Eribulin Mesylate

A Novel Halichondrin B Analogue for the Treatment of Metastatic Breast Cancer

Ali McBride, Pharm.D., M.S., BCPS; Sara K. Butler, Pharm.D., BCPS, BCOP

Am J Health Syst Pharm. 2012;69(9):745-755.

Pharmacology

Eribulin exerts its pharmacologic effects by binding to the plus ends of microtubules and suppressing microtubule growth, without affecting microtubule shortening, and by inducing the formation of nonproductive tubulin aggregates (Figure 1).^[17] This pattern of effects on microtubule stabilization is distinct from that of other clinically important tubulin-targeting agents, which include taxanes, epothilones, and vinca alkaloids. Vinca alkaloids (e.g., vincristine, vinblastine) bind to the plus ends and the sides of the microtubule, thereby reducing the concentration of tubulin aggregates and shrinking of the microtubules. Taxanes (e.g., paclitaxel, docetaxel) promote microtubule polymerization and maintain the microtubule structure, leading to the inhibition of mitotic spindle. Epothilones (e.g., ixabepilone) induce microtubule polymerization through a mechanism that appears to be similar to that of paclitaxel, as epothilones compete with paclitaxel for binding to microtubules and suppress microtubule dynamics.

(Enlarge Image)

Figure 1.

Mechanism of action of eribulin. The polymerization of microtubules occurs when heterodimers of α-tubulin and β-tubulin assemble to form a cylinder that is composed of tubulin heterodimers in a head-to-tail structure (A). Tubulin polymerizes in an end-to-end fashion with the α subunit of one tubulin dimer binding to the β subunit of the next. Therefore, one end will have the α subunit exposed while the other end will have the β subunit exposed. These ends are designated the minus (−) and plus (+) ends, respectively. The (−) end is capped so elongation of the microtubule occurs from the (+) direction. (B) Eribulin binds to the centromeric cap of the microtubule. A few molecules of vinblastine bound to high-affinity sites at the microtubule (+) end suffice to suppress microtubule cycling. A microtubule cutaway reveals the interior surface of the structure. Paclitaxel binds along the interior surface of the microtubule. Ixabepilone is known to share a common binding site with paclitaxel and has a high binding affinity for beta-III microtubulin. Despite the fact that epothilones bind close to or at the paclitaxel binding site on tubulin, the binding of epothilones to tubulin and the subsequent microtubule formation may be distinct from those of paclitaxel and require further research to elucidate all of the potential binding sites. (Adapted, with permission, from references 12–16).

Eribulin binds to a single site on soluble tubulin with low affinity and to a small number of sites at the microtubule ends with high affinity. This binding at the microtubule ends leads to the blockade of tubulin dimers from adding to the growing end of the microtubules. Eribulin binds at or near the tubulin vinca domain, a region located at the interface to two tubulin heterodimers.^[18] It appears to exert its activity by inhibiting microtubule growth. Unlike the antimitotic agents, paclitaxel and vinblastine, eribulin does not affect microtubule shortening.^[10,19]

In vitro data have shown that eribulin inhibits cancer cell proliferation via the induction of irreversible cell-cycle blocks at G2-M, disruption of mitotic spindles, and initiation of apoptosis.^[18,20] Although eribulin is a substrate for the P-glycoprotein drug efflux pump, it retains full in vitro activity against cancer cells that are taxane resistant due to β-tubulin mutations.^[4]

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Table 1. Recommended Dosage Modifications in Patients With Hepatic or Renal Impairment ^21,a
Impairment and Severity	Dose
Hepatic
Mild (Child-Pugh A)	1.1 mg/m²
Moderate (Child-Pugh B)	0.7 mg/m²
Severe (Child-Pugh C)	Not studied
Renal
Moderate (CLCL_cr, 30–50 mL/min)	1.1 mg/m²
Severe (CL_cr, <30 mL/min)	Not studied

^a CL_cr = creatinine clearance.

Table 2. Review of Phase I, II, and III Clinical Trials of Eribulin ^a
Ref.	n	Inclusion Criteria	Dose and Schedule	Response Rate	Adverse Effects
Phase I Trials
24	21	Age ≥18 yr, advanced solid tumors, measurable disease, progression after standard therapy, ≤2 prior chemotherapy regimens for metastatic disease, Karnofsky performance status of ≥70%, and life expectancy of ≥3 mo	Eribulin mesylate 0.25, 0.5,1, 2, 2.8, or 4 mg/m² given as 1-hr infusion every 21 days	Maximum tolerated dose: 2 mg/m² No complete responses, 1 partial response, 57% of pts had stable disease	Most frequently reported (all grades): neutropenia (38%), fatigue (33%), alopecia (33%); 10 pts had 22 serious adverse effects (all causalities); 7 pts had 9 serious treatment-related adverse effects (1 pt had grade 3 hyponatremia, 5 pts had grade 4 febrile neutropenia, and 1 pt had grade 4 febrile neutropenia, grade 2 pyrexia, and grade 3 infection ); 1 pt died of progressive disease
25	32	Age ≥18 yr, advanced solid tumors, measurable disease, progression after standard therapy, Karnofsky performance status of ≥70%, life expectancy of ≥3 mo, and adequate renal and hepatic functions	Eribulin mesylate 0.25-, 0.5-, 0.7-, 1-, or 1.4-mg/m² infusion on days 1, 8, and 15 of a 21-day cycle	Maximum tolerated dose: 1 mg/m² 1 partial response, 31% of pts had stable disease	Most common eribulin-related adverse effects: fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1 or 2), and anorexia (38% overall, 3% grade 3, no grade 4)
Phase II Trials
26	103	Age ≥18 yr, confirmed MBC not amenable to curative therapy, prior anthracycline and taxane therapy (sequential or combination), measurable disease, progression within 6 mo of last chemotherapy, ECOG performance status of 0–1, life expectancy of ≥3 mo, and adequate bone marrow, renal, and hepatic functions	Eribulin mesylate 1.4-mg/m² infusion on days 1, 8, and 15 of a 28-day or on days 1 and 8 of a 21- day cycle	Objective response rate: 10.2% in 28-day group, 14.3% in 21- day group, 11.5% overall17.2% of pts had overall clinical benefitMedian progression-free survival time, 2.6 mo; median overall survival, 9.0 mo	Most common drug-related toxicities (grade 3 or 4): neutropenia (64%), leukopenia (18%), fatigue (5%), peripheral neuropathy (5%), febrile neutropenia (4%)
27	291	Age ≥18 yr, confirmed locally advanced cancer or MBC, measurable disease, 2–5 prior chemotherapies (including anthracycline, taxane, or capecitabine), progression within 6 mo of last chemotherapy, ECOG performance status of 0–2, life expectancy of ≥3 mo, and adequate bone marrow, renal, and hepatic functions	Eribulin mesylate 1.4-mg/m² infusion over 2–5 min on days 1 and 8 of a 21-day cycle	Median overall response rate, 9.3%; median progression-free survival, 2.6 mo; median overall survival, 10.4 mo	Most common treatment-related grade 3 or 4 toxicities: neutropenia (54%), febrile neutropenia (5.5%), leukopenia (14%), asthenia or fatigue (10%, no grade 4) Grade 3 neuropathy occurred in 6.9% of pts (no grade 4)
Phase III Trials
28	1102	Age ≥18 yr, confirmed locally advanced cancer or MBC, measurable disease, ≤3 prior chemotherapies (including anthracycline or taxane), progression within 6 mo of last chemotherapy, ECOG performance status of 0–2, life expectancy of ≥3 mo, and adequate bone marrow, renal, and hepatic functions	Eribulin mesylate 1.4-mg/m² infusion over 2–5 min on days 1 and 8 of a 21-day cycle	Enrollment completed	Results pending
29	762	Age ≥18 yr, confirmed locally recurrent cancer or MBC, measurable disease, 2–5 prior chemotherapies (including anthracycline or taxane), progression within 6 mo of last chemotherapy, ECOG performance status of 0–2, life expectancy of ≥3 mo, and adequate bone marrow, renal, and hepatic functions	Eribulin mesylate 1.4-mg/m² infusion over 2–5 min on days 1 and 8 of a 21-day cycle (n = 508 or treatment of physician's choice (TPC) (n = 254)	Median overall survival: 13.1 mo in eribulin group vs. 10.6 mo in TPC group (p = 0.0410)Median progression-free survival: 3.7 mo in eribulin group vs. 2.2 mo in TPC group (p = −0.137) Objective response rate: 12% with eribulin vs. 5% with TPC (p = 0.002)	Neutropenia (grade 3: 21%; grade 4: 24%), febrile neutropenia (5%), peripheral neuropathy (all grades: 35%; grade 3: 8%); peripheral neuropathy led to discontinuation in 5% of pts

^a MBC = metastatic breast cancer, ECOG = Eastern Cooperative Oncology Group

Table 3. Recommended Dosage Modifications in Patients With Toxicities ^21,a
Toxicity or Previous Dosage Modification	Dose
Myelosuppression
ANC of <500 cells/μL for >7 days	1.1 mg/m²
ANC of <1,000 cells/μL with fever or infection	1.1 mg/m²
Platelet count of <25,000 cell/smm³	1.1 mg/m²
Platelet count of <50,000 cell/smm³ and requiring transfusion	1.1 mg/m²
Other
Nonhematologic grade 3 or 4 toxicities^b	1.1 mg/m²
Omission or delay of day 8 eribulin dose in previous cycle for toxicity	1.1 mg/m²
Occurrence of any event requiring permanent dosage reduction while receiving 1.1-mg/m² dose	0.7 mg/m²
Occurrence of any event requiring permanent dosage reduction while receiving 0.7-mg/m² dose	Discontinue treatment

^a ANC = absolute neutrophil count.
^b Toxicities graded in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

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