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

Disclosures

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

In This Article

Abstract and Introduction

Abstract

Purpose The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of eribulin in patients with metastatic breast cancer are reviewed.
Summary Classical chemotherapeutic agents for breast cancer have dominated treatment regimens even in the era of targeted therapy. Disease progression through these agents is often due to the development of resistance or lack of efficacy with these agents. Recently, a new nontaxane agent, eribulin mesylate, was approved for the treatment of metastatic breast cancer in patients who have received at least two prior chemotherapeutic agents. Eribulin is a member of a new class of synthetic cytotoxic agents derived from the Japanese sea sponge Halichondria okadai. Eribulin differs from other antimicrotubule agents in that it can bind to the microtubule cap and inhibit tubulin polymerization, leading to microtubule arrest. In Phase II clinical trials, eribulin demonstrated activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine and had shown disease progression within the last six months of treatment. In a pivotal Phase III clinical trial of heavily pre-treated patients, patients who received eribulin versus the physician's treatment of choice showed a significant increase in overall and progression-free survival. Eribulin has a manageable adverse-effect profile, consisting mainly of neutropenia and fatigue. Eribulin has been associated with a low incidence of peripheral neuropathy.
Conclusion Eribulin, a novel synthetic antimicrotubule 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.

Introduction

Breast cancer continues to be the leading cause of cancer among women and second to only lung cancer in terms of mortality.[1] Approximately one of every eight women will develop breast cancer during her lifetime. According to the American Cancer Society, an estimated 207,090 new cases of breast cancer in women were diagnosed in the United States in 2010, with 39,840 deaths. Approximately 20% of women diagnosed with breast cancer will develop metastatic breast cancer.[2] Although metastatic breast cancer remains incurable, overall breast cancer mortality rates have declined steadily since 1990 due to earlier detection, the development of improved treatment options, and new chemotherapeutic agents.[2] Taxane- and anthracycline-based chemotherapy regimens continue to remain the foundation of therapy for patients with advanced breast cancer.

Taxane compounds bind to β-tubulin subunits, preventing the depolymerization of microtubules (filaments formed by α-tubulin and β-tubulin subunits) and disruption of their dynamic disassembly and assembly. These processes are essential for the completion of cell division. Tumor cells are particularly susceptible to this type of microtubule-targeted mechanism because they divide at a much higher rate than most normal cells. Disruption of tubulin dynamics by taxanes leads to cell-cycle arrest and tumor cell death.[3]

The use of taxanes and anthracyclines is highly efficacious; however, treatment failure can occur in up to 90% of metastatic breast cancer patients, many times the result of acquired and intrinsic resistance.[3] One of the major causes of multi-drug resistance is the P-glycoprotein transmembrane efflux pump.[4] The protein, along with similar multi-drug resistancelike transporters of the ATP-binding cassette (ABC) transporter family, reduces the intracellular concentrations of chemotherapy agents in tumor cells. This prevents the accumulation of intracellular concentrations of the drug. Resistance to chemotherapy agents, specifically taxane-based regimens, can also include alteration in target proteins such as β-tubulin.[5] In patients who are refractory to anthra-cycline and taxanes, drug therapy such as capecitabine or ixabepilone is often used. Unfortunately, response rates to these therapies are often low.[6] Previously, capecitabine was the only drug with labeling approved by the Food and Drug Administration (FDA) for the treatment of metastatic breast cancer resistant to paclitaxel and anthracyclines, while ixabepilone was the only approved chemotherapy agent in the setting of resistance to a taxane, anthracycline, and capecitabine. Development of a new agent for patients with late- stage metastatic breast cancer would yield a niche in current treatment regimens.

Natural products have long harbored potential in the development of new drug entities.[7] These drug targets have served as templates for the development of novel semisynthetic and synthetic compounds with enhanced biological activity.[8] About 25% of drugs in the modern pharmacopoeia are derived from plants, including several anticancer drugs currently in clinical use (e.g., vinca alkaloids, taxanes, podophyllotoxin, camptothecin, halichondrins).[9] The halichondrins were first isolated from the Japanese sea sponge Halichondria okadai, and its structure was determined by x-ray crystallography. Subsequent studies revealed the molecules' inherent ability to inhibit tubulin, through a noncompetitive binding mechanism at the vinca alkaloid binding site, causing a characteristic G2-M cell-cycle arrest with disruption at the mitotic spindle.[10] A synthetic analogue created from halichondrin demonstrated enhanced biological activity and increased cell toxicity against numerous cell lines. Eribulin (previously known as E7389) has exhibited in vitro activity against a number of cancer cell lines, including breast, colon, lymphoma, prostate, and melanoma.[11] This article reviews the pharmacology, pharmacokinetics, clinical efficacy, safety, and role in therapy of eribulin in patients with locally advanced or metastatic breast cancer.

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