Eisai : and Merck & Co., Inc., Kenilworth, N.J., U.S.A. Receive Priority Review From FDA for LENVIMA (lenvatinib) Plus KEYTRUDA (pembrolizumab) Applications for Advanced Renal Cell Carcinoma and for Advanced Endometrial Carcinoma

TOKYO and KENILWORTH, N.J. - Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, 'Eisai') and Merck & Co., Inc., Kenilworth, N.J., U.S.A. (known as MSD outside the United States and Canada) today announced that the U.S. Food and Drug Administration (FDA) has accepted and granted priority review for applications seeking two new approvals for the combination of LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, plus KEYTRUDA, the anti-PD-1 therapy from Merck & Co., Inc., Kenilworth, N.J., U.S.A. The first set of applications (a supplemental New Drug Application [sNDA] for LENVIMA and a supplemental Biologics License Application [sBLA] for KEYTRUDA) are for the first-line treatment of patients with advanced renal cell carcinoma (RCC), based on progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) data from the pivotal Phase 3 CLEAR study (Study 307/KEYNOTE-581). The second set of applications are for the treatment of patients with advanced endometrial carcinoma who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation, based on PFS, OS, and ORR data from the pivotal Phase 3 Study 309/KEYNOTE-775 trial. These are the first applications to be submitted in the U.S. for this combination therapy based on Phase 3 clinical data. The FDA has set Prescription Drug User Fee Act (PDUFA) dates, or target action dates, of August 25 and 26, 2021, for the advanced RCC sNDA and sBLA applications, respectively, and September 3, 2021, for the advanced endometrial carcinoma applications.

'Advanced renal cell carcinoma and advanced endometrial carcinoma are aggressive cancers, and patients urgently need new treatment options that may help improve outcomes,' said Dr. Gregory Lubiniecki, Vice President, Oncology Clinical Research, Merck & Co., Inc., Kenilworth, N.J., U.S.A. Research Laboratories. 'We appreciate that the FDA has recognized this significant unmet need and the potential for the combination of KEYTRUDA plus LENVIMA in these patients by granting priority review for these applications.'

'We are pleased that the FDA has granted priority review for LENVIMA plus KEYTRUDA-both in advanced renal cell carcinoma and advanced endometrial carcinoma- underscoring the potential significance of the outcomes observed in the CLEAR study (Study 307/KEYNOTE-581) and Study 309/KEYNOTE-775 trials,' said Dr. Takashi Owa, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. 'Many patients are still in need of new and effective therapies, which fuels our commitment to advancing the development of this combination even more. These milestones reinforce our unwavering dedication to helping the patients we aim to serve.'

The applications in advanced RCC are based on results from the CLEAR study (Study 307/KEYNOTE-581), in which LENVIMA plus KEYTRUDA demonstrated statistically significant improvements in PFS, OS and ORR versus sunitinib. These data were presented in February at the virtual 2021 Genitourinary Cancers Symposium (ASCO GU) and simultaneously published in the New England Journal of Medicine. 1

The applications in advanced endometrial carcinoma are based on results from Study 309/KEYNOTE-775, in which LENVIMA plus KEYTRUDA demonstrated statistically significant improvements in PFS, OS and ORR versus chemotherapy (investigator's choice of doxorubicin or paclitaxel), regardless of mismatch repair (MMR) status. These data were presented in March at the virtual Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women's Cancer. Study 309/KEYNOTE-775 is the confirmatory trial for Study 111/KEYNOTE-146, which supported the 2019 accelerated approval of the combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication was an accelerated approval based on tumor response and durability of response and reviewed under the FDA's Real-Time Oncology Review pilot program and the FDA's Project Orbis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Eisai and Merck & Co., Inc., Kenilworth, N.J., U.S.A. are studying the LENVIMA plus KEYTRUDA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in 14 different tumor types (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer, pancreatic cancer and triple-negative breast cancer) across more than 20 clinical trials.

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About LENVIMA (lenvatinib) Capsules

LENVIMA, discovered and developed by Eisai, is an orally available kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases 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 (PDGFR?), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.

Currently, LENVIMA has been approved for monotherapy as a treatment for thyroid cancer in over 70 countries including Japan, in Europe, China and in Asia, and in the United States for radioiodine-refractory differentiated thyroid cancer. In addition, LENVIMA has been approved for monotherapy as a treatment for unresectable hepatocellular carcinoma in over 70 countries including Japan, the United States, in Europe, China and in Asia. It is also approved in combination with everolimus as a treatment for renal cell carcinoma following prior antiangiogenic therapy in over 60 countries, including the United States, in Europe and Asia. In Europe, the agent was launched under the brand name Kisplyx for renal cell carcinoma. In addition, it is approved in combination with KEYTRUDA (generic name: pembrolizumab) as a treatment for advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation in over 10 countries including the United States, Canada and Australia. Continued approval for this indication is contingent upon verification and description of clinical benefit in the confirmatory trials. LENVIMA has also been approved for monotherapy as a treatment for unresectable thymic carcinoma in Japan.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck & Co., Inc., Kenilworth, N.J., U.S.A. has the industry's largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

About CLEAR Study (Study 307/KEYNOTE-581)

The CLEAR study (Study 307/KEYNOTE-581) is a multicenter, randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT02811861) evaluating LENVIMA in combination with KEYTRUDA or in combination with everolimus versus sunitinib for the first-line treatment of patients with advanced RCC. The primary endpoint is PFS, as assessed by independent review per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key secondary endpoints include OS, ORR and safety. A total of 1,069 patients were randomized (1:1:1) to receive LENVIMA (20 mg orally once daily) in combination with KEYTRUDA (200 mg intravenously [IV] every three weeks for up to 24 months); or LENVIMA (18 mg orally once daily) in combination with everolimus (5 mg orally once daily); or sunitinib (50 mg orally once daily for four weeks on treatment, followed by two weeks off treatment).

In the trial's primary endpoint of PFS, as assessed by independent review per RECIST v1.1, LENVIMA plus KEYTRUDA reduced the risk of disease progression or death by 61% (HR=0.39 [95% CI: 0.32-0.49]; p

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