EU Commission Approves Lenvima and Keytruda Combination for Advanced or Recurrent Endometrial Cancer

TOKYO and KENILWORTH, N.J., Dec. 7, 2021 /PRNewswire/ --November 29, 2021，Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, hereinafter referred to as "Eisai") and MSD recently announced that the European Commission has approved the combination of Lenvima (an orally administered multi-target tyrosine kinase receptor inhibitor developed by Eisai) and Keytruda (an anti-PD-1 therapy from MSD) for the treatment of adult patients with advanced or recurrent endometrial cancer who have experienced disease progression during or after platinum-based chemotherapy in any setting and are not candidates for curative surgery or radiation therapy. This marks the first approval in Europe of a tyrosine kinase inhibitor combined with immunotherapy for the treatment of these patients with advanced or recurrent endometrial cancer.

This approval is based on the results of the pivotal Phase III 309 study/KEYNOTE-775 trial, in which the combination of Lenvima and Keytruda demonstrated statistically significant improvements across the following efficacy endpoints compared to investigator’s choice chemotherapy (doxorubicin or paclitaxel): a 38% reduction in the risk of death in terms of overall survival (OS) (HR=0.62 [95% CI, 0.51-0.75]; p<0.0001); and a 44% reduction in the risk of disease progression or death in terms of progression-free survival (PFS) (HR=0.56 [95% CI, 0.47-0.66]; p<0.0001). The median OS was 18.3 months for the Lenvima and Keytruda combination group versus 11.4 months for the chemotherapy group. The median PFS was 7.2 months for the Lenvima and Keytruda combination group versus 3.8 months for the chemotherapy group. The objective response rate (ORR) was 32% (95% CI, 27-37) for patients receiving the Lenvima and Keytruda combination versus 15% (95% CI, 11-18) for those receiving chemotherapy (p<0.0001). Among patients receiving the Lenvima and Keytruda combination, the complete response (CR) rate was 7%, and the partial response (PR) rate was 25%, while for those receiving chemotherapy, the CR rate was 3% and the PR rate was 12%.

MSD Research Laboratories Vice President of Clinical Research, Dr. Gregory Lubiniecki, stated: "This approval is welcome news for patients in Europe. It is based on the first Phase III study evaluating the combination of immunotherapy and tyrosine kinase inhibitors, which showed that this combination therapy is superior to chemotherapy in terms of overall survival for patients with advanced or recurrent endometrial cancer. Regardless of mismatch repair status, patients whose endometrial cancer has progressed or recurred after prior platinum-based systemic chemotherapy can now opt for the combination of Lenvima and Keytruda. Compared to chemotherapy alone, this combination reduces the risk of death by 38%."

Dr. Corina Dutcus, Vice President of Clinical Research for Eisai's Oncology Business, stated: "Until recently, women in Europe with advanced or recurrent endometrial cancer faced a difficult prognosis and had very few treatment options. In this context, the approval of the combination therapy Lenvima and Keytruda reflects the progress we, in collaboration with MSD, have made in developing solutions for patients with refractory cancers. We are extremely grateful to the patients, their families, and healthcare professionals who made this milestone possible."

In the 309 study, the most common adverse reactions (≥20%) to the combination of Lenvima and Keytruda* were hypertension (63%), diarrhea (57%), hypothyroidism (56%), nausea (51%), decreased appetite (47%), vomiting (39%), fatigue (38%), weight loss (35%), arthralgia (33%), proteinuria (29%), constipation (27%), headache (27%), urinary tract infection (27%), dysphonia (25%), abdominal pain (23%), asthenia (23%), palmar-plantar erythrodysesthesia syndrome (23%), stomatitis (23%), anemia (22%), and hypomagnesemia (20%).

This approval allows the combination of Lenvima and Keytruda to be marketed in all 27 EU member states as well as Iceland, Liechtenstein, Norway, and Northern Ireland. The European Commission has currently approved the use of Lenvima and Keytruda in combination for two different types of cancer: adult patients with advanced or recurrent endometrial carcinoma who have experienced disease progression during or after prior platinum-based chemotherapy and are not candidates for radical surgery or radiation therapy, and adult patients with advanced renal cell carcinoma as a first-line treatment.

*According to the information listed in the Summary of Product Characteristics (SmPC)

About309Research/KEYNOTE-775Test

This approval is based on Study 309/KEYNOTE-775 (ClinicalTrials.gov,NCT03517449) data, the study was a multicenter, open-label, randomized, active-controlled Phase III trial conducted in 827 patients with advanced endometrial cancer who had received a platinum-based chemotherapy regimen under any circumstances (including both first-line and subsequent treatments). If a platinum-based chemotherapy was used in first-line or subsequent treatment, participants could receive up to two platinum-based chemotherapy regimens. The study excluded patients with endometrial sarcoma, carcinosarcoma, pre-existing ≥ Grade 3 fistula, uncontrolled blood pressure (BP >150/90 mmHg), significant cardiovascular damage or events within the past 12 months, or those with active autoimmune diseases or conditions requiring immunosuppression. The primary efficacy endpoints assessed by the Blinded Independent Central Review Committee (BICR) based on RECIST v1.1 were OS and PFS. The secondary efficacy endpoint evaluated by BICR was ORR.

Patients were randomly assigned in a 1:1 ratio to receive either Lenvima (20 mg, orally, once daily) and Keytruda (200 mg, intravenously, once every three weeks) combination therapy or investigator’s choice of treatment, including doxorubicin (60 mg/m², once every three weeks) or paclitaxel (80 mg/m², once weekly, for 3 weeks on/1 week off). The combination of Lenvima and Keytruda was continued until disease progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (confirmed by BICR), unacceptable toxicity, or until Keytruda had been administered for a maximum of 24 months. If the treating investigator determined that a patient could achieve clinical benefit and tolerate the treatment, continuation of Lenvima and Keytruda beyond RECIST-defined disease progression was allowed. Among the 411 patients who received the combination of Lenvima and Keytruda, a total of 121 patients (29%) continued to receive study treatment after RECIST-defined disease progression. The median duration of post-progression treatment was 2.8 months. Tumor status assessments were performed every 8 weeks.

About Endometrial Cancer^1,2,3,4,5

Endometrial cancer occurs in the inner layer of the uterus (i.e., the endometrium) and is the most common type of uterine cancer. It is estimated that there were over 417,000 new cases globally in 2020, with more than 97,000 deaths from uterine corpus cancer (the aforementioned estimates include endometrial cancer and uterine sarcoma; over 90% of uterine corpus cancers occur in the endometrium, so the actual number of endometrial cancer cases and deaths is slightly lower than this estimate). In Japan, there were over 17,000 new cases of uterine corpus cancer in 2020, with more than 3,000 deaths from the disease. It is estimated that there were over 130,000 new cases of uterine corpus cancer in Europe in 2020, with more than 29,000 deaths. The estimated five-year relative survival rate for metastatic endometrial cancer (Stage IV) is about 17%.

About Lenvima^®(Lenvatinib) Capsules

Lenvima, an orally administered multiple kinase inhibitor discovered by Eisai, inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). In addition to normal cellular functions, Lenvima also inhibits other kinases involved in pathogenic angiogenesis, tumor growth, and cancer progression, including fibroblast growth factor (FGF) receptors FGFR1-4, platelet-derived growth factor receptor α (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, the combination of Lenvima and an anti-PD-1 monoclonal antibody demonstrated a reduction in tumor-associated macrophages, an increase in activated cytotoxic T cells, and enhanced antitumor activity compared to either drug used alone.

Currently, Lenvima has been approved in more than 75 countries (including Japan, China, Europe, and parts of Asia) for monotherapy in thyroid cancer. In the United States, it is approved for monotherapy in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. Additionally, Lenvima has been approved in Japan, Europe, China, and over 70 other countries for monotherapy in unresectable hepatocellular carcinoma, and in the U.S., it is approved as a first-line treatment for unresectable hepatocellular carcinoma. Lenvima has also been approved in Japan for monotherapy in unresectable thymic cancer. In more than 60 countries (including Europe and Asia), the combination of Lenvima and everolimus has been approved for the treatment of renal cell carcinoma after prior anti-angiogenic therapy. In the United States, this combination is approved for adult patients with advanced renal cell carcinoma who have received one prior anti-angiogenic therapy. In Europe, Lenvima is marketed under the trade name Kisplyx.^®Marketed for the treatment of renal cell carcinoma. In the United States and Europe, Lenvima has been approved in combination with Keytruda (generic name: pembrolizumab) for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). In the U.S., Lenvima has been approved in combination with Keytruda 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 in any setting and are not candidates for curative surgery or radiation. In Canada, Australia, and more than 10 other countries, this combination therapy has been approved for similar indications (including conditional approvals). In some regions, further approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trials. In Europe, Lenvima has been approved in combination with Keytruda (generic name: pembrolizumab) for the treatment of adult patients with advanced or recurrent endometrial carcinoma who have disease progression during or after prior platinum-based chemotherapy and are not candidates for curative surgery or radiation.

About Keytruda^®(Pembrolizumab) Injection,100 mg

Keytruda is an anti-programmed death receptor-1 (PD-1) therapeutic drug that works by enhancing the ability of the human immune system to monitor and combat 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.

MSD is currently conducting the largest immuno-oncology clinical research program in the industry. There are currently more than 1,600 trials investigating Keytruda across various cancers and treatment settings. The Keytruda clinical program aims to understand the role of Keytruda in cancer and the factors that may predict which patients are likely to benefit from Keytruda treatment, including the exploration of several different biomarkers.

About Eisai andMSDStrategic Cooperation

In March 2018, Eisai and MSD, through an affiliate, entered into a strategic collaboration for the global co-development and co-commercialization of Lenvima. Under the agreement, the two companies will jointly develop, manufacture, and commercialize Lenvima, both as a monotherapy and in combination with Keytruda (MSD's anti-PD-1 therapy).

In addition to ongoing evaluations of the combination of Lenvima and Keytruda in several different tumor types, the two companies have also jointly initiated new clinical studies through the LEAP (Lenvatinib and Pembrolizumab Combination) clinical program, and are evaluating the efficacy of this combination in more than 10 different tumor types across over 20 clinical trials.

Eisai Focuses on Cancer Treatment

Eisai focuses on the research and development of anti-cancer drugs, dedicating efforts to fields such as the tumor microenvironment (gaining extensive experience and knowledge from its existing self-developed compounds) and factors driving gene mutations and abnormal splicing (utilizing the RNA splicing platform).Ricchi), in these fields, the needs of many patients remain unmet. Eisai aims to become a leader in the field of oncology. Eisai hopes to address theseRicchiInnovative drugs with new targets, new mechanisms of action, and the potential to cure cancer have been discovered.

About Eisai

Eisai is a leading global research and development pharmaceutical company headquartered in Japan, with approximately 10,000 employees worldwide. Eisai defines its corporate mission as "placing the interests of patients and their families first and contributing to the enhancement of their well-being," a mission the company refers to asCaring for Human Health (hhc）Concept. Eisai is committed to providing innovative products in therapeutic areas with highly unmet medical needs, such as oncology and neurology, striving to realize the company'shhcConcept. In line withhhcIn the spirit of this commitment, Eisai will further fulfill this promise by utilizing its scientific expertise, clinical capabilities, and understanding of patients to discover and develop innovative solutions to help address society's most challenging unmet needs, including neglected tropical diseases and sustainable development goals.

For more information about Eisai, please visitwww.eisai.com(Global Headquarters: Eisai Co., Ltd.),us.eisai.com (U.S. Headquarters: Eisai, Inc.) orwww.eisai.eu (Headquarters for Europe, Middle East, Africa, Russia, Australia and New Zealand: Eisai Europe Ltd.), and through Twitter (United StatesAndGlobal) and LinkedIn (United StatesAndEMEA) Contact our company.

MSDFocus on Cancer Treatment

MSD's goal is to transform breakthrough science into innovative oncology drugs to help cancer patients worldwide. At MSD, the potential to bring new hope to cancer patients drives the company's mission, and ensuring the accessibility of cancer drugs is the company’s commitment. As part of its focus on cancer treatment, MSD is dedicated to exploring the potential of immuno-oncology, one of the largest development programs in the industry, covering more than 30 types of cancer. The company will also continue to strengthen its portfolio through strategic acquisitions and prioritize the development of several promising oncology drug candidates that have the potential to improve treatment for advanced cancers. For more information about the company’s oncology clinical trials, please visitwww.merck.com/clinicaltrials。

AboutMSD

For over 130 years, MSD has been committed to inventing medicines to prolong life, providing drugs and vaccines for some of the world’s most challenging diseases in fulfillment of its mission to save lives and improve quality of life. The company demonstrates its commitment to patient and population health by expanding access to healthcare through far-reaching policies, programs, and partnerships. Today, MSD remains at the forefront of research in preventing and treating diseases that threaten humans and animals, including cancer, HIV, Ebola, and other infectious diseases as well as emerging animal diseases, striving to be a global leader as a research-intensive biopharmaceutical company. For more information, please visitwww.merck.com, and throughTwitter、Facebook、Instagram、YouTubeAndLinkedInContact our company.

MSDForward-Looking Statements

MSD's press release contains "forward-looking statements" made under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. For pipeline products, there can be no guarantee that the products will receive the necessary regulatory approvals or prove commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties arise, 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 and competition; general economic factors, including fluctuations in interest rates and currency exchange rates; the impact of the globally outbreak of Coronavirus Disease 2019 (COVID-19); the effects of U.S. and international pharmaceutical industry regulation and healthcare legislation; global trends toward healthcare cost containment; technological advances, new products 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 and sovereign risks in international economies; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the risk of litigation, including patent litigation and/or regulatory actions.

The company has no obligation to publicly update any forward-looking statements, regardless of whether such updates are based on new information, future events, or any other reasons. Other factors that may cause results to differ materially from those stated in the forward-looking statements can be found in the company’s 2020 Annual Report on Form 10-K and other filings submitted to the Securities and Exchange Commission (SEC), which are accessible on the SEC's website (www.sec.gov) Consult these materials.

¹American Cancer Society, "Causes, Risk, Prevention," Endometrial Cancer.
https://www.cancer.org/content/dam/CRC/PDF/Public/8610.00.pdf.

²International Agency for Research on Cancer, World Health Organization, "Briefing on Cancer of the Corpus Uteri," Cancer Today, 2020.
https://gco.iarc.fr/today/data/factsheets/cancers/24-Corpus-uteri-fact-sheet.pdf.

³International Agency for Research on Cancer, World Health Organization, "Japan Briefing", Cancer Today, 2020.
https://gco.iarc.fr/today/data/factsheets/populations/392-japan-fact-sheets.pdf.

⁴American Cancer Society, "Relevant and Key Statistics," Endometrial Cancer.
https://www.cancer.org/content/dam/CRC/PDF/Public/8609.00.pdf.

⁵American Cancer Society, "Detection, Diagnosis, Staging," Endometrial Cancer.
https://www.cancer.org/content/dam/CRC/PDF/Public/8610.00.pdf.