New Mechanism of Action Results Renew Interest in Eribulin

There has been renewed interest in eribulin mesylate (Halaven) following its FDA approval for advanced or unresectable liposarcoma and with the introduction of a growing body of preclinical work suggesting the agent has a novel anti—mesenchymal mechanism of action.

Following its approval in 2010 for breast cancer, eribulin has been prescribed to over 40,000 patients with metastatic breast cancer in the United States. Eribulin is approved for patients with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens for metastatic disease, which should include an anthracycline and a taxane in either the adjuvant or metastatic setting.

"There have been approvals of 3 different agents in the past few years, including approval of new targeted agents with hormone therapies," said Ricardo H. Alvarez, MD, MSc, who discussed eribulin's mechanism of action during a product theater at the 2016 San Antonio Breast Cancer Symposium (SABCS). "Chemotherapy still remains an important treatment, especially for patients with triple-negative breast cancer."

Trials exploring eribulin in various settings were presented at SABCS. These sessions focused on various combinations of the drug with agents ranging from the PD-1 inhibitor pembrolizumab (Keytruda) to the combination of pertuzumab (Perjeta) and trastuzumab (Herceptin). Additionally, other studies focused on the agent’s ability to inhibit the epithelial—mesenchymal transition (EMT) and the induction of vascular remodeling and reoxygenation of the tumor.

Eribulin is a synthetic analog of halichondrin B, a polyether macrolide derived from the marine sponge Halichondria okadai. The agent irreversibly inhibits the assembly of microtubules by binding to the tubulin vinca domain. Eribulin also works by isolating the tubulin into clusters that are no longer capable of assembling microtubules. This process prevents normal mitotic spindle formation, causing cell cycle arrest and inducing apoptosis.

Additionally, new in vitro and in vivo preclinical studies of human breast cancer models have indicated that eribulin can alter the tumor microenvironment. The agent causes vascular remodeling, which restores oxygen flow to hypoxic regions within the tumor. Hypoxia has been associated with phenotypical changes that lead to metastasis.

In these breast cancer models, eribulin also effectively stopped the metastatic mesenchymal phenotype while promoting epithelial cells. Eribulin was capable of effectively stopping and reversing EMT to a mesenchymal—epithelial transition state, said Alvarez, director of Cancer Research & Breast Medical Oncologist at the Southeastern Regional Medical Center.

"Halaven has been shown to block mitosis, resulting in tumor cell death by apoptosis," he said, during his talk. "Halaven promotes the epithelial phenotype and makes tumor cells less prone to migration and invasiveness."

In the phase III EMBRACE trial, treatment with eribulin extended overall survival (OS) by 2.6 months compared with treatment of physician's choice for patients with metastatic breast cancer following 2 prior lines of therapy. The median OS with eribulin was 13.1 months compared with 10.6 months with physician's choice, which was equivalent to a 19% reduction in the risk of death (HR, 0.81; 0.66-0.99; P = .041).

"This is the first and only single agent that shows overall survival benefit in patients that have previously been exposed to 2 lines of chemotherapy for their metastatic breast cancer," said Alvarez.

In the EMBRACE trial, 762 patients were randomized to receive eribulin (n = 508) or physician's choice of a monotherapy (n = 254). Most patients had visceral disease (80%) and nearly half (43%) received eribulin as a third-line therapy. Eribulin was administered at 1.4 mg/m² on days 1 and 8 intravenously in 2 to 5 minute infusions.

"Something very important is the infusion time. The infusion time is very short, and this is something that the patients like. It takes only 2 to 5 minutes," said Alvarez. "This is a unique characteristic of the drug. If you compare with many other agents, especially microtubule agents, the patients have to stay an hour or a couple hours for infusion of chemotherapy."

Baseline patient characteristics were well balanced in the EMBRACE trial. In the eribulin arm, patients had an ECOG performance status of 0 (43%), 1 (48%), and 2 (8%). Eighteen percent of patients had triple-negative breast cancer (TNBC) and 43% had received 2 prior lines of chemotherapy.

In the physician's choice of therapy arm, 97% of patients received chemotherapy. The most common types of chemotherapy included vinorelbine (26%), gemcitabine (18%), capecitabine (18%), taxanes (16%), other chemotherapy (10%), and anthracyclines (9%). The remaining 3% of patients received hormonal therapy. "This is all of the agents that are available for the patients after 2 lines of treatment," Alvarez noted.

The most common grade ≥3 adverse events for eribulin versus chemotherapy, respectively, were neutropenia (57% vs 23%), anemia (2% vs 4%), asthenia/fatigue (10% vs 11%), peripheral neuropathy (8% versus 2%), nausea (1% vs 3%), and constipation (1% vs 1%). Five percent of patients in the eribulin arm had febrile neutropenia, and 45% of patients in the eribulin arm had alopecia versus 10% in the comparator.

"When the patient has a very moderate hepatic impairment—Child Pugh A—you can do a dose reduction from 1.4 mg/m² to 1.1 mg/m². If there is moderate hepatic impairment—Child-Pugh B—we do a second dose reduction to 0.7 mg/m²," said Alvarez. "For patients with moderate or severe renal function impairment—a creatinine clearance of 15 to 49 mL/min—we dose reduce to 1.1mg/m². This is always important to keep in mind."

In January 2016, the FDA expanded the approval for eribulin to include the treatment of patients with advanced or unresectable liposarcoma following prior treatment with an anthracycline-based chemotherapy. This approval was based on OS, making it the first agent to gain approval based on survival for patients with liposarcoma, according to the FDA.

In 143 patients with liposarcoma in the pivotal trial, eribulin demonstrated a median OS of 15.6 months compared with 8.4 months in those who received dacarbazine (HR, 0.51; 95% CI, 0.35-0.75). Median progression-free survival (PFS) with eribulin was 2.9 versus 1.7 months with dacarbazine (HR, 0.52; 95% CI, 0.35-0.78).

"The dosing is the same for both metastatic breast cancer and liposarcoma. On top of that, the treatment is quick," said Alvarez. "Halaven can be delivered in just 2 to 5 minutes, which is important since Halaven is effective in a really tough treatment population."

There are over 40 clinical trials currently exploring eribulin, as part of the investigational or comparator arm. In breast cancer, a phase III trial is assessing eribulin in combination with the novel HER2-targeted agent margetuximab (NCT02492711). Additionally, eribulin will act as a potential comparator in a phase III study examining NKTR-102 (NCT02915744).

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