Eisai Co., Ltd. and Merck & Co., Inc., Kenilworth, N.J., U.S.A. (known as MSD outside the United States and Canada), announced that the multiple receptor tyrosine kinase inhibitor Lenvima (generic lenvatinib mesylate) has been approved in Japan for unresectable hepatocellular carcinoma (HCC). This is the first approval worldwide for Lenvima for the indication of unresectable HCC and the first new systemic therapy to be approved in Japan for the front-line treatment of HCC in approximately 10 years. Additionally, this is the first regulatory approval for Lenvima under the global strategic collaboration agreement executed in March 2018 between Eisai and Merck & Co., Inc.,for the co-development and co-commercialization of Lenvima.

This approval was based on a phase III clinical study (Study 304 / REFLECT study) conducted by Eisai investigating Lenvima as a first-line treatment in patients with unresectable HCC. In this study, Lenvima demonstrated statistically significant non-inferiority of overall survival (OS) (13.6 months) compared to sorafenib (12.3 months) (hazard ratio [HR] 0.92, 95% confidence interval [CI]=0.79-1.06). Additionally, Lenvima showed highly statistically significant and clinically meaningful improvements as compared to sorafenib in the secondary endpoints of progression free survival (PFS) (HR 0.66, 95% CI=0.57-0.77, p<0.00001), time to progression (TTP) (HR 0.63, 95% CI=0.53-0.73, p<0.00001), and objective response rate (ORR) (Lenvima 24% versus sorafenib 9%, p<0.00001). Furthermore, Lenvima helped to delay deterioration in several quality of life (QOL) and symptom domains (pre-specified secondary endpoint) including in areas such as pain and diarrhea, compared to sorafenib (nominal p- value<0.05).

In this study, the five most common adverse events observed in the Lenvima arm were hypertension (42%), diarrhoea (39%), decreased appetite (34%), weight loss (31%) and fatigue (30%), which is consistent with the known safety profile of Lenvima.

Liver cancer is the second leading cause of cancer related deaths with approximately 750,000 deaths per year estimated globally. Additionally, approximately 780,000 cases are newly diagnosed each year, about 80 per cent of which occur in Asia, including Japan and China.(2) HCC accounts as the primary reason for 85 per cent to 90 per cent of liver cancer cases. It is estimated that there are approximately

42,000 HCC patients in Japan, with approximately 26,000 deaths every year. To-date, treatment options for unresectable HCC have been limited and the prognosis is very poor, emphasizing that this is an area of high unmet medical need.

"With the approval of this additional indication of unresectable HCC for Lenvima, we are proud to be able to deliver the first new front-line systemic therapy treatment option for HCC in Japan in approximately 10 years, and expect this will contribute to HCC treatment" said Dr. Takashi Owa, Eisai Oncology Business Group chief medicine creation officer. "Eisai will continue with its efforts in oncology research and development in order to deliver hopes for a potential cure for cancer to patients and their families."

"Today's approval is an important first for Lenvima and a significant first regulatory event under our collaboration with Eisai," said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck & Co. "We congratulate Eisai on the approval of this new indication and look forward to working together to bring this important treatment option to patients."

Having received approval of this indication, Eisai will receive a development milestone payment from Merck & Co.. There are no changes to Eisai's consolidated financial results forecasts for the fiscal year ending March 31, 2018 based on the receipt of this milestone payment.

Discovered by Eisai, Lenvima is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other pathway-related RTKs (including the platelet- derived growth factor (PDGF) receptor PDGFRalpha; KIT; and RET) involved in tumor angiogenesis, tumor progression and modification of tumor immunity.

Currently, Lenvima is approved as a treatment for refractory thyroid cancer in over 50 countries, including the United States, Japan, in Europe and Asia. Additionally, Eisai has obtained approval for the agent in combination with everolimus as a treatment for renal cell carcinoma (second-line) in over 40 countries, including the United States and in Europe. In Europe, the agent was launched under the brand name Kisplyx for renal cell carcinoma.

Outside of Japan, Eisai has submitted applications for an indication covering hepatocellular carcinoma in the United States and Europe (July 2017), China (October 2017), Taiwan (December 2017) and other countries.

In March 2018, Eisai and Merck & Co., Inc. Kenilworth N.J., U.S.A. entered into a strategic collaboration for the worldwide co-development and co-commercialization of Lenvima. Under the agreement, the companies will develop and commercialize Lenvima jointly, both as monotherapy and in combination with Merck & Co., Inc. Kenilworth N.J., U.S.A.'s anti-PD-1 therapy Keytruda (pembrolizumab). In addition to ongoing clinical studies of the combination, the companies will jointly initiate new clinical studies evaluating the Lenvima/Keytruda combination to support 11 potential indications in six types of cancer (endometrial cancer, non-small cell lung cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer and melanoma), as well as a basket trial targeting multiple cancer types.