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Positive Phase 3 Trial Results of Investigational Anticancer Agent Lenvatinib in Unresectable Hepatocellular Carcinoma (HCC) Published in The Lancet

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Friday, February 16, 2018

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WOODCLIFF LAKE, N.J. - Eisai Inc. announced that the positive results of a Phase 3 study (REFLECT study, Study 304) of its in-house discovered and developed anticancer agent lenvatinib mesylate (marketed as Lenvima) in patients with unresectable hepatocellular carcinoma (HCC) have been published in the online version of The Lancet, which is one of the world's most prestigious medical journals and was recently ranked second in the world in terms of Impact Factor (Lead author: Professor and Chairman Masatoshi Kudo of Kindai University Faculty of Medicine, Title of paper: "Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial"). Lenvatinib is not approved for HCC by any regulatory authority.

The REFLECT study reported on in the paper was a multicenter, open-label, randomized, global Phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib, a standard treatment for advanced hepatocellular carcinoma, as a first-line treatment in patients with unresectable HCC. In this study, lenvatinib demonstrated a treatment effect on the primary endpoint of Overall Survival (OS) by statistical confirmation of non-inferiority to sorafenib. Additionally, lenvatinib showed statistically significant and clinically meaningful improvements in the secondary endpoints of progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR).

The paper also reported on the results of an exploratory analysis of the secondary endpoints based on blinded independent imaging review (IIR). The IIR was conducted using both RECIST 1.1, which uses the traditional assessment of the effect on change in tumor diameter, and mRECIST, which takes into account areas of tumor necrosis in addition to the RECIST 1.1 criteria. Results of the IIR analyses were consistent with and corroborated those for the investigator assessments demonstrating an improvement in PFS and TTP, as well as an increase in ORR as compared with sorafenib.

In this study, the five most common adverse events observed in the lenvatinib arm were hypertension, diarrhea, decreased appetite, weight loss and fatigue, which is consistent with the known safety profile of lenvatinib.

Eisai submitted applications for lenvatinib for the treatment of HCC in Japan (June 2017), the United States and Europe (July 2017), China (October 2017), Taiwan (December 2017) and other countries. Eisai remains committed to providing additional clinical evidence for lenvatinib aimed at maximizing the value of the drug to patients as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families and healthcare providers.

This release discusses investigational uses for an FDA-approved product. It is not intended to convey conclusions about efficacy or safety. There is no guarantee that any investigational uses of such FDA-approved product will gain FDA approval.

About the REFLECT Trial (Study 304)
REFLECT was an international, multicenter, randomized, open-label, non-inferiority Phase 3 study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with uHCC. Patients (n=954) at 183 trial sites in 21 countries were randomized to receive lenvatinib 12 mg or 8 mg once a day depending on body weight (≥60 kg or <60 kg, respectively) (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of this study was overall survival. The secondary efficacy endpoints of this study were progression-free survival, time to progression and objective response rate.

The median OS for patients treated with lenvatinib was 13.6 months compared to 12.3 months for sorafenib (HR: 0.92; 95% CI: 0.79 – 1.06). Median PFS was 7.4 months with lenvatinib with a median TTP of 8.9 months compared to median PFS of 3.7 months (HR: 0.66; 95% CI: 0.57 – 0.77; p<0.0001) and median TTP of 3.7 months on sorafenib (HR 0.63; 95% CI; 0.53 – 0.73; p<0.0001). In addition, lenvatinib demonstrated significantly higher ORR (24.1%) compared to sorafenib (9.2%) (odds ratio: 3.13; 95% CI: 2.15 – 4.56; p<0.0001). Endpoints were evaluated using mRECIST and determined by investigator assessment. A health-related quality of life assessment and a blinded independent imaging review that confirmed the investigator assessment were also completed.

In this study, the most common treatment-emergent adverse events (TEAEs) observed in the lenvatinib arm were hypertension, diarrhea, decreased appetite, decreased weight, and fatigue. In the sorafenib arm, the most common TEAEs were palmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Patients who received lenvatinib had fewer instances of palmar-plantar erythrodysesthesia, diarrhea and alopecia, and more instances of hypertension, proteinuria, dysphonia, and hypothyroidism, than did patients who received sorafenib. Nine percent of patients treated with lenvatinib and 7% of patients treated with sorafenib discontinued treatment due to treatment-related adverse events. Forty-three percent of patients treated with lenvatinib and 30% of patients who received sorafenib experienced serious TEAEs.

About Unresectable Hepatocellular Carcinoma (uHCC)
Hepatocellular carcinoma is the most common type of liver cancer, accounting for about 90% of cases of primary liver cancer in the United States. In 2015, liver cancer accounted for approximately 788,000 deaths globally, making it the second leading cause of cancer-related deaths worldwide. The prevalence and mortality rate of liver cancer has been rising steadily over the past decade. In 2018, in the United States, an estimated 42,200 cases will be diagnosed and 30,200 people will die from their disease. uHCC, which could be Stage 3 or 4 disease, is an advanced stage of liver cancer that cannot be removed by surgery. Approximately 45% of patients have Stage 3 or 4 HCC at diagnosis and there are limited treatment options available for patients with advanced disease.

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 receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). 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.

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..

Eisai Inc. (Headquarters)
100 Tice Blvd.
Woodcliff Lake, NJ 07677
Phone: 201-692-1100
Fax: 201-692-1804

Source: Eisai Inc.
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