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.

Conclusion

Eribulin, a novel synthetic anti-microtubule agent that binds to the vinca domain of tubulin and inhibits the polymerization of tubulin, offers a new treatment option for metastatic breast cancer or locally advanced breast cancer.

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Acknowledgments
The research and editorial assistance of Romy Lea Topper-Cox, Pharm.D., and the computer graphics assistance provided by Marcy H. Hartstein, are acknowledged.

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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