research....weill cornell medical college iris cantor breast center 425 east 61st, 8th floor new...

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Eribulin mesylate

Sarika Jain, Linda T. Vahdat

Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, United States, 10065

Running title: eribulin mesylate and metastatic breast cancer Keywords: eribulin mesylate, anti-microtubule, breast cancer Corresponding author: Linda Vahdat, MD Weill Cornell Medical College Iris Cantor Breast Center 425 East 61St, 8th floor New York, NY 10065 Phone: 212 -821-0644 Fax: 212-821-0758 Email: [email protected]

Disclosure of Potential Conflicts of Interest: LT Vahdat receives research support and is on the Speaker’s Bureau for Eisai. S Jain declares no conflicts of interest.

Word Count: 2,777

Total number of figures: 1

Total number of tables: 1

Research. on May 17, 2020. © 2011 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 22, 2011; DOI: 10.1158/1078-0432.CCR-11-1807

http://clincancerres.aacrjournals.org/

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Abstract:

Eribulin mesylate, a non-taxane, completely synthetic microtubule inhibitor, has recently been

approved by the U.S. Food and Drug Administration as third-line treatment of metastatic breast cancer

refractory to anthracyclines and taxanes. Eribulin is a synthetic analog of halichondrin B, which inhibits

microtubule polymerization by a mechanism distinct from other available anti-tubulin agents. Eribulin

significantly increased overall survival (median OS for the eribulin-treated group was 13.1 months versus

10.6 months for the group treated by investigator’s choice) in a heavily pretreated metastatic breast cancer

population. Eribulin has a manageable side-effect profile, notably neutropenia and fatigue, and a relatively

low incidence of peripheral neuropathy. The mechanism of action, pharmacokinetics, preclinical antitumor

activity, and clinical trials of eribulin in the metastatic breast cancer setting are reviewed.

Introduction

The U.S. Food and Drug Administration (FDA) recently approved eribulin mesylate [Halaven,

E7389], a non-taxane microtubule dynamics inhibitor, for the treatment of patients with metastatic breast

cancer (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

2011, an estimated 232,620 individuals will be diagnosed with breast cancer in the U.S and 39,970 will die

from the disease. Nearly 30% of breast cancers are metastatic, either as 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 MBC, with

the goal of palliating symptoms and improving survival while minimizing toxicity and maintaining a good

quality of life.




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Pharmacodynamics and Mechanism of Action

Eribulin mesylate is an analog of the macrolide halichondrin B, originally isolated from a rare marine

Japanese sponge, Halichondria okadai (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-C38 moiety of the parent compound was

developed (3, 4). Eribulin appears to exert its cytotoxic effects by interfering with microtubule dynamics

(Figure 1). Microtubules, which are comprised of polymeric filaments of α-tubulin and β-tubulin

heterodimers, form the mitotic spindle critical for cell division (5). Unlike other anti-microtubule 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 only and not shortening. Tubulin is also sequestered into nonfunctional aggregates, resulting in

irreversible G2-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).

Pharmacokinetic Studies

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 tri-phasic elimination with t1/2 ranging from 36 to 48 hours (10-12) and is eliminated




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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 to patients with normal liver function (13). Renal excretion is minimal

with 5-11% 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 demonstrates 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).

Preclinical Data

Eribulin mesylate was shown to have remarkable in vitro anti-tumor activity against numerous

human cancer cell lines with inhibition of cell growth in the sub-nanomolar 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 anti-cancer

activity including complete tumor regressions in human cancer xenograft models of breast, colon, ovarian,

and melanoma. It was more effective at lower doses compared to paclitaxel at empirically determined MTD

levels, likely due to its unusually wide in vivo therapeutic window (3).

Clinical Studies

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 (PK) to guide dose escalation. Eribulin mesylate was administered to 38 patients

with advanced solid tumors as a weekly 1-2 minute IV bolus for 3 of 4 weeks. Two dose-limiting toxicities




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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 non-hematologic toxicities included hypoglycemia, hypophosphatemia, and fatigue.

(10).

In a subsequent phase I study, 32 patients with advanced solid malignancies received eribulin

mesylate (1 hour IV 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 1/2 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 1.4 mg/m2 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 may 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 MBC previously

treated with an anthracycline and taxane (median of 4 chemotherapy regimens). Patients received a 2-5

minute IV 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




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interruptions, delays, reductions or omissions in cycle 1 occurred more frequently in the 28-day cohort (54%)

compared to the 21-day cohort (18%), primarily due to 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 performed to further evaluate

the efficacy and toxicity in 291 patients with locally advanced and MBC, 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%, respectively. 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 pre-existing grade 1/2 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




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regulatory approval of eribulin mesylate. Seven hundred sixty-two women with locally recurrent or MBC

were randomized in a 2:1 ratio to receive eribulin mesylate 1.4 mg/m2 over 2-5 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, or biological therapy. The primary endpoint was OS in the

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 to 7) including an anthracycline and a taxane, unless

contraindicated. Majority of TPC was chemotherapy (96%), including vinorelbine (26%), gemcitabine

(18%), and capecitabine (18%), representing real-life treatment choices at the time (2006-08). The most

common metastatic sites were bone (61%) and liver (60%), with over half of patients with 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, respectively. Dose interruptions, delays, or

reductions were undertaken in 421 (84%) patients in the eribulin group compared to 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 to 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 significant (HR 0.87, 95%

CI .71-1.05, p=0.137). More patients were censored with independent review compared to investigator

review resulting in more progression events in the latter (521 versus 635). The ORR was 12% in eribulin-

treated patients compared to 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 1/2 in severity. Peripheral neuropathy occurred in

35% of eribulin-treated patients with only 8% being grade 3/4, however it led to treatment discontinuation in

only 5%. The authors of this trial concluded that eribulin mesylate is a potential new standard of treatment




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for women with heavily pretreated MBC based on its 2.5 month extension of median overall survival over

currently available cytotoxic therapies and a manageable toxicity profile (21).

A subsequent phase III trial (E 301) has completed accrual of 1102 women with MBC 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).

Advantages Over Other Agents

Treating MBC remains a challenge as oncology treatment providers attempt to balance efficacy and

toxicity. Though many chemotherapeutic agents are available including capecitabine (Xeloda), ixabepilone

(Ixempra), nab-paclitaxel (Abraxane), and gemcitabine (Gemzar), little guidance exists on how best to

sequence them to optimize patient care. Ixabepilone, a microtubule-targeted analog of the epothilones,

demonstrated single agent activity in an anthracycline, taxane, and capecitabine resistant MBC 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 to capecitabine alone,

however no significant improvement in OS was observed. A pre-planned subset analysis demonstrated an

improvement in OS in symptomatic patients with a low Karnofsy’s performance score (KPS) of 70-80%

(median OS, 14 months for combination versus 11.3 months for capecitabine monotherapy, HR 0.76, 95% CI

0.60-0.96) (24). While 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 over 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 to 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




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prepared in an aqueous solution and does not require a lipophilic vehicle that may cause hypersensitivity

reactions, precluding the need for premedications.

Comparisons of cost

The economic burden of MBC in developed countries is substantial. The price of eribulin mesylate is

approximately $4,000 per cycle in the U.S. based on the average female B.S.A of 1.6 m2 and 3-week cycle.

This is comparable to the approved drugs for late-line MBC therapy, capecitabine ($2,688 per cycle) and

ixabepilone ($2,560). Cost analysis of other commonly used treatments for MBC based on the above

parameters include nab-paclitaxel ($3,952 per cycle), docetaxel ($2,280), paclitaxel ($1,554), gemcitabine

($668), and vinorelbine ($192) (26).

Conclusions and Challenges

Eribulin mesylate represents a step forward in the treatment of MBC 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 MBC (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 MBC (NCT01268150), in combination with

capecitabine for pretreated MBC (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 cancer, 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.




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Legend:

Figure 1: Mechanism of action of eribulin mesylate and other microtubule-inhibitory agents. Eribulin

destabilizes microtubules by blocking tubulin polymerization and inhibiting microtubule growth but not

shortening. Referred to as “end-poisoning,” eribulin either binds directly to the microtubule ends or induces

tubulin aggregates, by competing with soluble tubulin for addition to the growing ends of the microtubule.

By contrast, vinca alkaloids destabilize microtubules by blocking polymerization as well as promoting

depolymerization, suppressing both growth and shortening. Taxanes (paclitaxel) and the epothilones

(ixabepilone) stabilize microtubules by inhibiting microtubule depolymerization and enhancing microtubule

assembly. Adapted by permission from MacMillan Publishers Ltd: Nature Reviews Neuroscience (28),

copyright 2009.

Table 1: Review of phase I to III clinical trials of eribulin in patients with metastatic breast cancer

Abbreviations: RR, response rate; SD, stable disease; DLT, dose-limiting toxicity; *, unconfirmed partial

response in cervical cancer patient; **, unconfirmed partial response in non-small cell lung cancer patient;

***, response in eribulin population; a, per protocol population; b, eligible population; c, 508 women

randomized to eribulin, 254 to TPC; †, toxicity is any grade unless otherwise noted




Table 1: Review of phase I to III clinical trials of eribulin in patients with metastatic breast cancer

Author Phase Cancer type n Dose RR, n (%) SD, n (%)

Median PFS,

months

(range)

Toxicity†

Synold et al (10) I Advanced solid tumors 38

0.125-2 mg/m2 over 2

minutes on days 1, 8, 15

every 28 days

2 (5) 12 (32) N/A DLT: febrile neutropenia at 2 mg/m2

Goel et al. (11) I Advanced solid tumors 32

0.25-1.4 mg/m2 over 1 hour

on days 1, 8, 15 every 28

days

1 (3)* 10 (31) N/A

DLT: neutropenia at 1.4 mg/m2.

Fatigue (53%), nausea (41%),

anorexia (38%), neuropathy (25%)

Tan et al. (12) I Advanced solid tumors 210.25-4 mg/m

2 over 1 hour

every 21 days1 (5)** 12 (57) N/A

DLT: neutropenia at 2 mg/m2.

Neutropenia (38%), alopecia (33%),

fatigue (33%), febrile neutropenia

(29%), nausea (19%), anorexia (14%)

Minami et al. (17) I Advanced solid tumors 15

0.7-2 mg/m2 over 5 minutes

on days 1 and 8 every 21

days

3 (20) 3 (20) N/ADLT: febrile neutropenia at 1.4

mg/m2.

Vahdat et al. (18) II Metastatic breast cancer 103 (87a)

Cohort 1: 1.4 mg/m2 over 2-

5 minutes on days 1, 8, 15

every 28 days. Cohort 2: 1.4

mg/m2 on days 1 and 8

every 21 days

Cohort 1: 6 (10.2)

Cohort 2: 4 (14.3)

Cohort 1: 21

(35.6) Cohort 2:

16 (57.1)

2.6 (0-14.9)

Neutropenia (75%), fatigue (52%),

nausea (37%), anorexia (15%),

neuropathy (31%), febrile neutropenia

(4%)

Cortes et al. (19) II Metastatic breast cancer 291 (269b)

1.4 mg/m2 over 2-5 minutes


days

25 (9.3) 125 (46.5) 2.6 (0.03-13.1)

Fatigue (65%), neutropenia (60%),

nausea (44%), neuropathy (32.6%),

febrile neutropenia (5.5%)

Iwati et al. (20) II Metastatic breast cancer 81



days

17 (21.3) 30 (37.5) 3.6 (2-4.4)

Grade 3/4 neutropenia (95.1%),

febrile neutropenia (13.6%), grade 3

neuropathy (3.7%)

Cortes et al. (21) III Metastatic breast cancer 762c



days

57 (13)*** 208 (44)***3.6 (3.3-

3.7)***

Fatigue (54%), neutropenia (52%),

nausea (35%), neuropathy (35%),

febrile neutropenia (5%)




Eribulin has noeffect on microtubule

shortening

Eribulin inhibitsonly microtubule

growth

MicrotubulestabilizersTaxanes

Epothilones

Vinca alkaloids and taxanesinhibit both growth and shortening

Growingmicrotubule

Shortening microtubule

Tubulinpolymerization

Tubulin depolymerization

Tubulin

Microtubule

β-tubulin

α-tubulin

Microtubuledestabilizers

EribulinVinca alkaloids

Eribulin inducesnonfunctional

tubulin aggregates




Published OnlineFirst August 22, 2011.Clin Cancer Res Sarika Jain and Linda T Vahdat Eribulin mesylate

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