Eribulin: another new chemotherapy for breast cancer
During the past several decades, significant advances in breast cancer management have led to increased OS for patients with this disease.
Many clinicians and researchers attribute this increase to the development of new anticancer drugs, which, when used sequentially, are able to extend the lives of our patients. Despite these advances, metastatic breast cancer remains incurable and extending survival with a single new drug has been difficult to demonstrate in the context of a traditional clinical trial design. Utilizing a novel trial design, researchers were recently able to demonstrate an improvement in OS in heavily pretreated metastatic breast cancer patients with the administration of eribulin (Halaven, Eisai Inc.).
Eribulin was approved by the FDA in November for treatment of metastatic breast cancer patients who have previously received at least two chemotherapeutic regimens in the metastatic setting, based primarily on results from one large, phase 3 randomized clinical trial. Eribulin is a synthetic analog of halichondrin B and is the first in a unique class of antineoplastic agents. Acting as a microtubule dynamics inhibitor, it exerts its effects in a novel way that differs from the taxanes, ixabepilone (Ixempra, Bristol-Myers Squibb) and the vinca alkaloids.
Eribulin inhibits the growth phase of microtubules, sequestering tubulin into nonproductive aggregates. Cells are unable to develop mitotic spindles, resulting in disruption of the cell cycle from the G2 to the M phase and, ultimately, causing cell death.
One potential benefit of eribulin over other agents that act on microtubules is a theoretical decrease in resistance to chemotherapy. In vitro, eribulin demonstrated activity against beta-III tubulin, an isotype that is overexpressed in cells exhibiting resistance to the taxanes. However, eribulin is a substrate for the drug efflux transporter P-glycoprotein (P-gp). Therefore, similar to other chemotherapy derived from natural products, the overexpression of P-gp may be a key mechanism of resistance to eribulin.
The phase 3 trial that led to the approval of eribulin was an open-label, randomized, multicenter trial that included 762 patients with heavily pretreated metastatic breast cancer. Patients included in the study had received an average of four previous chemotherapeutic regimens before enrollment. Exposure to a taxane and an anthracycline was also required (in the adjuvant or metastatic setting).
Participants were randomly assigned in a 2:1 ratio to receive eribulin at a dose of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle or a single agent therapy selected by their physician. Although there were no established guidelines for what patients were allowed to receive in the control arm, most of the therapies used were therapies likely to be effective in breast cancer vinorelbine, gemcitabine, capecitabine (Xeloda, Hoffmann-La Roche), taxane or ixabepilone, anthracycline. Three percent of patients received hormonal therapy for their breast cancer treatment and no patient in this group received biologic therapy alone or best supportive care only.
Eribulin significantly improved OS by 2.5 months compared with the control arm (13.1 months vs. 10.6 months, P=.041). Patients in the eribulin arm also had a significant increase in objective response rate compared with the control arm (12.2% vs. 4.7%, P=.002).
Because therapies utilized in the control arm were not standardized, 10% of patients received therapies without substantial evidence of efficacy in breast cancer. This is a controversial approach to drug development because it does not clearly identify an appropriate place in therapy for this new agent and may have unfairly advantaged the eribulin arm of the trial. However, it does allow rapid approval of a novel compound with the potential to help many patients.
The dose-limiting toxicity of eribulin is neutropenia, which is more frequent and severe in patients with elevated transaminases or bilirubin. Grade 3/4 neutropenia occurred in 57% of patients receiving eribulin, requiring a dose reduction in 12% of patients and drug discontinuation in less than 1% of patients in the phase 3 clinical trial. Febrile neutropenia occurred in 5% of patients, resulting in two deaths. Primary prophylaxis with granulocyte colonystimulating factors is not recommended because the risk for febrile neutropenia is relatively low.
Growth factor support may be warranted as secondary prophylaxis in patients who develop prolonged, severe neutropenia or febrile neutropenia with the use of eribulin. Dose reduction with subsequent cycles may be required for hematologic or other toxicities (Table 2), particularly in the palliative setting of metastatic breast cancer.
Peripheral neuropathy was the most common toxicity leading to discontinuation of eribulin (5% of patients.) Grade 3/4 neuropathy occurred in 8% of patients and lasted more than a year in 5% of patients. It is recommended to withhold eribulin upon development of grade 3/4 neuropathy until resolution to grade 2 or less. Although neuropathy was a cumulative dose-limiting toxicity of eribulin, the incidence and severity seen in clinical trials is slightly less than with other agents used in breast cancer that act on microtubules, such as the taxanes and ixabepilone.
The most common adverse reactions (all grades) seen with the use of eribulin (occurring in more than 20% of patients) were neutropenia (82%); anemia (58%); asthenia/fatigue (54%); alopecia (45%); peripheral neuropathy (35%); nausea (35%); constipation (25%); arthralgia/myalgia (22%); weight loss (21%) and pyrexia (21%). Transient elevations in alanine aminotransferase were seen in 18% of patients.
Delayed QT prolongation was observed on day 8 with a mean increase of QTc of 11.4 ms. It is recommended to monitor electrocardiograms in patients with congestive heart failure, bradyarrhythmias, concomitant QT prolonging medications and electrolyte abnormalities. Although electrolyte abnormalities were not significantly more frequent with the use of eribulin, hypokalemia and hypomagnesemia should be corrected before use and monitored throughout therapy in patients who meet these criteria for cardiac monitoring.
Dosing and administration
The recommended dose of eribulin is 1.4 mg/m2 administered intravenously over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. The dose may be given as undiluted drug or may be diluted in 100 mL of 0.9% sodium chloride. Eribulin should not be diluted in or administered through a line containing dextrose. An in-line filter should be used when administering eribulin, but administration sets with polyvinylchloride can be used as well. This improves the ease of administration over other agents such as paclitaxel or docetaxel.
Pharmacokinetic studies have demonstrated that eribulin exposure is increased 1.8 and 2.5 times in patients with mild and moderate hepatic impairment, respectively. Therefore, dose reductions are recommended in these patients (Table 3). Additionally, the safety of eribulin has not been evaluated in patients with severe hepatic impairment and is therefore not recommended for use in these patients. Further pharmacokinetic analysis revealed that systemic exposure to eribulin is doubled in patients with moderate renal impairment (creatinine clearance [CrCl] 30-50 mL/minute), so dose reduction is recommended in this group of patients as well (Table 3). An additional study in patients with renal impairment, including patients with severe renal impairment (CrCl < 30 mL/minute), is required by the FDA. Results of this analysis are expected to be available within the next 2 years.
Eribulin is a novel microtubule inhibitor approved for use in metastatic breast cancer after at least two other chemotherapeutic regimens in the metastatic setting. Most patients who received eribulin in the phase 3 study had a good performance status of 0 or 1, were heavily pretreated with an average of four regimens (including an anthracycline and a taxane in all patients, and capecitabine in about 75% of patients), and had visceral disease.
Response rates appear to be similar to or higher than those seen with other agents in heavily pretreated patients. Eribulin may be considered in patients who have already progressed on multiple lines of standard chemotherapy but require additional chemotherapy due to symptomatic or progressive metastatic disease. However, close attention should be paid to the risks of myelosuppression and peripheral neuropathy.
The cost of eribulin is significant, approximately $6,000 per cycle, which is comparable to ixabepilone (see Table 1). Both of these agents have patient assistance programs through their manufacturers, which may help offset the costs of treatment. However, a larger social concern looms regarding the cost of a 12% response rate and a 2.5-month gain in survival.
More clinical experience with eribulin will be necessary to clarify its role in treating breast cancer. In the meantime, patients have one more agent to turn to in the fight against their metastatic disease.
Karen Eckmann, PharmD is a clinical pharmacy specialist at MD Anderson Cancer Center.
Laura Boehnke Michaud, PharmD, BCOP, FASHP, is manager of Clinical Pharmacy Services at MD Anderson Cancer Center.
Disclosures: Eckmann and Michaud report no relevant financial disclosures.
For more information:
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- Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; November 2010.
- Newman S. Curr Opin Investig Drugs. 2007;8:1057-1066.
- Pazdur R. NDA 201532 approval letter. Food and Drug Administration website. Available at: www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/201532s000ltr.pdf. Accessed Jan. 11, 2011.
- Roché H. Ann Oncol. 2010;doi:10.1093/annonc/mdq429.
- Twelves C. Abstract 257. Presented at: The 2010 Breast Cancer Symposium; Oct. 1-3, 2010; National Harbor, Md.