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)

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 and Canada) 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 with unresectable 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 in overall 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 and advising 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 a statistically 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 not meet 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

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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 in these studies, and we will continue to evaluate KEYTRUDA plus LENVIMA across different types of 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 for patients 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. "While these 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 for the 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, gastric cancer 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 first- line 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

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(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 three- week 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 over the 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 It is 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 from 2012-2018 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 with unresectable and metastatic colorectal cancer that is pMMR or not MSI-H who have received and progressed on or after, or became intolerant to, prior treatment. Patients must have been previously 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 the participant is randomized:

• Fluoropyrimidine, irinotecan and oxaliplatin;

1. With or without an anti-vascular endothelial growth factor monoclonal antibody

(bevacizumab);

1. With 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 mutated metastatic 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 each six-week cycle); or
• Regorafenib (160 mg given orally once daily on Days 1 through 21 of each four-week cycle; 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 death worldwide.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

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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

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