Eisai Announces Additional Data from Ongoing Phase 1 Trial of Investigational Combination of HALAVEN® (eribulin mesylate) with Polyphor's CXCR4 Antagonist Balixafortide in HER2-Negative Metastatic Breast Cancer at ASCO 2019

WOODCLIFF LAKE, N.J., June 4, 2019 /PRNewswire/ -- Eisai today announced additional data from an ongoing Phase 1 trial exploring the investigational combination of eribulin and balixafortide, a CXCR4 antagonist, in patients with HER2-negative metastatic breast cancer (Abstract #2606), were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago from May 31-June 4.

This open-label, single-arm, Phase 1 trial enrolled 56 HER2-negative, CXCR4-positive women age 18 years or older with metastatic breast cancer (MBC), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had previously received one to three chemotherapy regimens for MBC. The primary endpoints were incidence of dose-limiting toxicities; type, frequency, and severity of adverse events; establishment of the maximum tolerated dose or the highest dose if no dose-limiting toxicity was observed; and pharmacokinetic parameters. Secondary objectives were progression-free survival, overall survival, and the proportion of patients who achieved an objective response.¹ Initial data were published in The Lancet Oncology and initial median OS data were presented at ESMO 2018. New at ASCO are the landmark overall survival (OS) data.

• For patients who received the combination of eribulin and balixafortide second line or later in the expanded cohort (EC), the landmark OS at 18 months was 50% (95% CI: 29.1-67.8) and at 24 months was 33.3% (95% CI: 15.9-51.9). For these patients in the overall efficacy population (OEP), the landmark OS at 18 months was 42.4% (95% CI: 28.9-55.2) and at 24 months was 25% (95% CI: 14.3-37.3).
• For patients who received the combination of eribulin and balixafortide third line or later in the EC, the landmark OS at 18 months was 40% (95% CI: 19.3-60.0) and at 24 months was 25% (95% CI: 9.1-44.9). For these patients in the OEP, the landmark OS at 18 months was 32.5% (95% CI: 18.3-47.6) and at 24 months was 19% (95% CI: 8.4-32.9).

The landmark 18 month and 24 month overall survival data are consistent with the efficacy data previously observed from this study; safety information is consistent with previous reports. In the study, the most frequently (>40%) reported adverse events were fatigue (79%), neutropenia (57%), infusion-related reactions (48%), constipation (46%), alopecia (46%) and nausea (45%).

"We are encouraged by the results of this study for patients who received the combination of eribulin and balixafortide as second line or later therapy for the treatment of HER-2 negative metastatic breast cancer," said David D'Adamo, MD, PhD, Senior Director, Clinical Research, Oncology at Eisai. "With up to 6 percent of new breast cancer cases diagnosed as metastatic, this combination merits further investigation in patients with HER-2 negative metastatic breast cancer as we continue our quest for potential new treatment options." 

CRX4 plays a critical role in tumor growth, survival, angiogenesis and metastasis. High CXCR4 levels are correlated with aggressive metastatic phenotypes and poor prognosis in breast cancer.² Preclinical evidence suggests that disrupting CXCR4-dependent pathways prevents development of breast cancer metastases, enhances the cytotoxic effect of chemotherapy and immunotherapy, and counteracts tumor cell evasion of the immune system.³

This release discusses an investigational compound and investigational use for an FDA-approved product. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational compounds or investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.

About the Study
In this open-label, single-arm, Phase I trial, patients received HALAVEN^® (eribulin) with increasing doses of balixafortide (0.5−5.5mg/kg) using a standard 3+3 dose escalation design followed by an expanded cohort at the highest dose of balixafortide as no dose limiting toxicity was observed. The majority of patients received eribulin 1.4mg/m², although Cohorts 2 and 3 received eribulin 1.1mg/m². This trial enrolled 56 HER2-negative, CXCR4-positive females age ≥ 18 years with MBC, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had previously received 1−3 chemotherapy regimens for MBC. All cohorts received 21-day Cycles of eribulin on Days 2 and 9, and balixafortide on Days 1−3, and 8−10. Cohorts 2−4 also received a 28-day run-in Cycle to better assess safety and potential pharmacokinetic interactions. All patients received treatment until disease progression or unacceptable toxicity.

The primary endpoints were incidence of dose-limiting toxicities; type, frequency, and severity of adverse events; establishment of the maximum tolerated dose or the highest dose if no dose-limiting toxicity was observed; and pharmacokinetic parameters. Secondary objectives were progression-free survival, overall survival, and the proportion of patients who achieved an objective response. In patients who received the combination of eribulin and balixafortide as second line or later therapy, the objective response rate (ORR) was 38% (95% CI: 19 - 59), median progression free survival (PFS) was 6.2 months (95% CI 2.9–8.1), and median OS was 18 months for the EC, and 30% (95% CI: 18 - 44), 4.6 months (95% CI: 3.1 – 5.7) and 16.8 months for the OEP, respectively. The association between various baseline biomarkers and treatment outcomes (including OS) were investigated in a multivariate analysis. Safety information was consistent with previous reports, and the most frequently (>40%) reported adverse events were fatigue (79%), neutropenia (57%), infusion-related reactions (48%), constipation (46%), alopecia (46%) and nausea (45%). Initial data were published in The Lancet Oncology and presented at ESMO 2018. Further data from the multivariate analysis will be presented in full later this year.

About HALAVEN^® (eribulin mesylate) Injection
HALAVEN^® (eribulin mesylate) Injection 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, eribulin 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.

HALAVEN^® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.

About Eisai
At Eisai Inc., human health care (hhc) is our goal. We give our first thoughts 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, manufacturing 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 eisai.com/us.

¹ https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30147-5/fulltext
² Xu TP, et al. Cancer Epidemiol. 2013; 37: 725-731
³ Pernas S, et al. Lancet Oncol. 2018; 19: 812-824

SOURCE Eisai Inc.

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