherapy or best supportive care).
A total of 762 patients were randomly allocated to treatment groups. No TPC patient received supportive care alone. In total, 96% of patients who received TPC were treated with chemotherapy, which was most often vinorelbine, gemcitabine or capecitabine. The median number of previous chemotherapy regimens was four. A total of 73% of patients had received capecitabine previously. As many as 16% of patients had HER2-positive disease and 19% were triple-negative. The most common metastatic sites were bone and liver; 51% of the patients had metastatic disease involving three or more organs.
The study met its primary objective, demonstrating a significant increase in overall survival for eribulin compared with TPC (hazard ratio [HR]: 0.81; 95% CI: 0.66-0.99; p = 0.041) (Figure 2). Median overall survival was 13.1 months (95% CI: 11.8-14.3) for the eribulin group and 10.6 months (95% CI: 9.3-12.5) in those assigned to TPC. One-year survival rates were 53.9% in patients receiving eribulin and 43.7% in the TPC group. The median progression-free survival was 3.7 months (95% CI: 3.3–3.9) with eribulin and 2.2 months (95% CI: 2.1–3.4) with the TPC (HR: 0.87; 95% CI: 0.71–1.04; p = 0.137) in the ITT population by independent review. Median progression-free survival was similar in the investigator assessment of the ITT population, but the difference between treatment groups was significant (HR: 0.76; 95% CI: 0.64–0.90; p = 0.002). Fewer patients were censored with investigator review compared with independent review, resulting in more progression events in the investigator than independent review [19].
Kaplan–Meier graph of overall survival.
In summary, this Phase III trial concluded that eribulin significantly improved overall survival in women with heavily pretreated MBC compared with available cytotoxic therapy (Table 3). This result is unprecedented as no other agent has ever shown an overall survival advantage in this setting.
Phase II and III clinical trials.
Patients randomized to eribulin.
PFS: Progression-free survival.
Another Phase III clinical trial compared ‘face-to-face’ eribulin with capecitabine in patients who had received prior therapy including an anthracycline and taxane. These patients were receiving study drug as first-, second- or third-line therapy for advanced disease. The coprimary end points of this study were overall survival and progression-free survival. The median overall survival was 15.9 and 14.5 months (HR: 0.879; 95% CI: 0.770–1.003; p = 0.056), and progression-free survival was 4.1 and 4.2 months (HR: 1.079; 95% CI: 0.932–1.250; p = 0.305) for eribulin and capecitabine, respectively [24,25].
In conclusion, in this Phase III clinical trial, eribulin was confirmed as an active drug in patients with MBC. Nevertheless, the trial failed to meet its primary end points (overall survival and progression-free survival) in the general population and eribulin was not shown as significantly better than capecitabine in this setting.
A prespecified exploratory analysis suggested that particular patient subgroups may have greater therapeutic benefit with eribulin. In the subgroup of triple-negative patients, the HR was 0.702 (95% CI: 0.545–0.906), in estrogen-negative patients there was a HR of 0.779 (95% CI: 0.635–0.995) and in HER2-negative patients the HR was 0.838 (95% CI: 0.715–0.983). Although this trial has to be considered as negative, this subanalysis suggests that the main question addressed by the trial is still an open matter.
With regard to cost–effectiveness, there is one study that was performed to evaluate the cost–effectiveness of eribulin and to compare it with other drugs. The aim of the analysis was to assess the cost–effectiveness of eribulin versus the three most commonly utilized drugs in the EMBRACE trial (vinorelbine, gemcitabine and capecitabine) and other FDA-approved drugs (ixabepilone, liposomal doxorubicin and nab-paclitaxel). Eribulin added 0.208 life-years saved and 0.119 quality-adjusted life years with an incremental cost over TPC of US$25,458 and an incremental cost–effectiveness ratio of US$213,742 per quality-adjusted life years. When looking specifically at eribulin relative to other drugs, such as ixabepilone, liposomal doxorubicin, nab-paclitaxel or capecitabine, the incremental cost–effectiveness ratio per quality-adjusted life years was US$76,823, 109,283, 129,773 and 167,267, respectively. Eribulin was not found to be cost effective in the treatment of MBC and locally advanced breast cancer compared with the chemotherapy drugs most commonly used as TPC (vinorelbine and gemcitabine). However, the drug acquisition costs of vinorelbine and gemcitabine are much lower than eribulin. Eribulin is more cost effective when compared with other branded chemotherapeutic agents, such as ixabepilone, nab-paclitaxel, liposomal doxorubicin or capecitabine.
Safety & tolerability
The clinical trials that have evaluated the safety of eribulin showed a manageable tolerability profile.
In the Phase I clinical trials, the most common dose-liming toxicity was grade 3 or 4 febrile neutropenia; other dose-limiting toxicities were grade 3 fatigue and grade 3 anorexia [12–14].
In the Phase II studies, grade 3 and 4 toxicities were neutropenia (54–64%), leukopenia (14.1–18%) and peripheral neuropathy (5–6.9%). Common grade 1 and 2 adverse events included alopecia (41–60.1%), asthenia or fatigue (48–55%), nausea (36–42.3%), anemia (26.1–35%) and peripheral neuropathy (25.8–26%) [17,18].
In the EMBRACE clinical trial, adverse events occurred in 497 of 503 patients (99%) receiving eribulin and 230 of 247 patients (93%) given TPC. Serious adverse events occurred in 126 of patients (25%) on eribulin and 64 (26%) of those on TPC, and adverse events leading to therapy discontinuation occurred in 67 (13%) of eribulin patients and 38 (15%) of TPC patients. The most common adverse events in both groups were asthenia or fatigue and neutropenia. Grade 3 or 4 adverse events that occurred more often with eribulin compared with TPC were neutropenia, leukopenia and peripheral neuropathy.
Neutropenia was the most common clinical grade 3 or 4 adverse event with eribulin (21% grade 3 patients and 24% grade 4 patients) and in TPC (14% grade 3 and 7% grade 4). It was managed with dose delays, reductions and granulocyte-colony stimulating factor. Febrile neutropenia occurred at a low incidence with eribulin (5% of the patients) and TPC (2%).
The incidence of peripheral neuropathy with eribulin was 35% (8% grade 3 and <1% grade 4) and in the TPC group it was 16% (2% grade 3). It was similar to that in the taxane subgroup (45%; 5% grade 3). It was the most common adverse event leading to discontinuation from eribulin (5% of the patients). In patients with grade 3 or 4 peripheral neuropathy who continued treatment, neuropathy improved to grade 2 or lower in later cycles after delays and dose reductions.
Alopecia occurred in 45% of patients on eribulin. Hypersensitivity related to the study drug occurred in four out of 503 patients (1%) in the eribulin group and one out of 147 patients (<1%) in the TPC group [19].
In conclusion, eribulin has a manageable toxicity profile.
Regulatory affairs
Based on the results from the EMBRACE trial, in November 2010, the FDA granted the approval of eribulin mesylate for the treatment of patients with MBC who have previously received an anthracycline and a taxane in either the adjuvant or metastatic setting, and at least two chemotherapeutic regimens for the treatment of metastatic disease.
In January 2011, the EMA approved eribulin monotherapy for the treatment of patients with locally advanced breast cancer or MBC who have progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments.
Conclusion
Eribulin is an antimicrotubule agent with a novel mechanism of action. It is the first single chemotherapy agent that improves overall survival in MBC with a very favorable toxicity profile. It has been approved by the FDA and the EMA for patients who have received at least two chemotherapeutic regimens for advanced disease with prior therapy including an anthracycline and a taxane, if appropriate.
It is remarkable that eribulin has not only demonstrated a manageable tolerability profile in heavily pretreated patients, but has also shown a statistically significant improvement in overall survival. Other drugs used in the same subset of patients have failed to demonstrate this. It represents an optimal choice in MBC that has progressed following anthracyclines, taxanes and capecitabine.
Executive summary
Breast cancer causes more than 480,000 annual deaths.
Metastatic breast cancer (MBC) is, nowadays, an incurable disease, and the 5-year survival rate is approximately 26%.
Anthracyclines and taxanes are treatment regimens used in the adjuvant and metastatic setting.
There is no widely accepted standard of care for third-line or later treatment.
Eribulin mesylate is a nontaxane, structurally simplified, synthetic analog of the marine natural product halichondrin B.
Eribulin inhibits microtubule dynamics via a novel mechanism of action, resulting in the suppression of microtubule polymerization.
Eribulin causes irreversible mitotic blockade (which ultimately leads to cell-cycle arrest in the G2/M phase) and apoptosis.
Eribulin has demonstrated potent antiproliferative activity against a broad range of human cancer cell lines including leukemia, melanoma, and breast, prostate and colorectal cancer.
Eribulin inhibited growth in a wide range of established human cancer cell lines via a tubulin-based antimitotic mechanism, leading to G2/M block.
The activity of eribulin against paclitaxel-resistant cancer cells was studied in vitro, showing activity with no significant resistance.
Eribulin was shown to have anticancer activity against a variety of human cancer xenograft models grown subcutaneously in athymic mice in in vivo studies.
Eribulin has a rapid distribution phase followed by a prolonged elimination phase.
Eribulin has a mean terminal half-life of approximately 40 h.
Eribulin has a large volume of distribution (range of means: 43–114 l/m2).
Eribulin is weakly bound to plasma proteins.
Eribulin is mainly eliminated through biliary excretion of nonmetabolized drug.
Two Phase II clinical trials in the advanced setting of breast cancer demonstrated an objective response rate of 11.5 and 9.3%, respectively.
There is one Phase III clinical trial that has demonstrated improvement in overall survival compared with currently available treatments in highly pretreated patients with manageable toxicity. This result is unprecedented in MBC.
The most common treatment-related adverse events are neutropenia, peripheral neuropathy, asthenia/fatigue, alopecia, nausea and anemia.
Eribulin has a manageable profile of toxic effects.
In November 2010, the US FDA granted approval for eribulin mesylate for the treatment of patients with MBC who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.
In January 2011, the EMA approved eribulin monotherapy for the treatment of patients with locally advanced breast cancer or MBC who have progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments.
Eribulin mesylate is an antimicrotubule agent with a novel mechanism of action.
It is the first single chemotherapy agent that improves overall survival in MBC previously treated with and anthracycline taxane, without severe toxicities.
It represents a standard of care in MBC that has progressed to anthracyclines and taxanes.
Eribulin, alone or in combination, is now being developed in early breast cancer and in multiple other clinical settings.
Future perspective in breast cancer
MBC is an incurable disease, with survival ranging from months to several years depending on patient and tumor characteristics. There is no clear standard of care for these patients. There are a wide range of antineoplastic treatments currently available, most of which have not shown an impact on survival in patients with MBC.
Eribulin prolongs survival in patients with heavily pretreated MBC and represents a new option in this group of patients.
There are clinical trials underway to assess the antitumor activity of eribulin for its earlier use in the course of metastatic disease.
This drug is likely to be partnered with other chemotherapeutic agents due to the results of the clinical trials. Further studies with eribulin in combination with other antineoplastic agents and biologic treatments are ongoing. Eribulin is being tested with HER-2 targeting drugs, such as lapatinib and trastuzumab, in combination with novel biologic treatments and also in combination with classic chemotherapy regimens, such as cyclophosphamide, capecitabine or carboplatin.
As a novel chemotherapeutic agent with a very favorable combination of efficacy and safety profiles, eribulin has to now be tested in the early breast cancer setting in order to explore its addition to the current standard (anthracyclines and taxanes). Therefore, the development of trials in the presurgical setting should guide trials in the adjuvant area.
In the current scenario of advanced disease, most patients have already been treated with anthracyclines and taxanes previously and the combination of chemotherapy with targeted agents is rising as the new standard in several tumor types. In this respect, eribulin may be a perfect chemotherapy back-bone to explore in combination with novel biologic therapies. Eribulin has shown activity irrespective of the tumor subtype (luminal and basal) and its low toxicity profile makes it a perfect candidate for combination therapy.
In summary, so far, eribulin is the only drug that has shown a survival advantage in late lines of therapy for patients with MBC. The benefit that this drug has demonstrated as a single agent in this setting suggests that eribulin could become a new standard of care for these patients. Future studies should look to establish the optimal use of eribulin.
Financial & competing interests disclosure
A Urruticoechea has received honoraria as advisor for EISAI Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.