Encouraging Updated Results from Phase 1b/2 Study Evaluating the Combination of Eribulin Mesylate and Pembrolizumab in Patients with Metastatic Triple-Negative Breast Cancer Presented at the 2017 SABCS

WOODCLIFF LAKE, N.J., Dec. 8, 2017 /PRNewswire/ -- Eisai Inc. today announced updated results of ENHANCE 1, a Phase 1b/2 trial investigating eribulin mesylate (marketed as HALAVEN^®, "eribulin"), in combination with the Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the United States and Canada) anti-PD-1 therapy, pembrolizumab (marketed as KEYTRUDA^®), in patients with metastatic triple-negative breast cancer (mTNBC).

Findings presented during the 2017 San Antonio Breast Cancer Symposium (SABCS) showed the combination of eribulin and pembrolizumab resulted in an objective response rate (ORR) of 26.4% (95% CI: 18.3 – 35.9), the primary efficacy endpoint of the study. Three complete responses were observed; one of which was in a patient with a PD-L1-negative tumor. Treatment-emergent adverse events (TEAEs) for the combination regimen were comparable to those observed with each treatment as a monotherapy. Eribulin and pembrolizumab are not approved for use in combination. 

"The results observed, namely the response rates and tolerability achieved with the eribulin and pembrolizumab combination regimen, broaden our knowledge base as to the possible effect of these two agents when used together in patients with metastatic TNBC," said Sara Tolaney, MD, MPH, medical oncologist, Dana-Farber Cancer Institute, Boston, and the principal investigator of the study. "The potential of the combination of eribulin plus pembrolizumab for this aggressive form of breast cancer is exciting for both patients and physicians alike."

The combination of eribulin and pembrolizumab demonstrated activity in patients with mTNBC regardless of PD-L1 status or prior treatment with chemotherapy. In the evaluable analysis set (n=106), patients who were PD-L1-positive (n=49) had an ORR of 30.6% and patients who were PD-L1-negative (n=49) had an ORR of 22.4%. Patients with mTNBC who had no prior chemotherapy treatment in the metastatic setting (n=65) had an ORR of 29.2% (95% CI: 18.6 – 41.8) and patients who received one or two prior lines of chemotherapy (n=41) had an ORR of 22.0% (95% CI: 10.6 – 37.6). The median duration of response was 8.3 months (6.5 – 12.9) and the response lasted longer than six months in 53.6% of responders. The clinical benefit rate (CBR, complete response + partial response + durable stable disease [duration greater than or equal to 24 weeks]) was 36.8%. Median overall survival and median progression-free survival for all patients in the trial (the full analysis set; n=107), both secondary endpoints, were 17.7 months (95% CI: 13.7 – not estimable) and 4.2 months (95% CI: 4.1 – 5.6), respectively.                                                                

The most common treatment-emergent adverse events (TEAEs) for the combination regimen were fatigue, peripheral neuropathy, nausea, alopecia, and constipation. The most common grade 3 or 4 TEAEs for the combination regimen were neutropenia, peripheral neuropathy, and anemia, fatigue, and hypokalemia. Dose reduction due to TEAEs occurred in 32% of patients. Drug withdrawal due to TEAEs occurred in 22% of patients.

"Most of the major advances in breast cancer treatment to date have been for patients whose cancers express the receptors currently identified as targets for treatment; limited options exist for patients with metastatic triple-negative breast cancer," said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "These updated results give us confidence to continue to study eribulin in the treatment of metastatic breast cancer in combination with new agents, like checkpoint inhibitors. We are very encouraged by the activity seen when adding pembrolizumab to eribulin, and we are eager to further assess these data and their meaning for patients with metastatic TNBC."  

Eisai will also be presenting data from Study 216, a Phase 2 trial evaluating a biweekly dosing schedule of eribulin in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (Poster Session 6: PD-14-05) and results from a study in TNBC evaluating the effect of eribulin on the TGF-β signaling pathway in two different preclinical breast cancer cell lines (Poster Session 5: P5-04-04).

About ENHANCE 1 (Also referred to as KEYNOTE-150; formerly referred to as Study 218)
ENHANCE 1 is a single-arm, multi-center phase 1b/2 study (ClinicalTrials.gov Identifier: NCT02513472) investigating the combination of KEYTRUDA (pembrolizumab) (200 mg intravenously on Day 1) with HALAVEN (eribulin mesylate) Injection (1.4 mg/m2 intravenously on Day 1 and Day 8) in 21-day cycles in patients with mTNBC who had previously been treated with up to two lines of chemotherapy or were not previously treated with chemotherapy. At the time of data cutoff (May 31, 2017), 107 subjects were enrolled, 106 of whom were evaluable. The primary endpoint of the Phase 1b portion of the study is to assess the safety and tolerability of the combination; for the Phase 2 portion of the study, the primary endpoint is investigator-assessed ORR and secondary endpoints include progression-free survival, overall survival and duration of response as well as efficacy in a subset of patients with PD-L1-positive tumors.

The results presented at 2017 SABCS were an updated analysis from the poster presentation "Phase 1b/2 Study to Evaluate Eribulin Mesylate in Combination with Pembrolizumab in Patients with Metastatic Triple-negative Breast Cancer" presented at 2016 SABCS.

The study is being conducted under an existing clinical trial collaboration agreement between the two companies.

About Metastatic Breast Cancer
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 2017, an estimated 252,710 women will be diagnosed with breast cancer in the United States and an estimated 40,610 women will die from the disease. It is estimated that approximately 5 to 10 percent 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.

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 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 www.eisai.com/US.

KEYTRUDA^® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., USA.

SOURCE Eisai Inc.