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°®¶¹´«Ã½. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced that the China Food and Drug Administration (CFDA) has accepted for review a New Drug Application (NDA) submitted for Eisai's in-house discovered and developed anticancer agent lenvatinib mesylate (product names: Lenvima® / Kisplyx®, “lenvatinib”) for use in the treatment of hepatocellular carcinoma (HCC) in China.

The NDA was based on the results of the REFLECT study (Study 304), a multicenter, open-label, randomized, global Phase Ⅲ trial comparing the efficacy and safety of lenvatinib versus sorafenib, a standard treatment for HCC, as a first-line treatment for the patients with unresectable HCC.¹

In the REFLECT study, lenvatinib demonstrated a treatment effect on the primary endpoint of Overall Survival (OS) by the statistical confirmation of non-inferiority to sorafenib. Additionally, lenvatinib showed highly statistically significant and clinically meaningful improvements compared to sorafenib in the secondary endpoints of Progression Free Survival (PFS), Time To Progression (TTP), and Objective Response Rate (ORR). 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 side-effect profile of lenvatinib.

Liver cancer is the second leading cause of cancer related deaths and is estimated to be responsible for approximately 750,000 deaths per year globally. Additionally, approximately 780,000 cases are newly diagnosed each year, about 80% of which occur in Asian regions. Specifically, in China, there are approximately 395,000 new cases and 380,000 deaths per year, accounting for approximately 50% of cases worldwide.² HCC accounts for 85% to 90% of primary liver cancer cases. Treatment options for unresectable HCC are limited. Therefore, HCC is extremely difficult to treat, and the development of new treatments is necessary.

Eisai submitted applications for an additional indication for lenvatinib for the treatment of HCC in Japan (June 2017), the United States and Europe (July 2017).

Eisai positions oncology as a key therapeutic area, and is aiming to discover revolutionary new medicines with the potential to cure cancer. Eisai is committed to exploring the potential clinical benefits of lenvatinib 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.

Discovered and developed in-house, lenvatinib 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 proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation.
Currently, Eisai has obtained approval for lenvatinib as a treatment for refractory thyroid cancer in over 50 countries, including the United States, Japan, and in Europe, under the brand name Lenvima. 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.
A Phase Ⅲ study of lenvatinib in separate combinations with everolimus and pembrolizumab in renal cell carcinoma (first-line) is underway. A Phase Ⅰb/Ⅱ study to investigate the agent in combination with pembrolizumab in select solid tumors (endometrial cancer, non-small cell lung cancer, renal cell carcinoma, urothelial cancer, head and neck cancer, and melanoma) and a Phase Ⅰb study in HCC are also underway. Additionally, a Phase Ⅰb study to investigate the agent in combination with nivolumab in HCC are initiated in Japan.

The REFLECT is a multicenter, open-label, randomized, global Phase Ⅲ study comparing the efficacy and safety of lenvatinib versus sorafenib. In the study, 954 patients were randomized in a 1:1 ratio to receive lenvatinib 12 mg (≥60 kg) or 8 mg (<60 kg) once a day, depending on baseline body weight (n = 478) or sorafenib 400 mg twice a day (n = 476). Treatment was continued until disease progression or unacceptable toxicity.
The primary endpoint of the study was OS with the goal of demonstrating non-inferiority. Other factors including PFS, TTP, ORR and Quality of Life (QOL) were assessed as secondary endpoints.
According to the results of the study, lenvatinib (13.6 months) met the statistical criteria for non-inferiority in the primary endpoint of median OS compared to sorafenib (12.3 months). (Hazard Ratio [HR] 0.92, 95% Confidence Interval [CI] = 0.79-1.06)
Additionally, lenvatinib showed statistically significant improvements in the three secondary efficacy endpoints, doubling sorafenib's median values and ratios: median PFS (lenvatinib 7.4 months versus sorafenib 3.7 months, HR 0.66, 95% CI = 0.57-0.77, P<0.00001), median TTP (lenvatinib 8.9 months versus sorafenib 3.7 months, HR 0.63, 95% CI = 0.53-0.73, P<0.00001) and ORR (lenvatinib 24% versus sorafenib 9%, P<0.00001).
Furthermore, EORTC QLQ-C30 and QLQ-HCC18 questionnaires were used to evaluate overall QOL. In both groups, scores decreased after the administration of the agents. However, within 3 categories in EORTC QLQ-C30 (role functioning, pain, diarrhea) and two categories in QLQ-HCC18 (nutrition, body image), it was found that Lenvatinib helped to delay deterioration of QOL compared to sorafenib (nominal P-value<0.01)
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 side-effect profile of lenvatinib.