Eribulin Mesylate

The U.S. Food and Drug Administration (FDA) recently approved eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, for the treatment of patients with metastatic breast cancer, who have previously received an anthracycline and a taxane in either the adjuvant or metastatic setting and at least 2 chemotherapeutic regimens for the treatment of metastatic disease. In 2011, an estimated 232,620 individuals will be diagnosed with breast cancer in the United States, and 39,970 will die of the disease. Nearly 30% of breast cancers are metastatic, as either initial presentation or following definitive treatment for primary breast cancer. Once metastases are detected, the median survival is 18 to 24 months (1). Anthracyclines and taxanes are highly effective and used extensively in both the adjuvant and metastatic setting, although resistance and, less often, toxicity limit their repeated use. Numerous chemotherapeutic agents are available for later lines of treatment; however, there is no single standard of care following second-line therapy. Therefore, a great, unmet need exists for effective treatments in metastatic breast cancer, with the goal of palliating symptoms and improving survival while minimizing toxicity and maintaining a good quality of life.

Eribulin mesylate is an analogue of the macrolide halichondrin B, originally isolated from Halichondria okadai, a rare marine Japanese sponge (2). Scarcity of the natural product once hampered efforts to develop halichondrin B as an anticancer drug, but a synthetic and structurally simplified derivative with retained high potency and the biologically active macrocyclic lactone C1 to C38 moiety of the parent compound was developed (3, 4). Eribulin seems to exert its cytotoxic effects by interfering with microtubule dynamics (Fig. 1). Microtubules, which are composed of polymeric filaments of α-tubulin and β-tubulin heterodimers, form the mitotic spindle critical for cell division (5). Unlike other antimicrotubule drugs, such as vinblastine and paclitaxel, which suppress the shortening and growth phases of microtubule dynamic instability, eribulin works through an end-poisoning mechanism, resulting in the inhibition of microtubule growth but not of shortening. Tubulin is also sequestered into nonfunctional aggregates, resulting in irreversible G₂ to M-phase arrest and apoptosis (6, 7). Eribulin inhibits tubulin polymer formation by binding to the interdimer interface or the β-tubulin subunit alone, unique from other microtubule-targeted agents, which may explain its ability to overcome taxane resistance conferred by β-tubulin mutations (8). Several biochemical correlates of apoptosis are seen in eribulin-treated human lymphoma and prostate cancer cells, including phosphorylation of Bcl-2, cytochrome c release from mitochondria, activation of caspase-3 and -9, and cleavage of PARP (6). In breast cancer cell lines, eribulin demonstrates significant activity against βIII-tubulin, an isotype that is overexpressed in cells resistant to microtubule inhibitors (9).

Plasma concentrations of eribulin mesylate increase linearly in a dose-dependent manner with rapid distribution, slow-to-moderate clearance, and slow elimination. A shorter infusion achieves higher peak plasma concentrations compared with the 1-hour infusion. At the maximum tolerated dose (MTD), plasma levels of eribulin are above concentrations required for in vitro cytotoxicity for >1 week. Eribulin demonstrates a triphasic elimination with a half-life ranging from 36 to 48 hours (10–12), and it is eliminated primarily by biliary excretion. In a dedicated hepatic impairment trial, eribulin was generally safe and well tolerated. Hepatic dysfunction decreased clearance and prolonged elimination half-life, resulting in increased exposure to eribulin, when compared with patients with normal liver function (13). Renal excretion is minimal with 5% to 11% of the administered dose eliminated in the urine (10–12). CYP3A4 is the major enzyme responsible for eribulin metabolism; however, metabolism represents a minor component in drug clearance as no major human metabolites are formed. A dedicated drug–drug interaction trial showed that eribulin clearance is not affected by ketoconazole, a strong CYP3A4 inhibitor (14). Eribulin is also a substrate for the P-glycoprotein (PgP) drug efflux pump and had decreased in vitro activity against multidrug-resistant cells overexpressing the PgP drug efflux pump (15).

Eribulin mesylate was shown to have remarkable in vitro antitumor activity against numerous human cancer cell lines, with inhibition of cell growth in the subnanomolar concentration range and potency superior to those of vinblastine and paclitaxel (3). It also inhibited tumor growth in taxane-resistant human ovarian cells harboring β-tubulin mutations, suggesting that it may have clinical activity in taxane-refractory tumors with such mutations (16). Furthermore, eribulin demonstrated extraordinary in vivo anticancer activity, including complete tumor regressions in human cancer xenograft models of breast, colon, ovarian, and melanoma. It was more effective at lower doses compared with paclitaxel at empirically determined MTD levels, likely due to its unusually wide in vivo therapeutic window (3).

Given the encouraging preclinical activity of eribulin mesylate, its safety and efficacy have been evaluated in multiple clinical settings (Table 1). Four dose-finding studies were conducted with eribulin (10–12, 17). The initial phase I trial by the California Cancer Consortium included a rapid titration design with real-time pharmacokinetics to guide dose escalation. Eribulin mesylate was administered to 38 patients with advanced solid tumors as a weekly 1- to 2-minute i.v. bolus for 3 of 4 weeks. Two dose-limiting toxicities occurred at 2.0 mg/m²/wk (1 grade 3 and 1 grade 4 febrile neutropenia), and 1.4 mg/m²/wk was determined as the MTD. Serious nonhematologic toxicities included hypoglycemia, hypophosphatemia, and fatigue (10).

In a subsequent phase I study, 32 patients with advanced solid malignancies received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Patients had received a median of 2 prior chemotherapeutic regimens (range 1–13), of which 62.5% had been treated with a taxane and/or vinca alkaloid. Neutropenia was dose limiting in 2 patients at the 1.4 mg/m² dose level, which led to termination of dose escalation. Three additional patients experienced grade 3 neutropenia and did not receive treatment on day 15 of cycle 1. Consequently, the MTD was 1.0 mg/m². Most frequent drug-related adverse effects were grade 1 to 2 fatigue, nausea, and anorexia. Notably, eribulin exhibited a low incidence of neuropathy (11). A similar phase I trial of eribulin mesylate involving 21 patients with advanced solid malignancies used a 1-hour infusion on day 1 of a 21-day cycle, based on an accelerated titration algorithm. All 3 patients in the 4 mg/m² cohort and 2 of 3 patients treated at the 2.8 mg/m² dose developed febrile neutropenia. The MTD was determined to be 2.0 mg/m² (12). A phase I trial in Japanese patients with refractory solid tumors similarly reported an MTD of 2.0 mg/m² when eribulin was administered over 5 minutes on days 1 and 8 every 21 days (17).

Phase II testing of eribulin mesylate was subsequently conducted in women with heavily pretreated breast cancer (18–20). It was hypothesized that eribulin might have activity in breast cancer refractory to other microtubule-targeted drugs, such as taxanes, given its unique mechanism of action and impressive preclinical activity. An open-label, single-arm, multicenter phase II trial enrolled 103 patients with metastatic breast cancer previously treated with an anthracycline and taxane (median of 4 chemotherapy regimens). Patients received a 2- to 5-minute i.v. infusion of eribulin mesylate (1.4 mg/m²) on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia at day 15 in this trial, an alternative regimen of eribulin on only days 1 and 8 of a 21-day cycle was administered to 33 patients. Objective response rate (ORR) was the primary endpoint. Median age was 55, and 54% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Dose interruptions, delays, reductions, or omissions in cycle 1 occurred more frequently in the 28-day cohort (54%) compared with the 21-day cohort (18%), primarily because of neutropenia. In the 87 (84%) patients who met the key inclusion criteria, eribulin achieved an independently reviewed ORR (all partial responses) of 11.5% [95% confidence interval (CI), 5.7–20.1]. The median duration of response was 5.6 months. The median progression-free survival (PFS) and overall survival (OS) were 2.6 and 9.0 months, respectively. Frequent toxicities recapitulated those seen in phase I studies, including neutropenia, fatigue, and nausea. Only 5 patients experienced grade 3 peripheral neuropathy with no grade 4 incidences (18).

A second open-label, single-arm phase II trial of eribulin mesylate was done to further evaluate the efficacy and toxicity in 291 patients with locally advanced and metastatic breast cancer previously treated with an anthracycline, taxane, and capecitabine. Women with a median of 4 prior chemotherapeutic regimens (range 2–5) received eribulin, 1.4 mg/m², over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. The median age was 56, and 63% had an ECOG score of 1 or 2. Of the 291 patients, 96 (33%) experienced treatment delays, omissions, or reductions in cycle 1, owing mainly to neutropenia. This acceptable number of dose reductions supported the results of the previous study, suggesting that the 21-day dosing schedule was optimal. The primary endpoint of ORR by independent review was 9.3% (95% CI, 6.1–13.4%, all partial responses), and the corresponding investigator-reported ORR was 14.1%. Partial responses were observed in 13.8% (9.3% by independent review) and stable disease in 49.1% (46.5% by independent review). The median duration of response was 4.1 months. The median PFS and OS were 2.6 months and 10.4 months, respectively. Toxicities were manageable, with neutropenia, fatigue, and nausea most commonly observed. Eribulin did not exacerbate preexisting grade 1 to 2 neuropathy (19). The 21-day dosing schedule was also investigated in 81 Japanese patients pretreated with an anthracycline and a taxane (median of 3 prior chemotherapy regimens), who received eribulin mesylate 1.4 mg/m² on days 1 and 8. The ORR was 21.3% and the median duration of response was 3.9 months (20).

The phase III Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389 (EMBRACE) trial (E 305, NCT00388726) is a global, open-label, randomized study that led to the regulatory approval of eribulin mesylate. A total of 762 women with locally recurrent or metastatic breast cancer were randomized in a 2:1 ratio to receive eribulin mesylate 1.4 mg/m² over 2 to 5 minutes on days 1 and 8 of a 21-day cycle (n = 508) or treatment of physician's choice (TPC; n = 254). TPC was defined as any monotherapy, including chemotherapy, hormonal therapy, and biological therapy. The primary endpoint was OS in the intention-to-treat (ITT) population. The median age was 55 years, and 57% had an ECOG score of 1 or 2. Patients had received a median of 4 prior chemotherapy regimens (range, 1–7), including an anthracycline and a taxane, unless contraindicated. The majority of TPC was chemotherapy (96%), including vinorelbine (26%), gemcitabine (18%), and capecitabine (18%), representing real-life treatment choices at the time (years 2006–2008). The most common metastatic sites were bone (61%) and liver (60%), with more than half of patients having 3 or more organs involved. The median duration of eribulin treatment and TPC was 3.9 months (range, 0.7–16.3) and 2.1 months (range, 0.03–21.2) for those receiving chemotherapy. Dose interruptions, delays, or reductions were undertaken in 421 (84%) patients in the eribulin group compared with 182 (76%) in the chemotherapy TPC group. The study met its primary objective, showing a significant improvement in median OS with eribulin (13.1 months; 95% CI, 11.8–14.3) compared with TPC [10.6 months; 9.3–12.5; hazard ratio (HR), 0.81; 95% CI, 0.66–0.99; P = 0.041]. The median PFS in the eribulin-treated and the TPC ITT population was 3.6 months and 2.2 months per the investigator review, respectively (HR, 0.76; 95% CI, 0.64–0.90; P = 0.002). The median PFS was similar by independent review but was not statistically significant (HR, 0.87; 95% CI, 0.71–1.05; P = 0.137). More patients were censored with independent review compared with investigator review, resulting in more progression events in the latter (521 versus 635). The ORR was 12% in eribulin-treated patients compared with 5% in patients receiving TPC (P = 0.002), including 3 complete responses with eribulin and none with TPC. Stable disease occurred in 44% in the eribulin-treated group. The median duration of response for eribulin was 4.2 months. The most common toxicities of eribulin were neutropenia (52%), fatigue (54%), and nausea (35%), primarily grade 1 to 2 in severity. Peripheral neuropathy occurred in 35% of eribulin-treated patients with only 8% being grade 3 to 4; however, it led to treatment discontinuation in only 5%. The authors concluded, based on its 2.5-month extension of median OS over currently available cytotoxic therapies and a manageable toxicity profile, that eribulin mesylate is a potential new standard of treatment for women with heavily pretreated metastatic breast cancer (21).

A subsequent phase III trial (E 301) has completed accrual of 1,102 women with metastatic breast cancer randomized to second-line eribulin mesylate or capecitabine. The primary endpoints are OS and PFS. A formal quality-of-life assessment is a secondary objective. Results are awaited (22).

Treating metastatic breast cancer remains a challenge as oncology treatment providers attempt to balance efficacy and toxicity. Though many chemotherapeutic agents are available, including capecitabine, ixabepilone, nab-paclitaxel, and gemcitabine, little guidance exists on how best to sequence them to optimize patient care. Ixabepilone, a microtubule-targeted analogue of the epothilones, demonstrated single-agent activity in an anthracycline, taxane, and capecitabine–resistant metastatic breast cancer population with an ORR of 11.5% and median duration of response of 5.3 months (23). When ixabepilone was combined with capecitabine, there was an improvement in ORR and PFS compared with capecitabine alone; however, no significant improvement in OS was observed. A preplanned subset analysis demonstrated an improvement in OS in symptomatic patients with a low Karnofsy performance score of 70% to 80% (median OS, 14 months for combination versus 11.3 months for capecitabine monotherapy; HR, 0.76; 95% CI, 0.60–0.96; ref. 24). Although neutropenia (92% all grades, 72% grade 3–4) was substantial, febrile neutropenia was also uncommon (7%), and growth factor use relatively low at <20%. Peripheral neuropathy was significant (66% all grades, 24% grade 3–4) in the ixabepilone arm and led to study discontinuation in 26% of patients.

Eribulin mesylate has a very manageable safety profile compared with other agents, with neutropenia and neuropathy the most frequently reported, although incidence of febrile neutropenia is <5%, and severe, limiting neuropathy is <8%. Alopecia also seems to be less common with eribulin. In EMBRACE, <20% of patients reported complete hair loss compared with 39% with ixabepilone and >80% with nab-paclitaxel (21, 23, 25). Other distinct advantages include the ease of administration and rapid infusion time. Eribulin is prepared in an aqueous solution and does not require a lipophilic vehicle that may cause hypersensitivity reactions, precluding the need for premedications.

The economic burden of metastatic breast cancer in developed countries is substantial. The price of eribulin mesylate is approximately $4,000 per cycle in the United States, based on the average female body surface area of 1.6 m² and a 3-week cycle, which is comparable with that of the approved drugs for late-line metastatic breast cancer therapy [capecitabine ($2,688 per cycle) and ixabepilone ($2,560)]. Costs of other commonly used treatments for metastatic breast cancer on the basis of the above parameters are as follows: nab-paclitaxel ($3,952 per cycle), docetaxel ($2,280), paclitaxel ($1,554), gemcitabine ($668), and vinorelbine ($192; ref. 26).

Eribulin mesylate represents a step forward in the treatment of metastatic breast cancer, as it is the first single chemotherapeutic agent to improve survival and does so without severe toxicities. Further study of eribulin mesylate in combination with cytotoxics and biologics, such as the HER2-targeted agents, as well as the efficacy of eribulin in distinct subtypes of breast cancer, is imperative and underway (27). These include phase II studies of eribulin and trastuzumab in HER2-positive metastatic breast cancer (ClinicalTrials.gov identifier, NCT01269346), eribulin in adjuvant HER2-positive disease following dose-dense doxorubicin and cyclophosphamide (NCT01328249), and neoadjuvant eribulin and carboplatin in the triple-negative population (NCT01372579). First-line single-agent eribulin for metastatic breast cancer (NCT01268150), in combination with capecitabine for pretreated metastatic breast cancer (NCT01323530), and the impact of eribulin versus ixabepilone on neuropathy (NCT00879086) are also under investigation. Eribulin has also shown promise in phase II studies in a variety of tumor types, including non–small cell lung, pancreatic, and urothelial tract cancers, and a phase III trial in sarcoma is actively recruiting patients (NCT01327885). The identification of biomarkers to predict therapeutic response to eribulin will greatly enhance its use in the breast cancer treatment armamentarium.

L.T. Vahdat: commercial research grant and consultant, Eisai; honoraria from speaker's bureau, Eisai and Bristol-Myers Squibb Oncology. S. Jain disclosed no potential conflicts of interest.

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