Eribulin

Eribulin is an antineoplastic medicine and microtubule dynamics inhibitor derived synthetically from the marine natural product halichondrin B. It binds to tubulin and suppresses microtubule growth, interfering with the normal processes required for cell division. This can inhibit the proliferation of rapidly dividing cancer cells. Eribulin is administered by intravenous injection and is generally given on specific days within a 21-day treatment cycle. It is used primarily for adults with previously treated locally advanced or metastatic breast cancer and for adults with unresectable or metastatic liposarcoma after prior anthracycline-containing therapy, subject to the applicable regulatory indication. Its clinical importance comes from its established role in later-line treatment of these cancers, particularly when the disease has progressed after previous systemic therapies. Because eribulin affects microtubules, its treatment effects are accompanied by predictable chemotherapy-related toxicities, including neutropenia, anemia, fatigue, hair loss, peripheral neuropathy, nausea and constipation. Appropriate blood-count monitoring and assessment for neurological, hepatic and cardiac risk factors are important during treatment. Dose modifications may be required in patients with certain adverse reactions or impaired liver or kidney function.

Eribulin is a synthetic analogue of halichondrin B, a natural product originally isolated from the marine sponge Halichondria okadai. Its development focused on the antitumor activity of halichondrin-derived compounds and their ability to interfere with microtubule dynamics. The U.S. FDA approved Halaven (eribulin mesylate) on November 15, 2010 for patients with metastatic breast cancer who had previously received at least two chemotherapy regimens for metastatic disease, including an anthracycline and a taxane when appropriate. FDA subsequently approved eribulin on January 28, 2016 for unresectable or metastatic liposarcoma following a prior anthracycline-containing regimen. The EMA granted marketing authorisation for Halaven on March 17, 2011 for previously treated locally advanced or metastatic breast cancer and subsequently for unresectable liposarcoma. In India, CDSCO records indicate that eribulin mesylate injection was approved in 2016 for the relevant proposed indication, with subsequent regulatory actions concerning additional presentations. Key clinical development included the phase III EMBRACE study in metastatic breast cancer and the randomized phase III E7389-G000-309 study in advanced liposarcoma.

Eribulin is used as monotherapy in adults with locally advanced or metastatic breast cancer that has progressed after previous chemotherapy. Regulatory indications generally require prior exposure to an anthracycline and a taxane unless those treatments were unsuitable; U.S. labeling specifically describes patients who have previously received at least two chemotherapy regimens for metastatic disease. Eribulin is also indicated for adults with unresectable or metastatic liposarcoma who have previously received an anthracycline-containing regimen, unless such therapy was unsuitable. The liposarcoma indication is specific to liposarcoma rather than all soft-tissue sarcomas. Eribulin is administered as a single-agent chemotherapy rather than as a routine combination regimen in these approved indications. Treatment selection depends on previous therapies, disease status, organ function, performance status and the patient's overall clinical circumstances.

Eribulin is administered intravenously, with the standard adult dose of 1.4 mg/m² given over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. Treatment cycles are generally repeated according to clinical response and tolerability, with treatment continued until disease progression or unacceptable toxicity. Dose interruption or reduction may be required for neutropenia, peripheral neuropathy, liver dysfunction or other significant adverse reactions. A lower starting dose is recommended for patients with mild or moderate hepatic impairment and for patients with moderate or severe renal impairment under U.S. prescribing information. Blood counts should be assessed before administration and as clinically appropriate during treatment. Electrolyte abnormalities and cardiac risk factors should also be considered, particularly because eribulin can prolong the QT interval. The medicine should be prepared and administered according to product-specific instructions and should not be mixed with incompatible solutions or other medicines in the same administration line.

Common side effects of eribulin include low white blood cell counts, anemia, fatigue or weakness, hair loss, peripheral neuropathy, nausea and constipation. Other reactions can include loss of appetite, vomiting, headache, joint or muscle pain, fever, weight loss and changes in liver-function tests. Peripheral neuropathy may present as numbness, tingling, burning sensations, increased sensitivity or weakness, particularly in the hands and feet. Blood-count abnormalities can increase susceptibility to infection or contribute to fatigue. The severity and frequency of side effects vary between patients and treatment settings. Many adverse effects can be managed through supportive care, treatment delays or dose modification under medical supervision.

Important risks associated with eribulin include severe neutropenia, febrile neutropenia, peripheral neuropathy, embryo-fetal toxicity and QT-interval prolongation. Severe reduction in neutrophil counts can increase the risk of serious infection and requires blood-count monitoring. Peripheral neuropathy may become clinically significant and can require treatment interruption or dose reduction. Eribulin can prolong the QT interval, so caution is appropriate in patients with congenital long-QT syndrome, cardiac disease, electrolyte abnormalities, bradyarrhythmias or concomitant medicines that prolong the QT interval. Severe hepatic impairment has not been adequately studied and requires particular caution. Eribulin can cause fetal harm, so pregnancy should be excluded or appropriately addressed before treatment and effective contraception should be discussed where applicable. Breastfeeding is not recommended during treatment.

Before treatment, clinicians should review the patient's previous chemotherapy, complete blood count, liver and kidney function, neurological status and cardiovascular history. Patients with pre-existing peripheral neuropathy require careful assessment because eribulin can worsen neurological symptoms. Electrolyte abnormalities should be corrected when clinically relevant, particularly in patients at risk of QT prolongation. Eribulin is primarily eliminated through hepatic metabolism and biliary excretion, with CYP3A4 playing a limited role in its metabolism; clinically significant CYP-mediated interactions are generally less prominent than with many oral targeted therapies. Nevertheless, the full medication list should be reviewed, particularly for drugs that can prolong the QT interval or contribute to overlapping toxicities. Eribulin should not be used during breastfeeding, and reproductive counselling is important because of potential fetal toxicity. Patients with hepatic or renal impairment may require a reduced starting dose and closer monitoring.

Confirm the indication and previous treatment history before initiating eribulin, particularly the required prior anthracycline and taxane exposure for breast cancer and prior anthracycline-containing therapy for liposarcoma. Obtain baseline blood counts and assess liver and kidney function, neurological symptoms and cardiac risk factors. Monitor neutrophil counts before each dose and throughout treatment, and assess patients for fever or other signs of infection. Ask specifically about numbness, tingling, burning, weakness or difficulty walking because peripheral neuropathy can require dose modification. Review concomitant medicines for QT-prolonging potential and correct clinically significant electrolyte abnormalities. For patients with hepatic or renal impairment, verify the appropriate reduced starting dose. Pharmacists and infusion staff should confirm the calculated body-surface-area dose, correct dilution and administration procedure, and treatment-day schedule. Patients should be counselled about infection symptoms, worsening neuropathy, severe weakness, palpitations and other clinically significant symptoms that require prompt medical assessment.