• For printing
• September 17, 2024

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

Eisai Co., Ltd. (headquartered in Tokyo, Representative Executive Officer and CEO: Haruo Naito, hereinafter Eisai) and Merck & Co., Inc., Rahway, NJ, USA (MSD outside of North America) are now announcing the oral tyrosine kinase inhibitor “Renbima” (generic name: lenvatinib mesylate) and Merck & Co., Inc., Rahway, NJ, USA's anti-PD-1 antibody “keytruda” (generic name: The first interim analysis results of the clinical phase III LEAP-012 trial to evaluate combination therapy (transarterial chemoembolization: TACE) with hepatic artery chemoembolization (TACE) added to pembrolizumab) as a treatment for unresectable nonmetastatic hepatocellular carcinoma compared to TACE monotherapy were presented on 9/14 (Central European Summer Time) by the European Society for Clinical Oncology (European Society for I would like to inform you that it was announced at the Presidential Symposium at the 2024 (Medical Oncology: ESMO) Annual General Meeting (abstract number: LBA3).

The combination therapy (present combination therapy) with TACE added to “Renbima” and “Keytruda” showed statistically significant and clinically significant improvements in progression-free survival (PFS), which is one of the main evaluation items, compared to TACE monotherapy, and reduced the risk of disease progression or death by 34% (HR = 0.66 [95% confidence interval (Confidence)) Interval: CI), 0.51-0.84]; p=0.0002). The median PFS was 14.6 months (95% CI, 12.6-16.7) in the combination therapy group and 10.0 months (95% CI, 8.1-12.2) in the TACE monotherapy group. In this analysis, overall survival (OS), which is another major endpoint, showed an improvement trend compared to TACE monotherapy (HR = 0.80 [95% CI, 0.57-1.11]; p=0.0867). OS data is immature (immature) and did not reach statistically significant standards at the time of this interim analysis. The median follow-up period for this analysis was 25.6 months (range: 12.6-43.5 months). Testing is ongoing, and OS follow-up is ongoing. Note that the safety profile of this combination therapy was similar to what has been reported so far for the combination therapy of “Renbima” and “Keytruda.”

Dr. Josep Llovet, Liver Cancer Program Director and Professor of Medicine at Mount Sinai Icahn School of Medicine, said, “Hepatocellular carcinoma is one of the leading causes of cancer deaths worldwide, and new treatments are being sought 1,2. “These findings from the LEAP-012 trial suggest that lenvatinib plus pembrolizumab plus TACE may prolong progression-free survival in unresectable nonmetastatic hepatocellular carcinoma.”

Dr. Gregory Lubiniecki, vice president of global clinical development at the MSD Research and Development Division, said, “The global incidence rate of hepatocellular carcinoma is expected to increase by 50% or more over the next 20 years, and new treatments for patients with unresectable non-metastatic hepatocellular carcinoma are limited3. “The results of this interim analysis show our commitment to exploring treatment options for these patients, including early stages, and we are encouraged that in addition to existing Keytruda and Renvima monotherapy indications, combination therapy with TACE added to Keytruda and Renbima may be a new treatment option for patients with unresectable nonmetastatic hepatocellular carcinoma.”

Oncology Global Clinical Development Lead Corina Dutcus M.D., senior vice president of Eisai Inc. said, “TACE has been used as a standard treatment for patients with unresectable nonmetastatic hepatocellular carcinoma for many years, but many patients progress within 1 year 4,5,6,7. Data from the clinical phase III LEAP-012 trial showed that adding Renbima and Keytruda combination therapy to TACE could improve progression-free survival for patients with this disease, and that this combination therapy may meet unmet needs. We would like to thank the patients who cooperated with this study and the physicians responsible for the clinical trial.”

This combination therapy was given to 237 patients, and TACE monotherapy was 241. Treatment-related adverse events (treatment-related adverse events: TRAEs) occurred in 98.7% with this combination therapy and 84.6% with TACE monotherapy, and administration of the investigational drug was discontinued due to TRAES in 8.4% and 1.2%, respectively. Serious adverse events (SAEs) occurred in 33.3% of patients with this combination therapy and 12.4% with TACE monotherapy. Grade 3 or 4 TREs occurred in 71.3% of the present combination therapy and 31.1% with TACE monotherapy. Also, deaths due to TREs were 1.7% (4 cases) with this combination therapy and 0.4% (1 case) with TACE monotherapy.

“Renbima” monotherapy has obtained approval for indications relating to unresectable hepatocellular cancer in over 80 countries, including Japan, the United States, Europe, and China.

“Keytruda” monotherapy has been approved in the United States as a treatment for hepatocellular cancer caused by hepatitis B with a history of systemic therapy other than regimens containing PD-1/PD-L1, and in China as a treatment for hepatocellular cancer that has been treated with chemotherapy containing sorafenib or oxaliplatin, respectively.

The combination therapy of “Renbima” and “Keytruda” has obtained approval for indications relating to advanced renal cell cancer and advanced endometrial cancer (endometrial cancer in Japan) in countries around the world, starting with Japan, the United States, and Europe. “Renbima” is sold under the product name “Kisplyx” for indications related to renal cell cancer in Europe. Both companies are conducting multiple clinical trials on various cancer types, including hepatocellular cancer, renal cell cancer, head and neck cancer, stomach cancer, and esophageal cancer of this combination therapy through the LEAP (Lenvatinib And Pembrolizumab) clinical program.

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For press inquiries regarding this matter, please contact

• Eisai Co., Ltd

  PR department

  TEL: 03-3817-5120

• Merck & Co., Inc. Rahway, NJ, USA

  Media Relations

  Julie Cunningham: +1- (617) 519-6264

  John Infanti: +1- (609) 500-4714

＜Reference Materials＞

About the LEAP-012 exam

This trial (ClinicalTrials.gov, NCT04246177) is a multicenter, randomized, double-blind clinical phase III trial that evaluates combination therapy with “Renbima” and “Keytruda” with TACE in comparison with TACE monotherapy for unresectable non-metastatic hepatocellular carcinoma. The main evaluation items were PFS and OS by independent central imaging under blind examination based on ReciSTv1.1 (evaluation criteria for using changes in tumor size for solid cancer to determine effects), with a maximum total of 5 target lesions evaluated (new intrahepatic lesions must meet the criteria of LI-RADS5 [imaging diagnostic criteria for hepatocellular carcinoma using CT/MRI]). Secondary evaluation items were response rate, disease control rate, response period, no progression period, PFS by independent central image judgment based on RECIST v1.1 and modified RECIST (evaluation standard that enables evaluation of tumor necrosis due to treatment and evaluation of surviving tumors), PFS by independent central image judgment based on modified RECIST, and safety. In this test, 480 test subjects were randomly assigned 1:1 as shown below.

• “Renbima” (12 mg [when body weight is 60 kg or more at screening] or 8 mg [when body weight is less than 60 kg at screening], given orally once a day) + “Keytruda” (400 mg, intravenously every 6 weeks) +TACE (performed according to basic procedures for hepatic artery chemoembolization therapy) or
• Oral placebo (once a day) +placebo intravenous (every 6 weeks) +TACE

All study drugs were administered until discontinuation criteria set in the protocol were met. “Keytruda” was administered in combination with “Renvima,” and the longest period was 2 years (approximately 18 doses). After completing the 2-year combination therapy, “Renbima” could be administered as monotherapy until discontinuation criteria set in the protocol were met.

About hepatocellular carcinoma

　Liver cancer is one of the leading causes of cancer-related deaths worldwide1. In the United States, the incidence of liver cancer has more than tripled since 1980, and the death rate has doubled during that time 8. Incidence rates are expected to continue to rise in various regions around the world until 2040, including in countries with advanced healthcare systems3. The number of new cases of liver cancer is estimated to be more than 0.86 million5,000 people worldwide in 2022, and it is estimated that more than 0.75 million7,000 people died 1. In Japan, it is estimated that more than 0.04 million1,000 people were newly diagnosed in 2022, and approximately 0.02 million6,000 people died 9. In the United States, it is estimated that approximately 0.04 million2 thousand people will be newly diagnosed in 2024, and approximately 0.03 million people will die 10. According to SEER data from 2013 to 2019, the 5-year relative survival rate for liver cancer in the United States is 22% 11. Hepatocellular cancer is the most frequently occurring type of liver cancer, and is estimated to account for 90% of primary liver cancer12.

About “Renbima” (generic name: lenvatinib mesylate)

In addition to VEGFR1, VEGFR2, VEGFR3, which are vascular endothelial growth factor receptors (VEGFR), and FGFR4, fibroblast growth factor receptors (FGFR), “Renbima” has selective inhibitory activity against platelet-derived growth factor receptor (PDGFR) receptor type tyrosine kinases involved in tumor angiogenesis or tumor malignancy such as PDGFRα, KIT, RET, etc., and can be administered orally FGFR2 FGFR3 It is a multi-kinase inhibitor developed by Eisai.

In non-clinical research models, “Renbima” reduced the ratio of tumor-associated macrophages known as immunosuppressors in the cancer microenvironment and increased the ratio of activated cytotoxic T cells, and showed antitumor activity that surpassed both “Renbima” and anti-PD-1 monoclonal antibody monotherapy when used in combination with anti-PD-1 monoclonal antibodies. The adaptations obtained by “Renbima” are as follows.

thyroid cancer

・Indications for monotherapy (approved in Japan, the United States, Europe, China, Asia, etc.)

Japan: Unresectable Thyroid Cancer

United States: Locally Recurrent, Metastatic, or Progressive Radioiodine Treatment-Resistant Differentiated Thyroid Cancer

Europe: advanced or recurrent differentiated thyroid cancer (papillary cancer, follicular cancer, Hürtley cell cancer) resistant to radioactive iodine treatment in adults

hepatocellular carcinoma

・Indications for monotherapy (approved in Japan, the United States, Europe, China, Asia, etc.)

Japan: Unresectable Hepatocellular Carcinoma

United States: First-line Treatment for Unresectable Hepatocellular Carcinoma

Europe: first-line treatment for adult patients with advanced or unresectable hepatocellular carcinoma

thymic cancer

・Suitable for monotherapy (approved in Japan)

Japan: Unresectable Thymic Cancer

Renal cell cancer (sold under the product name “Kisplyx” in Europe)

・Indications for combination therapy with everolimus (approved in the US, Europe, Asia, etc.)

United States: advanced renal cell cancer in adults with previous treatment with 1-regimen angiogenesis inhibitors

Europe: advanced renal cell cancer in adults with a history of prior treatment with 1-regimen vascular endothelial growth factor (VEGF) targeting agents

・Indications for combination therapy with “Keytruda” (approved in Japan, the United States, Europe, Asia, etc.)

Japan: Unresectable or Metastatic Renal Cell Carcinoma

United States: First-line Treatment for Advanced Renal Cell Carcinoma in Adults

Europe: First-line Treatment for Advanced Renal Cell Carcinoma in Adults

endometrial cancer

・Indications for combination therapy with “Keytruda” (approved in Japan, the United States, Europe, Asia, etc.)

Japan: Unresectable progressive/recurrent endometrial cancer that worsened after cancer chemotherapy

United States of America: Progressive endometrial cancer that worsens after systemic therapy regardless of treatment line, does not have high-frequency instability-high (MSI-H) unsuitable for radical surgery or radiation therapy, or does not have mismatch repair deficits (dMMR)

Europe: advanced or recurrent endometrial cancer in adults unsuitable for radical surgery or radiation therapy that worsened during or after prior treatment involving platinum, regardless of treatment line

About “Keytruda” (generic name: pembrolizumab)

“Keytruda” is an anti-bacterial death receptor-1 (PD-1) antibody that boosts one's immunity and helps find and attack cancer cells. “Keytruda” is a humanized monoclonal antibody that inhibits the interaction between PD-1 and PD-L1 and PD-L2, which are its ligands, and activates T lymphocytes that attack cancer cells. Merck & Co., Inc., Rahway, NJ, USA is running the industry's largest cancer immunotherapy clinical research program, and is currently conducting more than 1,600 clinical trials of “keytruders,” and is considering a wide range of cancers and treatment settings. In the “Keytruda” clinical program, we are searching for factors that predict the role of “keytruda” in various cancers and the possibility of obtaining therapeutic effects from “keytruda,” and are also searching for various biomarkers.

About the strategic partnership between Eisai and Merck & Co., Inc., Rahway, NJ, USA

In 2018/3, Eisai and Merck & Co., Inc., Rahway, NJ, USA (MSD outside of the US and Canada) agreed on a strategic alliance to jointly develop and promote “Renbima” globally. Based on this agreement, the two companies will jointly develop, co-manufacture, and jointly promote “Renbima” in monotherapy and combination therapy with Merck & Co., Inc., Rahway, NJ, USA's anti-PD-1 antibody “Keytruda.”

Both companies are conducting multiple clinical trials of this combination therapy in various cancer types through the LEAP (LenvaTinib And Pembrolizumab) clinical program.

About Eisai's efforts in the cancer area

Eisai has the “cancer area” as one of the strategically important areas, and under the Deep Human Biology Learning drug discovery system, it is focusing on research and development of anticancer drugs in drug discovery areas (domains) such as “microenvironment,” “protein homeostasis failure,” “cell lineage and cell differentiation,” and “inflammation associated with cell aging, hypoxia, and oxidative stress,” based on human biology. We aim to contribute to the realization of cancer cure by creating innovative drugs with new targets and mechanisms of action from these domains.

About Eisai

Eisai Co., Ltd. puts the joys and sorrows of patients and consumers first, and has a corporate philosophy of “human health care (hhc),” which contributes to improving benefits, and based on this philosophy, it aims to efficiently realize the social good of “resolving health concerns” and “correcting medical care ranges.” We have a global R&D, production, and sales base network, and are working to create and provide innovative new drugs in disease areas with high unmet medical needs centered on the “neurological area” and “cancer area,” which are strategically important areas.

Furthermore, we are actively working with partners around the world on activities aimed at controlling “neglected tropical diseases (NTDs),” which is the target (3.3) of the United Nations Sustainable Development Goals (SDGs).

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Merck & Co., Inc., Rahway, NJ, USA's cancer initiatives

At Merck & Co., Inc., Rahway, NJ, USA, we work every day to discover innovative new drugs that can save patients at any stage of cancer, based on scientific knowledge. As a leading oncology company, we are pursuing research where scientific opportunities and medical needs are concentrated while being supported by a diverse pipeline of over 25 novel mechanisms. With one of the largest clinical development programs spanning over 30 cancer types, we are striving to advance revolutionary science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening, and treatment, we are working urgently to reduce disparities and help patients receive high-quality cancer care. Our unwavering commitment will bring us closer to realizing our goal of saving the lives of more cancer patients. Please refer to our website for details.

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

Merck & Co., Inc., Rahway, NJ, USA (MSD in countries and regions other than the US and Canada) are united under the purpose of saving lives and improving the lives of people around the world by making full use of cutting-edge science. For over 130 years, we have brought hope to humanity through the discovery of important medicines and vaccines. Aiming to be a world-class research and development biopharmaceutical company, we are working at the forefront of research and development to provide innovative healthcare solutions that contribute to the prevention and treatment of human and animal diseases. We continue to operate responsibly every day to foster a diverse and inclusive work environment and bring a safe, sustainable, and healthy future to people and communities around the world. For details, please refer to our website, Merck & Co., Inc., Rahway, NJ, USA's X (formerly Twitter), Facebook, Instagram, YouTube, and LinkedIn.

Statement on the future of Merck & Co., Inc., Rahway, NJ, USA

This news release contains “forward-looking statements” as defined by the disclaimer of the Private Securities Litigation Reform Act of 1995 (the Private Securities Litigation Reform Act of 1995) of the United States. These statements are based on the current beliefs and expectations of Merck & Co., Inc., Rahway, NJ, USA management, and include substantial risks and uncertainties. There is no guarantee of revenue from obtaining approval for a new drug pipeline or commercializing it. If predictions are not accurate or if risks or uncertainties materialize, actual results may differ from those described in future statements.

Risks and uncertainties include the general state of the industry and the competitive environment; general economic factors such as interest rate and exchange rate fluctuations; effects of pharmaceutical industry regulations and healthcare-related US and international laws; global trends in health care cost containment; issues specific to new drug development, such as technological advances, new product development and patent acquisition, and approval applications by competitors; and future market forecasts by Merck & Co., Inc., Rahway, NJ, USA There are, but are not limited to, accuracy, manufacturing issues or delays, financial instability such as international economic and government credit risk, etc., reliance on the effectiveness of Merck & Co., Inc., Rahway, NJ, USA patent rights and other protections for revolutionary products, and the possibility of being subject to patent lawsuits and regulatory actions.

Merck & Co., Inc., Rahway, NJ, USA is under no obligation to update future statements when new information, new events, or any other circumstances are added. These other factors, which may cause results that differ significantly from those described in future statements, can be confirmed in the 2023 Annual Report on Form 10-K relating to Merck & Co., Inc., Rahway, NJ, USA and other documents against the SEC available on the US Securities and Exchange Commission (SEC) internet site (www.sec.gov).

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