Halaven Mechanism of Action

Pharmacotherapeutic group: Other antineoplastic agents. ATC code: L01XX41.
Pharmacology: Pharmacodynamics: Eribulin mesilate is a microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. It is 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. Eribulin exerts 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.
Clinical efficacy: The efficacy of HALAVEN in breast cancer is supported by two single arm Phase 2 studies and a randomized Phase 3 comparative study.
The 762 patients in the pivotal Phase 3 EMBRACE study had locally recurrent or metastatic breast cancer, and had previously received at least two and a maximum of five chemotherapy regimens, including an anthracycline and a taxane (unless contraindicated). Patients must have progressed within 6 months of their last chemotherapeutic regimen. They were randomized 2:1 to receive either HALAVEN at a dose of 1.23 mg/m² (equivalent to 1.4 mg/m² eribulin mesylate) on Days 1 and 8 in a 21-day cycle administered intravenously over 2 to 5 minutes, or treatment of physician's choice (TPC), defined as any single-agent chemotherapy, hormonal treatment, or biologic therapy approved for the treatment of cancer; or palliative treatment or radiotherapy, reflecting local practice. The TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), or 3% hormonal therapy.
The study met its primary endpoint with an overall survival result that was statistically significantly better in the eribulin group compared to TPC at 55% of events. The median survival of the HALAVEN group (median 399 days/13.1 months) compared with the TPC group (median 324 days/10.6 months) improved by 75 days/2.5 months (HR 0.809, 958% CI: 0.660, 0.991, p=0.041). This result was confirmed with an updated overall survival analysis carried out at 77% of events with the median survival of the HALAVEN group (median 403 days/13.2 months) compared with the TPC group (median 321 days/10.5 months) improved by 82 days/2.7 months (HR 0.805, 95% CI: 0.677, 0.958, nominal p=0.014). (See Figure 1 and Table 1.)


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In response evaluable patients who received HALAVEN, the objective response rate by the RECIST criteria was 12.2% (95% CI: 9.4%, 15.5%) by independent review and 13.2% (95% CI: 10.3%. 16.7%) by investigator review. The median response duration in this population by independent review was 128 days (95% CI: 116, 152 days) (4.2 months).
The positive effect on OS and PES was seen in both taxane-refractory and non-refractory groups of patients. In the OS update, the HR for eribulin versus TPC was 0.90 (95% CI: 0.71, 1.14) in favour of eribulin for taxane-refractory patients and 0.73 (95% CI: 0.56, 0.96) for patients not taxane-refractory. In the Investigator assessment-based analysis of PFS (based on original data cut-off), the HR was 0.77 (95% CI: 0.61, 0.97) for taxane-refractory patients and 0.76 (95% CI: 0.58, 0.99) for patients not taxane-refractory.
The positive effect on OS was seen both in capecitabine-naïve and in capecitabine pre-treated patient groups. The analysis of updated OS showed a survival benefit for the eribulin group compared to TPC both in capecitabine pre-treated patients with a HR of 0.787 (95% CI: 0.645, 0.961), and for the capecitabine-naïve patients with a corresponding HR of 0.865 (95% CI: 0.606, 1.233). Investigator assessment-based analysis of PES (based on original data cut-off), also showed a positive effect in the capecitabine pre-treated group with a HR of 0.68 (0.56, 0.83). For the capecitabine-naïve group the corresponding HR was 1.03 (0.73, 1.45).
Liposarcoma: In liposarcoma the efficacy of eribulin is supported by the pivotal Phase 3 sarcoma study (Study 309). The patients in this study (n=452) had locally recurrent, inoperable and/or metastatic softy tissue sarcoma of one of two subtypes leiomysarcoma or liposarcoma. Patients had received at least two prior chemotherapy regimens, one of which must have been an anthracycline (unless contraindicated).
Patients must have progressed within 6 months of their last chemotherapeutic regimen. They were randomized 1:1 to receive either eribulin 1.23 mg/m² on days 1 and 8 of a 21 day cycle or dacarbazine 850 mg/m², 1000 mg/m² or 1200 mg/m² (dose determined by the investigator prior to randomization), every 21 days.
In Study 309, a statistically significant improvement in OS was observed in patients randomized to the eribulin arm compared to the control arm. This translated into 2 month improvement in median OS (13.5 months for eribulin treated patients vs. 11.5 months for dacarbazine treated patients). There was no significant difference in progression-free survival or overall response rate between the treatment arms in the overall population.
Treatment effects of eribulin were limited to patients with liposarcoma (45% dedifferentiated, 37% myxoid/round cell and 18% pleomorphic in Study 309) based on pre-planned subgroup analyses of OS and PFS. (See Table 2, Figure 2 and Figure 3.)


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Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with eribulin in all subsets of the paediatric population in the indication of breast cancer (see Dosage & Administration for information on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies with HALAVEN in one or more subsets of the paediatric population for the treatment of rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. See Dosage & Administration for information on paediatric use.
Pharmacokinetics: Distribution: The pharmacokinetics of eribulin are characterized by a rapid distribution phase followed by a prolonged elimination phase, with a mean terminal half-life of approximately 40 h. It has a large volume of distribution (range of means 43 to 114 l/m²).
Eribulin is weakly bound to plasma proteins. The plasma protein binding of eribulin (100-1000 ng/ml) ranged from 49% to 65% in human plasma.
Biotransformation: Unchanged eribulin was the major circulating species in plasma following administration of ¹⁴C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin.
Elimination: Eribulin has a low clearance (range of means 1.16 to 2.42 l/h/m²). No significant accumulation of eribulin is observed on weekly administration. The pharmacokinetic properties are not dose or time dependent in the range of eribulin mesylate doses of 0.25 to 4.0 mg/m².
Eribulin is eliminated primarily by biliary excretion. The transport protein involved in the excretion is presently unknown. Preclinical studies indicate that eribulin is transported by Pgp. However, it is unknown whether Pgp is contributing to the biliary excretion of eribulin.
After administration of ¹⁴C-eribulin to patients, approximately 82% of the dose was eliminated in faeces and 9% in urine indicating that renal clearance is not a significant route of eribulin elimination.
Unchanged eribulin represented most of the total radioactivity in faeces and urine.
Hepatic impairment: A study evaluated the pharmacokinetics of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=4) hepatic impairment due to liver metastases. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 3-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 0.97 mg/m² to patients with mild hepatic impairment and 0.62 mg/m² to patients with moderate hepatic impairment resulted in a somewhat higher exposure than after a dose of 1.23 mg/m² to patients with normal hepatic function. HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). There is no study in patients with hepatic impairment due to cirrhosis. See Dosage & Administration for dosage recommendation.
Renal impairment: A study in patients with different degrees of impaired renal function showed that the exposure of eribulin in patients with moderate renal function (creatinine clearance ≥40 to 59 ml/min, n=6) was similar to patients with normal renal function while the exposure in patients with severe impairment was increased by 75% (creatinine clearance <40 ml/min, n=4). See Dosage & Administration for treatment recommendations.
Toxicology: Preclinical safety data: Eribulin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Eribulin was positive in the mouse lymphoma mutagenesis assay and was clastogenic in the in vivo rat micronucleus assay.
No carcinogenicity studies have been conducted with eribulin.
A fertility study was not conducted with eribulin, but based on non-clinical findings in repeated-dose studies where testicular toxicity was observed in both rats (hypocellularity of seminiferous epithelium with hypospermia/aspermia) and dogs, male fertility may be compromised by treatment with eribulin. An embryofoetal development study in rat confirmed the developmental toxicity and teratogenic potential of eribulin mesylate. Pregnant rats were treated with 0.01, 0.03, 0.1 and 0.15 mg/kg at gestation days 8, 10 and 12. Dose related increased number of resorptions and decreased foetal weight were observed at doses ≥0.1 mg/kg and increased incidence of malformations (absence of lower jaw, tongue, stomach and spleen) was recorded at 0.15 mg/kg.