HALAVEN

What it is

Halaven is eribulin mesilate. It is a solution for injection, presented as a clear, colourless aqueous solution. Each vial contains 1 mg eribulin mesilate. Halaven is a first-in-class halichondrin B-based, microtubule dynamics inhibitor and a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into non-productive aggregates, exerting its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles and ultimately apoptotic cell death after prolonged and irreversible mitotic blockage.

Approved indications

— Treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease, with prior therapy having included an anthracycline and a taxane in either the adjuvant or metastatic setting unless contraindicated. — Treatment of patients with unresectable liposarcoma who have received prior chemotherapy for advanced or metastatic disease.

Dosing overview

The recommended dose of Halaven is 1.4 mg/m² administered intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle. In patients with mild hepatic impairment (Child-Pugh A), the recommended dose is 1.1 mg/m², and in patients with moderate hepatic impairment (Child-Pugh B), the recommended dose is 0.7 mg/m², each administered on Days 1 and 8 of a 21-day cycle. In patients with stage 3 chronic kidney disease (GFR 30–59 mL/min/1.73 m²) or stage 4–5 chronic kidney disease (GFR < 30 mL/min/1.73 m²), the recommended dose is 0.7 mg/m² administered over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. Halaven administration should be delayed on Day 1 or Day 8 for a maximum of 1 week if absolute neutrophil count is < 1 × 10⁹/L, platelets are < 75 × 10⁹/L, or Grade 3 or 4 non-haematological toxicities occur. If toxicities do not resolve or improve to Grade 2 or lower by Day 15, the dose should be omitted. If toxicities resolve or improve to Grade 2 or lower by Day 15, Halaven should be administered at a reduced dose and the next cycle initiated no sooner than 2 weeks later.

Key safety warnings

Myelosuppression is dose dependent and primarily manifested as neutropenia. In the EMBRACE study, neutropenia occurred in 82% of breast cancer patients treated with Halaven, with severe neutropenia (Grade 3 or higher) in 57% of patients. Complete blood counts should be monitored on all patients prior to each dose, and treatment should only be initiated in patients with absolute neutrophil count values ≥ 1.5 × 10⁹/L and platelets > 100 × 10⁹/L. Peripheral neuropathy occurred in 35% of breast cancer patients treated with Halaven, with severe peripheral neuropathy (Grade 3 or higher) occurring in 8% of patients and leading to discontinuation in 5% of patients. Patients should be closely monitored prior to each dose for signs of peripheral motor and sensory neuropathy, and the development of severe peripheral neurotoxicity requires a delay or reduction of dose. QT prolongation was observed on Day 8 in an uncontrolled ECG study. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias or concomitant treatment with medicinal products known to prolong the QT interval. Hypokalaemia or hypomagnesaemia should be corrected prior to initiating Halaven and monitored periodically during therapy. Halaven should be avoided in patients with congenital long QT syndrome.

Contraindications

Hypersensitivity to eribulin mesilate or to any of the excipients. Breastfeeding.

PBS listing

Halaven was recommended by PBAC in November 2016 for unresectable or metastatic liposarcoma following chemotherapy, listed under Section 100 at a reduced price.

Regulatory history

Halaven eribulin mesilate 1 mg/2 mL solution for injection was first registered on the ARTG on 4 September 2012 (ARTG 187136) under licence category RE. An AusPAR was approved on 16 November 2016 following the TGA's approval of an extension of indication for Halaven for the treatment of patients with unresectable liposarcoma who have received prior chemotherapy for advanced or metastatic disease.