Eisai Inc. announced that the US Food and Drug Administration (FDA) approved Halaven (eribulin mesylate) injection (0.5 mg per ml) for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. This marks the second indication for which Halaven has been approved by the FDA based on a statistically significant extension of survival.

"There is an unmet medical need for patients with soft tissue sarcoma whose disease no longer responds to treatment," said George Demetri, MD, Professor of Medicine at Harvard Medical School and director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute. "Halaven has been shown to help patients with advanced liposarcoma live longer, a meaningful result for patients with this rare and hard-to-treat disease."

This approval was based on the results of the pivotal phase 3 trial, Study 309, which demonstrated that previously treated liposarcoma patients who received Halaven (n=71) experienced a median overall survival (OS) of 15.6 months compared with 8.4 months for those who received dacarbazine (n=72) (HR 0.51; 95 per cent CI: 0.35-0.75), making it the first single agent to demonstrate an OS benefit in this stage of the disease. Median progression-free survival (PFS), a secondary endpoint, was longer in patients with liposarcoma treated with Halaven than in those who received dacarbazine (2.9 months vs. 1.7 months; HR 0.52; 95 per cent CI: 0.35-0.78).

"Although liposarcoma accounts for less than 1 per cent of all malignant tumors, it is a challenging journey for patients, since diagnosis and treatment can be difficult," said Alison Olig, executive director at Sarcoma Alliance. "The approval of Halaven is important for these patients, as it represents a new treatment choice where limited options have existed."

The adverse events seen in Study 309 were consistent with the known profile of Halaven. Serious side effects from treatment with Halaven may include neutropenia, peripheral neuropathy, embryo-fetal toxicity and QT prolongation. The most common adverse reactions (incidence greater than or equal to 25 per cent) in study patients with liposarcoma and leiomyosarcoma treated with Halaven were fatigue (62 per cent), nausea (41 per cent), alopecia (35 per cent), constipation (32 per cent), peripheral neuropathy (29 per cent), abdominal pain (29 per cent) and pyrexia (28 per cent). The most common (=5 per cent) Grade 3-4 laboratory abnormalities reported in patients receiving Halaven were neutropenia (32 per cent vs. 8.9 per cent in the dacarbazine arm), hypokalemia (5.4 per cent vs. 2.8 per cent) and hypocalcemia (5 per cent vs. 1.4 per cent). The most common serious adverse reactions reported in patients receiving Halaven were neutropenia (4.9 per cent) and pyrexia (4.5 per cent). The most common adverse reactions resulting in discontinuation of Halaven were fatigue and thrombocytopenia (0.9 per cent each). Additional Important Safety Information including use in specific populations is presented below.

Halaven was first approved in the United States on November 15, 2010, for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Previous therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Halaven is the first and only single agent to significantly extend overall survival in the third-line for patients with metastatic breast cancer.

"The initial approval of Halaven for metastatic breast cancer more than five years ago and today's approval for advanced liposarcoma underscore the ability of this treatment to provide an overall survival benefit in two difficult-to-treat cancers," said Kenichi Nomoto, Ph.D., president, Oncology Product Creation Unit, Eisai Product Creation Systems. "As a company focused on human health care (hhc), we are proud of our commitment to providing new treatment options to address the unmet medical needs of patients."

First in the halichondrin class, Halaven is a microtubule dynamics inhibitor with a distinct binding profile. Discovered and developed by Eisai, Halaven is a synthetic analog of halichondrin B, a natural product that was isolated from the marine sponge Halichondria okadai. Based on in vitro studies, Halaven exerts its effect via a tubulin-based antimitotic mechanism, ultimately leading to apoptotic cell death after prolonged and irreversible mitotic blockage. In addition, treatment of human breast cancer cells with Halaven caused changes in cell structure and gene expression as well as decreased migration and invasiveness in vitro. Halaven treatment in preclinical models of human breast cancer was also associated with increased vascular perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype.

The FDA approved Halaven for the treatment of advanced liposarcoma following a priority review, which is designated for drugs the FDA believes, if approved, have the potential to provide a significant improvement in the safety or effectiveness of the treatment, prevention or diagnosis of a serious condition. Halaven was granted orphan drug designation for soft tissue sarcoma in the United States in May 2012.

Study 309 was a randomized, open-label, multicenter, active-controlled trial of Halaven 1.4 mg/m2 administered intravenously (IV) on days one and eight of a 21-day cycle versus dacarbazine IV on day one, every 21 days (dose range of 850 mg/m2 to 1,200 mg/m2) to patients (n=452) with unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma following treatment with at least two systemic chemotherapies, one of which must have included an anthracycline, and disease progression within six months of the most recent chemotherapy regimen.

In this study, Halaven demonstrated a statistically significant improvement in overall survival compared to dacarbazine. Median OS in all treated patients was 13.5 months with Halaven vs. 11.3 months with dacarbazine (HR 0.75; 95 per cent CI: 0.61-0.94; p=0.011), and PFS was 2.6 months with Halaven vs. 2.6 months with dacarbazine (HR 0.86; 95 per cent CI: 0.69-1.06). The treatment effects of Halaven were limited to patients with liposarcoma, based on pre-planned, exploratory subgroup analyses of OS and PFS. There was no evidence of efficacy of Halaven in patients with advanced or metastatic leiomyosarcoma.

Soft tissue sarcomas (STS) are cancers that develop from cells in the soft, supporting tissues of the body, such as fat, muscle, nerves, fibrous tissues and blood vessels. Approximately 12,000 new cases of soft tissue sarcoma are diagnosed each year. Liposarcoma (adipocytic soft tissue sarcoma) refers to tumors that arise from fat cells and can occur anywhere in the body. Liposarcomas make up approximately 17 per cent of all cases of soft tissue sarcoma, accounting for about 2,000 new cases each year.

Many patients with STS, including liposarcoma, are amenable to complete surgical removal, yet relapse rates can be as high as 50 per cent, and outcomes for patients with advanced disease are poor.

EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus Eribulin E7389) was an open-label, randomized, global, multicenter Phase 3 study designed to compare overall survival in patients treated with Halaven (1.4 mg/m2 administered intravenously for two to five minutes on days 1 and 8 of a 21-day treatment cycle) versus a treatment of their physician's choice (TPC) (control group). The study, which was designed to reflect a real-world clinical practice, included 762 patients with metastatic breast cancer who had been treated with an average of four prior chemotherapies.

EMBRACE met its primary endpoint of overall survival, showing that patients who received Halaven survived a median of 13.1 months (compared with 10.6 months for patients who received TPC, p=0.041). These results were consistent with an updated analysis conducted when 77 per cent of events had occurred that showed patients who received Halaven experienced a median of 13.2 months of OS versus 10.6 months with TPC. In patients with metastatic breast cancer receiving Halaven, the most common adverse reactions (= 25 per cent) were neutropenia (82 per cent), anemia (58 per cent), asthenia/fatigue (54 per cent), alopecia (45 per cent), peripheral neuropathy (35 per cent), nausea (35 per cent) and constipation (25 per cent). Febrile neutropenia (4 per cent) and neutropenia (2 per cent) were the most common serious adverse reactions. The most common adverse reaction resulting in discontinuation was peripheral neuropathy (5 per cent).

Metastatic breast cancer is an advanced stage of the disease that occurs when cancer spreads beyond the breast to other parts of the body. In 2015, an estimated 231,840 women will be diagnosed with breast cancer in the United States and nearly 40,300 women will die from the disease. It is estimated that approximately 5 to 10 per cent of women with breast cancer will have metastatic disease at the time of diagnosis. Of these women, an estimated one in five is expected to survive five years.

Halaven (eribulin mesylate) is a microtubule dynamics inhibitor indicated for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.

Halaven is also indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.