WOODCLIFF LAKE, N.J., Feb. 5, 2018 /PRNewswire/ -- Eisai Inc. today announced the publication of results from a subgroup analysis of the pivotal Phase 3 study comparing eribulin mesylate (marketed as Halaven^® Injection) with dacarbazine in previously treated patients with advanced liposarcoma (LPS) or leiomyosarcoma (LMS) in the Journal of Clinical Oncology. This preplanned subanalysis of the LPS subgroup in Study 309 supported the FDA approval of Halaven in patients with advanced liposarcoma.

Additional exploratory analyses of LPS histologic subtypes are also being reported in this publication. These LPS subgroup analyses showed that overall survival (OS) results favored eribulin compared to dacarbazine across different histologic subtypes (dedifferentiated and pleomorphic) and tumor grades (high and intermediate). The results in patients with myxoid/round cell LPS in the eribulin arm were numerically longer, but not statistically significant when compared to dacarbazine. Results also favored eribulin independent of geographic region, ECOG performance status (0 or 1), or sex.

Halaven is approved by the FDA for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. Halaven is not approved for patients with leiomyosarcoma, and in this Phase 3 international trial there was no evidence of superior efficacy in patients with advanced or metastatic leiomyosarcoma treated with eribulin compared with dacarbazine.

"Results from this subgroup analysis further establish eribulin as a useful treatment option in patients with these aggressive forms of treatment-refractory liposarcomas," 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. "Soft tissue sarcomas, such as liposarcomas, are very challenging to treat effectively once they metastasize and progress through other therapy. Eribulin is the first single-agent shown to improve OS significantly in a Phase 3 trial for advanced liposarcomas."

In this histology-driven subgroup analysis of patients with LPS from a randomized, open-label Phase 3 study, OS was improved with eribulin compared with dacarbazine (HR: 0.511; 95% CI: 0.35 – 0.75; nominal P < 0.001). Median OS for patients treated with eribulin (n=71) was 15.6 months (95% CI: 10.2 – 18.6 months) compared to 8.4 months (95% CI: 5.2 – 10.1 months) for patients treated with dacarbazine (n=72).

"The results of this subgroup analysis showing patients with advanced liposarcoma who received eribulin experienced longer overall survival when compared with patients who received dacarbazine indicate the importance of eribulin as a treatment option for these patients," said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai.

When examined by LPS histologic subtype, OS differences favored eribulin for patients with dedifferentiated (eribulin n=31, dacarbazine n=34, median OS: 18 mos v 8.1 mos) or pleomorphic LPS (eribulin n=11, dacarbazine n=12, median OS: 22.2 mos v 6.7 mos) but were only numerically longer for patients with myxoid/round cell LPS (eribulin n=29, dacarbazine n=26, median OS: 13.5 mos v 9.6 mos). When examined by tumor grade, median OS with eribulin was longer than with dacarbazine both in patients with high-grade tumors (eribulin n=38, dacarbazine n=39, 14.8 v 6.3 months, respectively; HR: 0.38; 95% CI: 0.206 to 0.691) and in patients with intermediate-grade tumors (eribulin n=32, dacarbazine n=32, 17.3 v 10 months, respectively; HR: 0.55; 95% CI: 0.302 to 0.999).

Further, median progression-free survival (PFS) was longer in patients with LPS treated with eribulin than in those who received dacarbazine (2.9 months vs. 1.7 months; HR: 0.52; 95% CI: 0.35 to 0.78; nominal p=0.0015). The hazard ratios (HR) for PFS favored eribulin treatment compared with dacarbazine in patients with dedifferentiated, myxoid/round cell, or pleomorphic LPS subtypes (HR: 0.69, 95% CI: 0.36 to 1.33; HR: 0.57, 95% CI: 0.29 to 1.11; and HR: 0.34, 95% CI: 0.09 to 1.30; respectively).

The adverse events observed in the subgroup analysis of Study 309 were consistent with the known profile of eribulin with no new or unexpected safety signals noted. The most frequent treatment-emergent adverse events (TEAEs) with eribulin were alopecia (40.0%), fatigue (40.0%), neutropenia (38.6%), and nausea (38.6%). The most frequent TEAEs with dacarbazine were nausea (44.4%), anemia (34.7%), fatigue (31.9%), and decreased appetite (30.6%). The incidence of grade ≥ 3 TEAEs was higher with eribulin compared with dacarbazine (62.9% v 51.4%, respectively).

About Study 309, the Phase 3 Pivotal Trial in Advanced Soft Tissue Sarcoma
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% CI: 0.61-0.94; p=0.011), and progression-free survival (PFS) was 2.6 months with Halaven vs. 2.6 months with dacarbazine (HR 0.86; 95% 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.

About Liposarcoma, a Type of Soft Tissue Sarcoma
Soft tissue sarcomas (STS) are cancers that develop from cells in the connective tissues of the body other than bone or cartilage, 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 or their precursors and can occur anywhere in the body. Liposarcomas make up approximately 17% of all cases of soft tissue sarcoma.

Many patients with STS, including liposarcoma, are amenable to complete surgical removal, yet outcomes for patients with disease that is not curable by surgery or following metastatic spread to other sites in the body are poor, with 5-year relative survival rates for regional and distant disease of 54% and 16%, respectively.

About Halaven^® (eribulin mesylate) Injection
Halaven^® (eribulin mesylate) is a microtubule dynamics inhibitor 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.
• Unresectable or metastatic liposarcoma who have received a prior anthracycline- containing regimen.

Discovered and developed by Eisai, eribulin is a synthetic analog of halichondrin B, a natural product that was isolated from the marine sponge Halichondria okadai. First in the halichondrin class, Halaven is a microtubule dynamics inhibitor. Eribulin is believed to work primarily via a tubulin-based mechanism that causes prolonged and irreversible mitotic blockage, ultimately leading to apoptotic cell death. Additionally, in preclinical studies of human breast cancer, eribulin demonstrated complex effects on the tumor biology of surviving cancer cells, including increases in vascular perfusion resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype, promoting the epithelial phenotype, opposing the mesenchymal phenotype. Eribulin has also been shown to decrease the migration and invasiveness of human breast cancer cells.

Important Safety Information

Warnings and Precautions
Neutropenia: Severe neutropenia (ANC <500/mm³) lasting >1 week occurred in 12% of patients with mBC and liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 5% of patients with mBC and 2 patients (0.4%) died from complications. Febrile neutropenia occurred in 0.9% of patients with liposarcoma or leiomyosarcoma, and fatal neutropenic sepsis occurred in 0.9% of patients. Patients with mBC with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels. Monitor complete blood cell counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting >7 days.

Peripheral Neuropathy: Grade 3 peripheral neuropathy occurred in 8% of patients with mBC (Grade 4=0.4%) and 22% developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Neuropathy lasting >1 year occurred in 5% of patients with mBC. Grade 3 peripheral neuropathy occurred in 3.1% of patients with liposarcoma and leiomyosarcoma receiving HALAVEN and neuropathy lasting more than 60 days occurred in 58% (38/65) of patients who had neuropathy at the last treatment visit. Patients should be monitored for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

Embryo-Fetal Toxicity: HALAVEN can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with HALAVEN and for 3.5 months following the final dose.

QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome.

Adverse Reactions
In patients with mBC receiving HALAVEN, the most common adverse reactions (≥25%) were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%). Febrile neutropenia (4%) and neutropenia (2%) were the most common serious adverse reactions. The most common adverse reaction resulting in discontinuation was peripheral neuropathy (5%).

In patients with liposarcoma and leiomyosarcoma receiving HALAVEN, the most common adverse reactions (≥25%) reported in patients receiving HALAVEN were fatigue (62%), nausea (41%), alopecia (35%), constipation (32%), peripheral neuropathy (29%), abdominal pain (29%), and pyrexia (28%). The most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN were neutropenia (32%), hypokalemia (5.4%), and hypocalcemia (5%). Neutropenia (4.9%) and pyrexia (4.5%) were the most common serious adverse reactions. The most common adverse reactions resulting in discontinuation were fatigue and thrombocytopenia (0.9% each).

Use in Specific Populations
Lactation: Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final dose.

Hepatic and Renal Impairment: A reduction in starting dose is recommended for patients with mild or moderate hepatic impairment and/or moderate or severe renal impairment.

For more information about HALAVEN, click here for the full Prescribing Information.

About Eisai Inc.
At Eisai Inc., human health care (hhc) is our goal. We give our first thought to patients and their families, and helping to increase the benefits health care provides. As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate commitment to patient care that is the driving force behind our efforts to discover and develop innovative therapies to help address unmet medical needs.

Eisai is a fully integrated pharmaceutical business that operates in two global business groups: oncology and neurology (dementia-related diseases and neurodegenerative diseases). Each group functions as an end-to-end global business with discovery, development, and marketing capabilities. Our U.S. headquarters, commercial and clinical development organizations are located in New Jersey; our discovery labs are in Massachusetts and Pennsylvania; and our global demand chain organization resides in Maryland and North Carolina. To learn more about Eisai Inc., please visit us at www.eisai.com/US.

SOURCE Eisai Inc.