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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Eisai and Merck & Co., Inc., Rahway, NJ, USA Provide Update on Phase 3 Trials of
LENVIMA® (lenvatinib) Plus KEYTRUDA® (pembrolizumab) in Certain Patients With
Advanced Melanoma (LEAP-003) and Metastatic Colorectal Cancer (LEAP-017)

TOKYO and RAHWAY, N.J., Apr. 7, 2023 – Eisai (Headquarters: Tokyo, CEO: Haruo
Naito) and Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States andCanada) today provided updates on two Phase 3 trials, LEAP-003 and LEAP-017 investigating
LENVIMA®, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai,plus KEYTRUDA®, the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA.
LEAP-003: Eisai and Merck & Co., Inc., Rahway, NJ, USA are discontinuing the Phase 3
LEAP-003 trial evaluating LENVIMA plus KEYTRUDA for the first-line treatment of adults withunresectable or metastatic melanoma. This decision is based on the recommendation of an
independent Data Monitoring Committee (DMC), which reviewed data from a planned interim
analysis and determined LENVIMA plus KEYTRUDA did not demonstrate an improvement inoverall survival (OS), one of the study’s dual primary endpoints, versus KEYTRUDA alone. Eisai
and Merck & Co., Inc., Rahway, NJ, USA are informing study investigators of the decision andadvising them to reach out to patients in the study regarding treatment. At an earlier interim
analysis, the trial’s other dual primary endpoint, progression-free survival (PFS), showed astatistically significant improvement in the LENVIMA plus KEYTRUDA arm versus the
KEYTRUDA plus placebo arm.
LEAP-017: The Phase 3 LEAP-017 trial evaluating LENVIMA plus KEYTRUDA did notmeet its primary endpoint of OS for the treatment of patients with unresectable and metastatic
colorectal cancer that is mismatch repair proficient (pMMR) or not microsatellite instability-high(MSI-H) who experienced disease progression on, or became intolerant to, prior therapy. In the
final pre-specified analysis of OS, a trend toward improvement was observed with LENVIMA plus
KEYTRUDA versus regorafenib or TAS-102 (trifluridine and tipiracil hydrochloride); however,these results did not meet statistical significance per the pre-specified statistical analysis plan. A-1-trend toward improvement was also observed in key secondary endpoints of PFS, objective
response rate (ORR) and duration of response (DOR) with LENVIMA plus KEYTRUDA versus
regorafenib or TAS-102; however, per the pre-specified statistical analysis plan, these results
were not tested for statistical significance.
In both the LEAP-003 and LEAP-017 trials, the safety profile of LENVIMA plus
KEYTRUDA was consistent with previously reported data on the combination. A full evaluation of
the data from these studies including pre-planned key subgroup analyses is ongoing. The
companies will work with investigators to share the results with the scientific community.
“We are grateful to all the investigators, patients and their families for their participation inthese studies, and we will continue to evaluate KEYTRUDA plus LENVIMA across different typesof cancer where additional treatment options are needed. We remain fully committed to building
on existing treatments, as part of our efforts to help as many appropriate patients with cancer as
we can,” said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck & Co.,
Inc., Rahway, NJ, USA Research Laboratories.
“With the LEAP-003 and LEAP-017 trials, we set out to help improve outcomes forpatients with two difficult-to-treat advanced cancers, melanoma and colorectal cancer,” said
Corina Dutcus, M.D., Senior Vice President, Clinical Development, Oncology at Eisai Inc. “Whilethese results are different from our initial expectation, insights from both studies will help
contribute to our understanding of LENVIMA plus KEYTRUDA. We remain confident in LENVIMA
as a pillar of Eisai’s oncology portfolio and will continue to evaluate its potential in ongoing trials
within the LEAP program.”
LENVIMA plus KEYTRUDA is approved in the U.S., the EU, Japan and other countries forthe treatment of advanced renal cell carcinoma (RCC) and certain types of advanced endometrial
carcinoma. Lenvatinib is marketed as KISPLYX® for advanced RCC in the EU. Results from the
LEAP-003 and LEAP-017 trials do not affect the current approved indications for the LENVIMA
and KEYTRUDA combination.
Eisai and Merck & Co., Inc., Rahway, NJ, USA are studying the LENVIMA plus
KEYTRUDA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in
multiple tumor types, including but not limited to endometrial carcinoma, hepatocellular carcinoma,
melanoma, non-small cell lung cancer, RCC, head and neck cancer, colorectal cancer, gastriccancer and esophageal cancer, across more than 10 clinical trials.
About LEAP-003
LEAP-003 is a randomized, placebo-controlled Phase 3 trial (ClinicalTrials.gov,
NCT03820986) evaluating LENVIMA plus KEYTRUDA versus KEYTRUDA alone for the firstline treatment of adults with unresectable or metastatic melanoma. The dual primary endpoints
are OS and PFS, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1-2-

(RECIST v1.1). Key secondary endpoints include ORR and DOR, both as assessed by RECIST
v1.1, and safety. The study enrolled 674 patients who were randomized 1:1 to receive:

LENVIMA (20 mg orally once daily) plus KEYTRUDA (200 mg intravenously [IV] on
Day 1 of each three-week cycle); or

placebo via oral capsule daily plus KEYTRUDA (200 mg IV on Day 1 of each threeweek cycle)

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.
About Melanoma
Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled
growth of melanocytes, pigment producing cells.1 The rates of melanoma have been rising overthe past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020.1,2 In the
U.S., skin cancer is one of the most common types of cancer diagnosed. Although melanoma
accounts for only 1% of skin cancers, it accounts for a large majority of skin cancer deaths.1 Itis estimated there will be nearly 100,000 new cases of melanoma diagnosed and approximately
8,000 deaths resulting from the disease in the U.S. in 2023.1 The five-year survival rates from2012-2018 are estimated to be 71% for regional disease and 32% for distant disease.3
About LEAP-017
LEAP-017 is a randomized, open label, Phase 3 trial (ClinicalTrials.gov, NCT04776148)
evaluating LENVIMA plus KEYTRUDA versus regorafenib or TAS-102, for patients withunresectable and metastatic colorectal cancer that is pMMR or not MSI-H who have received andprogressed on or after, or became intolerant to, prior treatment. Patients must have beenpreviously treated for colorectal cancer and have shown disease progression as defined by
RECIST v1.1 on or after, or could not tolerate, standard treatment. The standard treatment must
include all of the following agents, if approved and locally available in the country where theparticipant is randomized:•

Fluoropyrimidine, irinotecan and oxaliplatin;oWith or without an anti-vascular endothelial growth factor monoclonal antibody(bevacizumab);oWith anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or
panitumumab) for RAS (KRAS/NRAS) wild-type (WT) participants; and

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•

BRAF inhibitor (in combination with cetuximab +/- binimetinib) for BRAF V600E mutatedmetastatic colon cancer.
The primary endpoint is OS and key secondary endpoints include PFS, ORR and DOR,

according to RECIST v1.1 per blinded independent central review (BICR). The study enrolled 480
patients randomized 1:1 to receive:• LENVIMA (20 mg given orally once daily) plus KEYTRUDA (400 mg IV on Day 1 of eachsix-week cycle); or• Regorafenib (160 mg given orally once daily on Days 1 through 21 of each four-weekcycle; or TAS-102 (35mg/m2 given orally twice daily on Days 1 through 5 and Days 8
through 12 of each four-week cycle).
KEYTRUDA was administered for up to 18 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.

About colorectal cancer
Colorectal cancer can be referred to as colon cancer or rectal cancer, depending on where
the cancer starts.4 Colorectal cancer often begins with growths on the inner lining of the colon or
rectum called polyps, which can change into cancer over time.4 Colorectal cancer is the third
most commonly diagnosed cancer and the second most common cause of cancer-related deathworldwide.5 It is estimated there were more than 1,880,000 new cases of colorectal cancer
globally in 2020.5 In Japan, it is estimated there were more than 147,000 new cases of colorectal
cancer diagnosed and more than 59,000 deaths from this disease in 2020.6 In the United States,
it is estimated there will be approximately 107,000 new cases of colon cancer and approximately
46,000 new cases of rectal cancer, resulting in more than 52,000 deaths from colorectal cancer
in 2023.7 The five-year relative survival rates in the U.S. for metastatic colon cancer and rectal
cancer (stage IV) are estimated to be 13% and 17%, respectively.8
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-4-

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(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-5-

(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 (generic name: pembrolizumab)(Approved in over 40 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
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 understand-6-

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 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
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.

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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 tohealth 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

biopharmaceutical company 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.
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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 American Cancer Society. Key Statistics for Melanoma Skin Cancer. https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html .
2 International Agency for Research on Cancer, World Health Organization. “Skin Fact Sheet.” Cancer Today, 2020.

https://gco.iarc.fr/today/data/factsheets/cancers/16-Melanoma-of-skin-fact-sheet.pdf .
3 National Cancer Institute, Surveillance, Epidemiology, and End Results Program. “Cancer Stat Facts: Melanoma of

the Skin” https://seer.cancer.gov/statfacts/html/melan.html .
4 American Cancer Society. “What is Colorectal Cancer?” About Colorectal cancer.

https://www.cancer.org/cancer/colon-rectal-cancer/about/what-is-colorectal-cancer.html .
5 Cancer. Net®. Colorectal Cancer: Statistics

https://www.cancer.net/cancer-types/colorectal-cancer/statistics .
6 International Agency for Research on Cancer, World Health Organization. “Japan Fact Sheet.” Cancer Today, 2020.

https://gco.iarc.fr/today/data/factsheets/populations/392-japan-fact-sheets.pdf .
7 American Cancer Society. Cancer Facts & Figures 2023.

https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-andfigures/2023/2023-cancer-facts-and-figures.pdf .
8 American Cancer Society. “Survival Rates for Colorectal Cancer” Early detection, Diagnosis, and Staging.
https://www.cancer.org/cancer/colon-rectal-cancer/detection-diagnosis-staging/survival-rates.html .

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