New Halaven® (eribulin) and Lenvima® (lenvatinib) Data to be Presented at ESMO Demonstrate Continued Commitment to Eisai Oncology Portfolio

WOODCLIFF LAKE, N.J., Sept. 29, 2016 /PRNewswire/ -- Eisai Inc. announced today the presentation of seven abstracts featuring data on its cancer treatments at the European Society of Medical Oncology (ESMO) 2016 Congress. The abstracts highlight new results for the company's oncology agents, Halaven^® (eribulin) and Lenvima^® (lenvatinib), for investigational uses in difficult-to-treat cancers and provide new information about these agents across multiple tumor types. ESMO 2016 will be held from October 7-11 in Copenhagen, Denmark.

"The breadth of data to be presented at ESMO—from interim results from the Phase 1b portion of our trial evaluating lenvatinib in combination with the anti-PD-1 immunotherapy pembrolizumab to results from multiple sub-group analyses of registrational studies for eribulin and lenvatinib—underscores Eisai's commitment to researching and developing treatment options for patients with advanced cancers," said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "We are continually looking to improve understanding of Eisai's oncology therapies, and through these data, we hope to support the medical community and the patients we both serve."

Presentations of note include:

• Studies assessing the use of lenvatinib in combination with anti-PD-1 immunotherapy, including:
  • Initial results of an ongoing, open-label, multicenter, Phase 1b trial of lenvatinib in combination with pembrolizumab in patients with select solid tumors
  • A preclinical study analyzing the immune response in mouse tumor models to understand the anti-tumor effect and mechanism of action of the combination of lenvatinib and PD-1 blockade treatment in multiple cancer types
• Sub-analyses of the Phase 3 SELECT study investigating responses in specific sites of metastasis (lung, liver, lymph nodes and bone) following treatment with lenvatinib for locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer
• A preclinical study analyzing the role of FGFR and VEGFR signaling pathways in tumor growth and angiogenesis in human renal cell carcinoma xenografts treated with lenvatinib in combination with everolimus

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

About LENVIMA^® (lenvatinib)
LENVIMA^® (lenvatinib) is a kinase inhibitor that is indicated for:

• Differentiated Thyroid Cancer (DTC): single agent for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
• Renal Cell Cancer (RCC): in combination with everolimus for patients with advanced RCC following one prior anti-angiogenic therapy.

Lenvatinib, discovered and developed by Eisai, is a multiple receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1-3. Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.

Important Safety Information

Warnings and Precautions

• In DTC, hypertension was reported in 73% of patients on LENVIMA vs 16% with placebo (44% vs 4% grade ≥3). In RCC, hypertension was reported in 42% of patients on LENVIMA + everolimus vs 10% with everolimus alone (13% vs 2% grade 3). Blood pressure should be controlled prior to treatment and monitored throughout. Withhold dose for grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose when controlled at grade ≤2. Discontinue for life-threatening hypertension
• In DTC, cardiac dysfunction was reported in 7% of patients on LENVIMA vs 2% with placebo (2% vs 0% grade ≥3). In RCC, cardiac dysfunction was reported in 10% of patients on LENVIMA + everolimus vs 6% with everolimus alone (3% vs 2% grade 3). Monitor for signs/symptoms of cardiac decompensation. Withhold for grade 3 cardiac dysfunction. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction
• In DTC, arterial thromboembolic events were reported in 5% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, arterial thromboembolic events were reported in 2% of patients on LENVIMA + everolimus vs 6% with everolimus alone (2% vs 4% grade ≥3). Discontinue following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months
• Across clinical studies in which 1,160 patients received LENVIMA monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis in 1 patient. In DTC, ALT and AST increases (grade ≥3) occurred in 4% and 5% of patients on LENVIMA, respectively, vs 0% with placebo. In RCC, ALT and AST increases (grade ≥3) occurred in 3% of patients on LENVIMA + everolimus vs 2% and 0% with everolimus alone, respectively. Monitor liver function before initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold dose for liver impairment grade ≥3 until resolved to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity/persistence of hepatotoxicity. Discontinue for hepatic failure
• In DTC, proteinuria was reported in 34% of patients on LENVIMA vs 3% with placebo (11% vs 0% grade 3). In RCC, proteinuria was reported in 31% of patients on LENVIMA + everolimus vs 14% with everolimus alone (8% vs 2% grade 3). Monitor for proteinuria before and during treatment. Withhold dose for proteinuria ≥2 g/24 h. Resume at reduced dose when proteinuria is <2 g/24 h. Discontinue for nephrotic syndrome
• In RCC, diarrhea was reported in 81% of patients on LENVIMA + everolimus vs 34% with everolimus alone (19% vs 2% grade ≥3). Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Withhold dose for diarrhea grade ≥3. Resume at a reduced dose when diarrhea resolves to grade 1 or baseline. Discontinue for grade 4 diarrhea despite medical management
• In DTC, events of renal impairment were reported in 14% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, events of renal impairment were reported in 18% of patients on LENVIMA + everolimus vs 12% with everolimus alone (10% vs 2% grade ≥3). Withhold LENVIMA for grade 3 or 4 renal failure/impairment. Resume at reduced dose or discontinue, depending on severity/persistence of renal impairment. Active management of diarrhea and any other gastrointestinal (GI) symptoms should be initiated for grade 1 events
• In DTC, events of GI perforation or fistula were reported in 2% of patients on LENVIMA vs 0.8% with placebo. In RCC, events of GI perforation, abscess, or fistula (grade ≥3) were reported in 2% of patients on LENVIMA + everolimus vs 0% with everolimus alone. Discontinue in patients who develop GI perforation or life-threatening fistula
• In DTC, QT/QTc interval prolongation was reported in 9% of patients on LENVIMA vs 2% with placebo (2% vs 0% >500 ms). In RCC, QTc interval increases >60 ms were reported in 11% of patients on LENVIMA + everolimus (6% >500 ms) vs 0% with everolimus alone. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold dose for QTc interval prolongation >500 ms. Resume at reduced dose when QTc prolongation resolves to baseline
• In DTC, hypocalcemia (grade ≥3) was reported in 9% of patients on LENVIMA vs 2% with placebo. In RCC, hypocalcemia (grade ≥3) was reported in 6% of patients on LENVIMA + everolimus vs 2% with everolimus alone. Monitor blood calcium levels at least monthly and replace calcium as necessary. Interrupt and adjust LENVIMA as necessary
• Across clinical studies in which 1,160 patients received LENVIMA monotherapy, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 4 patients. Withhold LENVIMA for RPLS until fully resolved. Resume at reduced dose or discontinue based on the severity and persistence of neurologic symptoms
• In DTC, hemorrhagic events occurred in 35% of patients on LENVIMA vs 18% with placebo (2% vs 3% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (11% grade 1, 1% grade 2). Discontinuation due to hemorrhagic events occurred in 1% of patients on LENVIMA. There was 1 fatal intracranial hemorrhage case among 16 patients who received LENVIMA and had central nervous system metastases at baseline. In RCC, hemorrhagic events occurred in 34% of patients on LENVIMA + everolimus vs 26% with everolimus alone (8% vs 2% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (23% for LENVIMA + everolimus vs 24% with everolimus alone). There was 1 fatal cerebral hemorrhage case. Discontinuation due to hemorrhagic events occurred in 3% of patients on LENVIMA + everolimus. Consider the risk of severe or fatal hemorrhage associated with tumor invasion/infiltration of major blood vessels (eg, carotid artery). Withhold dose for grade 3 hemorrhage. Resume at reduced dose or discontinue based on severity/persistence of hemorrhage. Discontinue for grade 4 hemorrhage
• In DTC patients with normal baseline thyroid-stimulating hormone (TSH), elevation of TSH level above 0.5 mU/L was observed postbaseline in 57% of patients on LENVIMA vs 14% with placebo. In RCC, grade 1 or 2 hypothyroidism occurred in 24% of patients on LENVIMA + everolimus vs 2% with everolimus alone. In RCC patients with normal or low TSH at baseline, elevation of TSH was observed postbaseline in 60% of patients on LENVIMA + everolimus vs 3% with everolimus alone. Monitor thyroid function prior to treatment initiation and monthly thereafter. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state
• LENVIMA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy

Adverse Reactions

• In DTC, the most common adverse reactions observed in LENVIMA-treated patients vs placebo-treated patients were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decrease (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%)
• In DTC, adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and in 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (≥10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%)
• In RCC, the most common adverse reactions observed in patients treated with LENVIMA + everolimus vs everolimus alone were diarrhea (81% vs 34%), fatigue (73% vs 40%), arthralgia/myalgia (55% vs 32%), decreased appetite (53% vs 18%), vomiting (48% vs 12%), nausea (45% vs 16%), stomatitis/oral inflammation (44% vs 50%), hypertension/increased blood pressure (42% vs 10%), peripheral edema (42% vs 20%), cough (37% vs 30%), abdominal pain (37% vs 8%), dyspnea/exertional dyspnea (35% vs 28%), rash (35% vs 40%), weight decreased (34% vs 8%), hemorrhagic events (32% vs 26%), and proteinuria/urine protein present (31% vs 14%)
• In RCC, adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA + everolimus and in 54% of patients receiving everolimus. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA + everolimus–treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA + everolimus–treated group and in 12% of patients in the everolimus-treated group

Use in Specific Populations

• Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment
• LENVIMA may result in reduced fertility in females of reproductive potential and may result in damage to male reproductive tissues, leading to reduced fertility of unknown duration

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

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.

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