Pharmacology Update

Eribulin Mesylate Injection (Halaven™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A new chemotherapeutic agent has been approved for the treatment of metastatic breast cancer previously treated with other chemotherapeutic agents. Erbulin mesylate is a member of a new chemical class of halichondrins that exerts its pharmacologic effect by inhibiting the growth phase of microtubules. Eribulin mesylate is marketed by Eisai Inc., as Halaven™.

Indications

Eribulin is indicated for the treatment of metastatic breast cancer in patients who have been treated with at least two chemotherapeutic regimens that included an anthracycline and a taxane (either as adjuvant or in a metastatic setting).1

Dosage

The recommended starting dose is 1.4 mg/m2 given intravenously over 2-5 minutes on day 1 and 8 of a 21-day cycle.1 The dose should be reduced in patients with mild-to-moderate hepatic impairment and moderate renal impairment. The dose should be delayed or reduced based on the severity of hematologic and non-hematologic toxicities.

Eribulin mesylate injection is available as 1 mg/2 mL single-use vial.

Potential Advantages

Eribulin showed an overall survival advantage over treatment of physician's choice (13.12 months vs 10.65 months) in patients with metastatic breast cancer who were previously treated with a median of four regimens that included an anthracycline and a taxane.1,2 There are no known drug-drug interactions involving CYP450 isoenzymes or P-glycoprotein.1

Potential Disadvantages

Dose-limiting adverse events are mainly neutropenia (57% grade 3) and peripheral neuropathy (8% grade 3).1 Other adverse events include asthenia/fatigue and alopecia. Eribulin may cause QT prolongation. ECG monitoring is recommended in patients susceptible to QT prolongation (e.g., CHF, bradyarrhythmias, or on drugs known to prolong QT interval).

Comments

Eribulin is an inhibitor of microtubules, but unlike other inhibitors such as taxanes and vinca alkaloids, which inhibit both the shortening and growth phases, enibulin only inhibits growth phases.2 The efficacy of eribulin was shown in a phase III study (EMBRACE). Women with locally recurrent or metastatic breast cancer who had received two or more chemotherapy regimens for advanced disease were randomized 2:1 to eribulin (1.4 mg/m2 on days 1 and 8 of a 21-day cycle; n = 508) or treatment of the physician's choice (TPC; n = 254).1,3 Approximately two-thirds of patients were estrogen receptor-positive, 28% negative; 49% progesterone receptor-positive, 39% negative; 16% HER2/neu receptor-positive, 74% negative; and 19% were triple negative. Patients had experienced disease progression within 6 months of their last chemotherapy regimen. TPC included any monotherapy or supportive care. Ninety-seven percent were on chemotherapy with the most common regimens being vinorelbine (26%), gemcitabine (18%), taxane (16%). The primary endpoint was overall survival and secondary endpoints were objective response rate (ORR), progression-free survival (PFS), and duration of response. The median survival was 13.1 months for eribulin and 10.6 months for TPC (hazard ratio, 0.81; 95% confidence interval [CI], 0.66-0.99; P = 0.041). ORR was 12% compared to 5% (P = 0.005). Median PFS was 3.7 months vs 2.3 months (P = 0.09). The median duration of response was 4.1 months for eribulin (56 responders) and 6.7 months for TPC (11 responders). Serious treatment-related adverse events associated with eribulin were asthenia/fatigue, neutropenia, and peripheral neuropathy. A second trial is in progress (n = 1102), which compares eribulin to capecitabine as second-line therapy for metastatic breast cancer.4

Clinical Implications

Metastatic breast cancer has a 5-year survival of 23%.5 Eribulin provides an alternative third-line therapeutic regimen for patients who have previously been treated but experience disease progression.

References

1. Halaven Prescribing Information. Woodcliff Lake, NJ: Eisai, Inc.; November 2010.

2. Jordan MA, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 2005;4:1086-1095.

3. Twelves C, et al. Abstract No: CRA1004. Chicago, IL: American Society of Clinical Oncology Annual Meeting; June 4-8, 2010.

4. Twelves C, et al. Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer. Clin Breast Cancer 2010;10:160-163.

5. American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Available at: www.cancer.org/acs/groups/content/@nho/documents/document/f861009final90809pdf.pdf. Accessed Jan. 3, 2011.