Eisai Presents Updated Phase I Clinical Data of Liposomal Formulation of HALAVEN (E7389-LF) in HER2-Negative Breast Cancer at ESMO 2020

Tokyo, September 25, 2020 /PRNewswire/ -- Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced that it presented the latest results from the cohort of patients with HER2-negative breast cancer in the Phase 1 clinical trial of E7389-LF, a novel liposomal formulation of Halaven (eribulin mesylate, “eribulin”), an anticancer therapy discovered in-house, at the 2020 European Society for Medical Oncology (ESMO) Virtual Congress (Abstract No.: 346P).

E7389-LF is a novel formulation that utilizes liposomes composed of lipid bilayers to encapsulate eribulin, a halichondrin B-derived microtubule dynamics inhibitor. In tumor tissues, gaps between vascular endothelial cells, attributable to an incomplete vasculature, are considered permeable to macromolecules. This phenomenon, combined with impaired lymphatic function, is expected to facilitate the delivery and retention of high-molecular-weight drugs, including liposomal formulations, in tumors at higher concentrations than in normal tissues via the enhanced permeability and retention (EPR) effect. Consequently, E7389-LF is anticipated to increase the concentration of eribulin in tumor tissues.

This presentation reports the efficacy and safety results of E7389-LF in a cohort of 28 patients with recurrent HER2-negative breast cancer (hormone receptor-positive: 21 cases; triple-negative: 7 cases), who had previously received anthracycline or taxane therapy and were eribulin-naïve (data cutoff date: January 24, 2020; progression-free survival and overall survival cutoff date: April 17, 2020), as part of an open-label Phase 1 clinical trial (Study 114) in selected patients with previously treated solid tumors. Patients received intravenous E7389-LF at a dose of 2.0 mg/m² body surface area (as free eribulin) once every three weeks. The overall response rate (ORR) in the entire HER2-negative breast cancer cohort was demonstrated to be 35.7% (95% confidence interval [CI]: 18.6–55.9). Within this cohort, the ORR was 42.9% (95% CI: 21.8–66.6) in patients with hormone receptor-positive disease and 14.3% (95% CI: 0.4–57.9) in those with triple-negative disease. The disease control rate, comprising stable disease, partial response, and complete response, was 89.3% (95% CI: 71.8–97.7). Furthermore, the median progression-free survival (PFS) was 5.7 months (95% CI: 3.9–8.3), and the median overall survival (OS) was not reached (95% CI: 10.3–not reached). The top five Grade ≥3 adverse events were neutropenia (67.9%), leukopenia (42.9%), thrombocytopenia (32.1%), febrile neutropenia (25.0%), and elevated alanine aminotransferase (21.4%), consistent with the safety profile of eribulin established to date. Additionally, prophylactic treatment with pegfilgrastim (a glycolated granulocyte colony-stimulating factor [G-CSF]) demonstrated a reduced incidence of febrile neutropenia (treated group: 10.0%; untreated group: 33.3%).

Eisai positions oncology as a key therapeutic area, aiming to discover revolutionary new drugs with the potential to cure cancer. Eisai will continue to innovate in the development of new drugs based on cutting-edge cancer research, striving to further meet the diverse needs of cancer patients, their families, and healthcare providers, and to enhance their well-being.

[[Editor's Note]

1. About E7389-LF

E7389-LF is a novel formulation designed to more effectively deliver the halichondrin-based microtubule dynamics inhibitor “Halaven” (eribulin mesylate) to cancer cells via liposomal encapsulation. A Phase I clinical study in selected solid tumors is currently underway in Japan. Furthermore, a Phase Ib/II clinical trial evaluating the combination therapy of E7389-LF and nivolumab for targeted treatment of selected solid tumors is currently being conducted in Japan in collaboration with Ono Pharmaceutical Co., Ltd.

2. AboutHalaven(Halaven) (Generic Name: Eribulin Mesylate)

Halaven (eribulin) is a microtubule dynamics inhibitor of the halichondrin class, featuring a novel mechanism of action. Structurally, Halaven (eribulin) is a simplified, synthetically produced analog of halichondrin B, a natural product isolated from the marine sponge *Halichondria okadai*. Halaven (eribulin) is believed to exert its effect by inhibiting the growth phase of microtubule dynamics, thereby preventing cell division. Non-clinical studies have also demonstrated unique effects on the tumor microenvironment, such as increased vascular perfusion and permeability in the tumor core.¹, promoting epithelial state changes and reducing the metastatic potential of breast cancer cells²etc.

Halaven (eribulin mesylate) was first approved in the United States in November 2010 for the treatment of patients with metastatic breast cancer. Halaven is currently approved for the treatment of breast cancer patients in more than 75 countries worldwide, including Japan, China, and countries in Europe, the Americas, and Asia.

Furthermore, Halaven (eribulin mesylate) was first approved in the United States in January 2016 for the treatment of soft tissue sarcoma and has been approved in 65 countries, including Japan, Europe, and Asia. Additionally, Halaven (eribulin mesylate) has been designated as an orphan drug for soft tissue sarcoma in both the United States and Japan.

Specifically, Halaven (eribulin mesylate) has been approved for the following indications.

In the United States, it is used to treat the following patients:

In Japan, used for the treatment of the following patients:

In Europe, it is used to treat the following adult patients:

Two open-label, randomized, Phase III trials (EMBRACE and Study 301) of Halaven (eribulin mesylate) were conducted in patients with locally advanced or metastatic breast cancer who had previously received anthracycline- and taxane-based therapies. Pooled analysis based on combined results³Compared with the control group, the Halaven (eribulin) group demonstrated a significantly prolonged overall survival (OS) (hazard ratio [HR]=0.85 [95% confidence interval (CI)=0.77-0.95], p=0.003; median OS for Halaven: 15.2 months vs. 12.8 months for the control group). Compared with the control group, the Halaven (eribulin) group also showed prolonged progression-free survival (PFS) (HR=0.90 [95% CI=0.81-0.997], p=0.046; median PFS for Halaven: 4.0 months vs. 3.4 months for the control group).

The overall response rate (ORR) in the HER2-negative breast cancer group was 13.5%. Within this group, the ORR was 14.3% for hormone receptor-positive patients and 12.0% for triple-negative patients. The median progression-free survival (PFS) in the HER2-negative breast cancer group was 4.0 months.

Regarding the safety profile in the pooled analysis, there were no significant differences across the clinical studies. Patients in these Phase III studies received Halaven (eribulin mesylate) once every 21 days (1.4 mg/m² administered intravenously on Days 1 and 8).

¹ Funahashi Y et al., Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci., 2014; 105, 1334-1342

² Yoshida T et al., Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer, 2014; 110, 1497-1505

³ Twelves C et al., Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies. Breast Cancer Res Treat, 2014; 148, 553-561