Eisai Co., Ltd.

Merck & Co., Inc., Rahway, NJ, USA

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Eisai Co., Ltd.

Merck & Co., Inc., Rahway, NJ, USA

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LENVIMA® (lenvatinib) Plus KEYTRUDA® (pembrolizumab) Demonstrates
Long-Term, Durable Survival Benefit Versus Sunitinib as First-Line Treatment for
Patients With Advanced Renal Cell Carcinoma
After four years of follow-up, LENVIMA plus KEYTRUDA reduced the risk ofdeath by 21% versus sunitinib in
the pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial
Final results will be presented at ASCO 2023 in an oral abstract session
TOKYO and RAHWAY, N.J., May.26, 2023 – Eisai (Headquarters: Tokyo, CEO: Haruo
Naito) and Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States andCanada) today announced data from the final pre-specified overall survival (OS) analysis of thepivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial investigating LENVIMA, the orally
available multiple receptor tyrosine kinase inhibitor discovered by Eisai, plus KEYTRUDA,
Merck’s anti-PD-1 therapy, for the first-line treatment of patients with advanced renal cell
carcinoma (RCC). These data will be presented on Monday, June 5 at 11:54 a.m. Central Daylight
Time during an oral abstract session at the 2023 American Society of Clinical Oncology (ASCO)
Annual Meeting (Abstract #4502).
After four years of follow-up, LENVIMA plus KEYTRUDA maintained a clinicallymeaningful OS benefit versus sunitinib, reducing the risk of death by 21% (HR=0.79 [95% CI,
0.63-0.99]). The 24- and 36-month estimated OS rates were 80.4% and 66.4% for LENVIMA plus
KEYTRUDA versus 69.6% and 60.2% for sunitinib, respectively. Results from the final prespecified OS analysis were consistent with the superior results versus sunitinib from the primary
OS analysis of the CLEAR/KEYNOTE-581 trial.
Additionally, LENVIMA plus KEYTRUDA reduced the risk of disease progression or deathby 53% (HR=0.47 [95% CI, 0.38-0.57]), with a median progression-free survival (PFS) of 23.9
months (95% CI, 20.8-27.7) for LENVIMA plus KEYTRUDA versus 9.2 months (95% CI, 6.0-11.0)-1-

for sunitinib; the objective response rate (ORR) was 71.3% (95% CI, 66.6-76.0) with a complete
response (CR) rate of 18.3% for LENVIMA plus KEYTRUDA versus an ORR of 36.7% (95% CI,
31.7-41.7) with a CR rate of 4.8% for sunitinib.
There were no new safety signals and the safety profile at the final OS analysis wasconsistent with the primary analysis. Grade ≥3 treatment-related adverse events (TRAE) occurredin 74.1% of patients who received LENVIMA plus KEYTRUDA versus 60.3% of patients who
received sunitinib. The six most common TRAEs of any grade of patients in the LENVIMA plus
KEYTRUDA arm were diarrhea (56.0%), hypertension (54.3%), hypothyroidism (44.9%),
decreased appetite (35.5%), fatigue (34.1%) and stomatitis (32.7%). In the sunitinib arm, the six
most common TRAEs of any grade were diarrhea (45.3%), hypertension (40.3%), stomatitis(37.4%), palmar-plantar erythrodysesthesia (36.2%), fatigue (32.9%) and nausea (28.2%).
“LENVIMA plus KEYTRUDA continues to demonstrate durable clinical benefit as a firstline treatment for patients with advanced renal cell carcinoma, as shown by the clinicallymeaningful improvement in overall survival sustained with four years of follow up,” said Dr.
Thomas Hutson, DO, Pharm.D., FACP, Director of the Urologic Oncology Program and Co-chairof the Urologic Cancer Research and Treatment Center, Texas Oncology at Baylor Sammons
Cancer Center. “Furthermore, these data also showed clinically meaningful improvements inmedian PFS and ORR compared to sunitinib. These findings reinforce the important role of
LENVIMA plus KEYTRUDA as a first-line standard of care treatment option for patients withadvanced renal cell carcinoma.”“Long-term follow up data from the CLEAR/KEYNOTE-581 trial show the responses tofirst-line use of KEYTRUDA plus LENVIMA were durable for many of these patients,” said Dr.
Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories.
“Through our joint clinical development program with Eisai, we’re continuing to advance ourresearch evaluating KEYTRUDA plus LENVIMA for other challenging cancers as we strive to help
even more patients.”“At the final pre-specified analysis, LENVIMA plus KEYTRUDA continued to demonstrateclinically meaningful efficacy across PFS, ORR and OS, providing patients and their physicianswith new information about treating people living with advanced renal cell carcinoma,” said Corina
Dutcus, M.D., Senior Vice President, Clinical Development, Oncology at Eisai Inc. “These results
are a testament to our steadfast commitment to people living with advanced cancers, and we are
grateful for the support from the patients, families and healthcare provider community for their
participation in this research.”
LENVIMA plus KEYTRUDA is approved in the U.S., the EU, Japan and other countries
for the treatment of advanced RCC and certain types of advanced endometrial carcinoma.
Lenvatinib is marketed as KISPLYX® for advanced RCC in the EU. Eisai and Merck are studying
the LENVIMA plus KEYTRUDA combination through the LEAP (LEnvatinib And Pembrolizumab)
clinical program in various tumor types, including but not limited to endometrial carcinoma,-2-

hepatocellular carcinoma, non-small cell lung cancer, RCC, head and neck cancer, gastric cancer
and esophageal cancer across multiple clinical trials.
Study design and additional data from CLEAR/KEYNOTE-581
The CLEAR/KEYNOTE-581 trial 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 major efficacy outcome measures were PFS, as assessed by independent radiologic
review (IRC) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1), and OS. Additional efficacy outcome measures included confirmed ORR as assessed by
IRC, health-related quality of life (HRQoL) and safety.
The trial enrolled 1,069 patients who were randomized 1:1:1 to receive LENVIMA (20mg orally once daily) plus KEYTRUDA (200 mg intravenously every three weeks for up to 24
months), or LENVIMA (18 mg orally once daily) plus everolimus (5 mg orally once daily), or
sunitinib (50 mg orally once daily for four weeks on treatment, followed by two weeks offtreatment). KEYTRUDA was administered for up to 35 cycles (approximately two years) or until
protocol-specified discontinuation criteria were met. After completing two years of combination
therapy, LENVIMA may have been administered as a single agent until protocol-specified
discontinuation criteria were met.
This final pre-specified OS analysis was event driven and was triggered byapproximately 304 OS target events in the two treatment arms (149 events out of 355 patientsfor KEYTRUDA plus LENVIMA versus 159 events out of 357 patients for sunitinib).
The median duration of response was 26.7 months (95% CI, 22.8-34.6) for LENVIMA
plus KEYTRUDA versus 14.7 months (95% CI, 9.4-18.2) for sunitinib.
Efficacy results were consistent across the pre-specified Memorial Sloan Kettering
Cancer Center (MSKCC) risk groups (favorable, intermediate and poor) and International
Metastatic RCC Database Consortium (IMDC) risk groups. Across the pre-specified Memorial
Sloan Kettering Cancer Center (MSKCC) risk groups (favorable, intermediate and poor), OS
and PFS were improved with LENVIMA plus KEYTRUDA versus sunitinib. Interpretation OS infavorable risk patients is limited by low number of events.
Fewer patients who were treated with LENVIMA plus KEYTRUDA received subsequentanti-cancer therapies (181 out of 355 patients, 51.0%) versus those who were treated withsunitinib (246 out of 357 patients, 68.9%), with 56 patients (15.8%) and 195 patients (54.6%)
who went on to receive PD-1/PD-L1 checkpoint inhibitors, respectively. In an exploratory
analysis using a 2-stage model, LENVIMA plus KEYTRUDA reduced the risk of death by 45%
versus sunitinib when adjusted for subsequent anticancer medications (HR=0.55 [95% CI, 0.440.69]).

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About renal cell carcinoma (RCC)
Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer
diagnosed and more than 179,000 deaths from the disease in 2020. 1 Renal cell carcinoma is
by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses
are RCC. 2 Renal cell carcinoma is about twice as common in men as in women. 3 Most casesof RCC are discovered incidentally during imaging tests for other abdominal diseases.4
Approximately 30% of patients with RCC will have metastatic disease at diagnosis. 4 Survival ishighly dependent on the stage at diagnosis, and the five-year survival rate is 15% for patientsdiagnosed with metastatic disease. 5
About LENVIMA® (lenvatinib) Capsules
LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor
tyrosine 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 (PDGFRα), 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. LENVIMA has been
approved for the indications below.
Thyroid cancer Indication as monotherapy(Approved in over 80 countries including Japan, the United States, China, and countries in Europe
and Asia)
Japan: Unresectable thyroid cancer
The United States: The treatment of patients with locally recurrent or metastatic, progressive,
radioiodine-refractory differentiated thyroid cancer (DTC)
Europe: The treatment of adult patients with progressive, locally advanced or metastatic,
differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive
iodine (RAI)
Hepatocellular carcinoma
 Indication as monotherapy-4-

(Approved in over 80 countries including Japan, the United States, China, and countries in Europe
and Asia)
Japan: Unresectable hepatocellular carcinoma
The United States: The first-line treatment of patients with unresectable hepatocellular carcinoma(HCC)
Europe: The treatment of adult patients with advanced or unresectable hepatocellular carcinoma(HCC) who have received no prior systemic therapy
Thymic carcinoma
 Indication as monotherapy (Approved in Japan)
Japan: Unresectable thymic carcinoma
Renal cell carcinoma (In Europe, the agent was launched under the brand name Kisplyx®)
 Indication in combination with everolimus(Approved in over 65 countries including the United States, and countries in Europe and Asia)
The United States: The treatment of adult patients with advanced renal cell carcinoma (RCC)
following one prior anti-angiogenic therapy
Europe: The treatment of adult patients with advanced renal cell carcinoma following one priorvascular endothelial growth factor (VEGF) targeted therapy
 Indication in combination with KEYTRUDA(Approved in over 45 countries including Japan, the United States, and countries in Europe andAsia)
Japan: Radically unresectable or metastatic renal cell carcinoma
The United States: The first-line treatment of adult patients with advanced renal cell carcinoma
Europe: The first-line treatment of adult patients with advanced renal cell carcinoma
Endometrial carcinoma
 Indication in combination with KEYTRUDA(Approved [including conditional approval] in over 45 countries including Japan, the United States,
and countries in Europe and Asia)
Japan: Unresectable, advanced or recurrent endometrial carcinoma that progressed after cancer
chemotherapy
The United States: The treatment of patients with advanced endometrial carcinoma (EC) that is
mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite-5-instability-high (MSI-H), who have disease progression following prior systemic therapy in any
setting and are not candidates for curative surgery or radiation.
Europe: The treatment of adult patients with advanced or recurrent endometrial carcinoma (EC)
who have disease progression on or following prior treatment with a platinum-containing therapy
in any setting and are not candidates for curative surgery
About KEYTRUDA® (pembrolizumab) Injection, 100mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works byincreasing 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 andits ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells
and healthy cells.
Merck & Co., Inc., Rahway, NJ, USA has the industry’s largest immuno-oncology clinicalresearch program. There are currently more than 1,600 trials studying KEYTRUDA across a wide
variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understandthe 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 the Eisai and Merck & Co., Inc., Rahway, NJ, USA Strategic Collaboration
In March 2018, Eisai and Merck & Co., Inc., Rahway, NJ, USA, known as MSD outside
the United States and Canada, through an affiliate, entered into a strategic collaboration for theworldwide co-development and co-commercialization of LENVIMA. Under the agreement, thecompanies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy
and in combination with KEYTRUDA, the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ,
USA.
In addition to ongoing clinical studies evaluating the LENVIMA plus KEYTRUDA
combination across several different tumor types, the companies have jointly initiated clinicalstudies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating
the combination in multiple tumor types across more than 10 clinical trials.
Eisai’s Focus on Cancer
Eisai acknowledges “Oncology” as one of its key strategic areas, and will continue to focus
on the discovery and development of anti-cancer drugs within drug discovery domains including“microenvironment”, “proteostasis disruption”, “cell lineage and cell differentiation”, and“inflammation, hypoxia, oxidative stress and cell senescence” under the Deep Human Biology
Learning (DHBL) drug discovery and development organization. Eisai aspires to discover-6-

innovative new drugs with new targets and mechanisms of action from these domains, with theaim of contributing to the cure of cancers.
About Eisai
Eisai’s Corporate Concept is “to give first thought to patients and people in the daily living
domain, and to increase the benefits that health care provides.” Under this Concept [also known
as our human health care (hhc) Concept], we aim to effectively achieve social good in the form ofrelieving anxiety over health and reducing health disparities. With a global network of R&D
facilities, manufacturing sites and marketing subsidiaries, we strive to create and deliver
innovative products to target diseases with high unmet medical needs, with a particular focus in
our strategic areas of Neurology and Oncology.
In addition, our continued commitment to the elimination of neglected tropical diseases(NTDs), which is a target (3.3) of the United Nations Sustainable Development Goals (SDGs), isdemonstrated by our work on various activities together with global partners.
For more information about Eisai, please visit www.eisai.com (for global headquarters:
Eisai. Co., Ltd.), us.eisai.com (for U.S. headquarters: Eisai, Inc.) or www.eisai.eu (for Europe,
Middle East, Africa, Russia, Australia and New Zealand headquarters: Eisai Europe Ltd.), andconnect with us on Twitter (U.S. and global) and LinkedIn (for U.S. and EMEA).

Merck & Co., Inc., Rahway, NJ, USA’s Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help
people with cancer worldwide. At Merck & Co., Inc., Rahway, NJ, USA, the potential to bring newhope to people with cancer drives our purpose and supporting accessibility to our cancer
medicines is our commitment. As part of our focus on cancer, Merck & Co., Inc., Rahway, NJ,
USA is committed to exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor types. We also continue tostrengthen our portfolio through strategic acquisitions and are prioritizing the development ofseveral promising oncology candidates with the potential to improve the treatment of advanced
cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck & Co., Inc., Rahway, NJ, USA
For over 130 years, Merck & Co., Inc., Rahway, NJ, USA, known as MSD outside of theUnited States and Canada, has been inventing for life, bringing forward medicines and vaccines
for many of the world’s most challenging diseases in pursuit of our mission to save and improve
lives. We demonstrate our commitment to patients and population health by increasing access to-7-

health care through far-reaching policies, programs and partnerships. Today, Merck & Co., Inc.,
Rahway, NJ, USA continues to be at the forefront of research to prevent and treat diseases thatthreaten people and animals – including cancer, infectious diseases such as HIV and Ebola, andemerging animal diseases – as we aspire to be the premier research-intensive biopharmaceuticalcompany in the world. For more information, visit www.merck.com and connect with us on Twitter,
Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc., Rahway, NJ, USA
This news release of Merck & Co., Inc., Rahway, NJ, USA (the “company”) includes“forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs
and expectations of the company’s management and are subject to significant risks anduncertainties. There can be no guarantees with respect to pipeline candidates that the candidates
will receive the necessary regulatory approvals or that they will prove to be commerciallysuccessful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual
results may differ materially from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general industry conditions andcompetition; general economic factors, including interest rate and currency exchange rate
fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); theimpact of pharmaceutical industry regulation and health care legislation in the United States andinternationally; global trends toward health care cost containment; technological advances, newproducts and patents attained by competitors; challenges inherent in new product development,
including obtaining regulatory approval; the company’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial instability of international economies andsovereign risk; dependence on the effectiveness of the company’s patents and other protections
for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any forward-looking statement,
whether as a result of new information, future events or otherwise. Additional factors that could
cause results to differ materially from those described in the forward-looking statements can befound in the company’s Annual Report on Form 10-K for the year ended December 31, 2022 andthe company’s other filings with the Securities and Exchange Commission (SEC) available at the
SEC’s Internet site (www.sec.gov).
1 International Agency for Research on Cancer, World Health Organization. “Kidney Fact Sheet.” Cancer Today,

2020. https://gco.iarc.fr/today/data/factsheets/cancers/29-Kidney-fact-sheet.pdf .
2 American Cancer Society. “What Is Kidney Cancer?” About Kidney Cancer.

https://www.cancer.org/cancer/types/kidney-cancer/about/what-is-kidney-cancer.html .

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3 American Cancer Society. “Key Statistics About Kidney Cancer” About Kidney Cancer.

https://www.cancer.org/cancer/types/kidney-cancer/about/key-statistics.html .
4 American Family Physician. Renal Cell Carcinoma: Diagnosis and Management.

https://www.aafp.org/pubs/afp/issues/2019/0201/p179.html .
5 American Cancer Society. “Survival Rates for Kidney Cancer” Early detection, Diagnosis, and Staging.

https://www.cancer.org/cancer/types/kidney-cancer/detection-diagnosis-staging/survival-rates.html .

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