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.

Summary

Eribulin is a halichondrin B analogue with a novel mechanism of action distinct from taxanes, vinca alkaloids, and ixabepilone. The unique mechanism of action, including the formation of nonfunctional tubulin aggregates, contributes to eribulin's efficacy in patients whose disease has progressed during taxane and anthracycline chemotherapy.

EMBRACE demonstrated an improvement of 2.1 months in overall survival with eribulin over a physician's choice chemotherapy in heavily pretreated patients with metastatic breast cancer.^[29] Despite this information, many questions about eribulin remain. Currently, there are no data comparing eribulin with other single-agent chemotherapy regimens, such as capecitabine, taxanes, and anthracyclines. In the Phase III trials, the chemotherapy agents in the TPC group were very diverse and the efficacy of each chemotherapy drug used varied greatly. More information is needed to directly compare eribulin with standard chemotherapy agents used in the metastatic or advanced breast cancer setting. This information will help further define the treatment strategy for metastatic breast cancer.

The Phase III data that have been published thus far are for women who were heavily pretreated with a median of four previous chemotherapy regimens. The publication of Study 301 will help define the role of eribulin earlier in the treatment strategy for locally advanced or metastatic disease in patients who have received up to three prior chemotherapy regimens but no more than two prior regimens for advanced or metastatic disease. Study 301 will help determine where eribulin should be used in the arsenal of chemotherapy agents that are available for patients with metastatic breast cancer as it will provide information regarding overall survival and progression-free survival in patients receiving either eribulin or capecitabine.^[28] Enrollment in Study 301 has been completed, and clinical results should be released in 2012.

As with many other breast cancer chemotherapies that are originally studied in the metastatic setting, the question remains of establishing eribulin's efficacy and safety in the adjuvant setting or in the first-line metastatic setting. Research is ongoing in this area.

Peripheral neuropathy is a significant concern and toxicity is common to women with metastatic breast cancer. While peripheral neuropathy remains one of eribulin's DLTs, the frequency is comparable to other chemotherapy regimens utilized in breast cancer. Studies will need to continue to observe the adverse effects of eribulin, especially neuropathy.

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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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