KENILWORTH, N.J., & WOODCLIFF LAKE, N.J.– September 17, 2019 — (BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced that the U.S. Food and Drug Administration (FDA) approved the combination of Keytruda, Merck’s anti-PD-1 therapy, plus Lenvima, the orally available kinase inhibitor discovered by Eisai, 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 and are not candidates for curative surgery or radiation. This marks the first U.S. approval for the combination of Keytruda plus Lenvima and the first time an anti-PD-1 therapy is approved in combination with a kinase inhibitor for advanced endometrial carcinoma in the U.S. Following submission on June 17, this is an accelerated approval reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to improve the efficiency of the review process for applications to ensure that treatments are available to patients as early as possible. This approval is based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. According to the FDA, this review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among its international partners. Under this project, the FDA, the Australian Therapeutic Goods Administration (TGA) and Health Canada collaboratively reviewed applications for two oncology drugs, allowing for simultaneous decisions in all three countries.
“When diagnosed early, endometrial carcinoma can have a good prognosis; however, for women whose cancer has progressed following prior systemic therapy, there are few FDA-approved treatment options,” said Dr. Vicky Makker, medical oncologist, Memorial Sloan Kettering Cancer Center. “Based on objective response rate and the duration of response, this approval of the Keytruda plus Lenvima combination will help address a significant unmet medical need for patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.”
Immune-mediated adverse reactions, which may be severe or fatal, can occur with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, Keytruda should be withheld or discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.
Adverse reactions, some of which can be serious or fatal, may occur with Lenvima, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, and wound healing complications. Based on the type and/or severity of the adverse reaction, Lenvima may be interrupted, reduced and/or discontinued. Based on its mechanism of action and data from animal reproduction studies, Lenvima can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. For more information, see “Selected Safety Information” below.
“Today’s approval of the Keytruda plus Lenvima combination for advanced endometrial carcinoma that has progressed following prior systemic therapy brings the first approved combination treatment to women with this type of cancer whose tumors are not MSI-H or dMMR and who are not candidates for curative surgery or radiation, and demonstrates the potential of our collaboration with Eisai,” said Dr. Jonathan Cheng, Vice President, Oncology Clinical Research, Merck Research Laboratories. “Merck is committed to developing this combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program, which is under active investigation.”
“At least 75% of endometrial cancer cases are not microsatellite instability-high or mismatch repair deficient, and these women have been in need of new treatment options,” said Dr. Takashi Owa, Vice President, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai. “We are excited for the advancement that today’s approval of the Keytruda plus Lenvima combination treatment represents for these women whose advanced endometrial carcinoma is not microsatellite instability-high or mismatch repair deficient, has progressed following prior systemic therapy and who are not candidates for curative surgery or radiation, and we look forward to the possibilities that our collaboration holds.”
Data Supporting the Approval
The approval was based on data from KEYNOTE-146/Study 111, a Phase 2, multi-cohort, multicenter, open-label, single-arm trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were treated with Keytruda 200 mg intravenously every three weeks in combination with Lenvima 20 mg orally once daily until unacceptable toxicity or disease progression as determined by the investigator.
Administration of Keytruda plus Lenvima was permitted beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Keytruda dosing was continued for a maximum of 24 months; however, treatment with Lenvima could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every six weeks until week 24, followed by every nine weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) by independent radiologic review committee (IRC) using RECIST 1.1.
Among the 108 patients, 87% (n=94) had tumors that were not MSI-H or dMMR, 10% (n=11) had tumors that were MSI-H or dMMR, and 3% (n=3) had tumors that had unknown status. The baseline characteristics of the 94 patients with tumors that were not MSI-H or dMMR were: median age of 66 years, with 62% age 65 or older; 86% White, 6% Black, 4% Asian, and 3% other races; and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 (52%) or 1 (48%). All 94 patients had received prior systemic therapy for endometrial carcinoma; 51% had one, 38% had two, and 11% had three or more prior systemic therapies.
In the 94 patients with tumors that were not MSI-H or dMMR, the Keytruda plus Lenvima combination demonstrated an ORR of 38.3% (95% CI, 29%-49%), with a complete response rate of 10.6% (n=10) and a partial response rate of 27.7% (n=26). The median follow-up time was 18.7 months. In the patients who had a response as determined by independent review (n=36), at the time of data cutoff, the median DOR was not reached (range: 1.2+ to 33.1+ months), and 69% of these patients experienced responses lasting six months or greater.
The median duration of study treatment was seven months (range: 0.03 to 37.8 months), and the median duration of exposure to Keytruda was six months (range: 0.03 to 23.8 months). Fatal adverse reactions occurred in 3% of patients treated with Keytruda plus Lenvima, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome (RPLS) with intraventricular hemorrhage, and intracranial hemorrhage. Serious adverse reactions occurred in 52% of patients receiving Keytruda plus Lenvima. The most common serious adverse reactions (≥3%) with the Keytruda plus Lenvima combination were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage, fatigue, nausea, confusional state, and pleural effusion (4% each), adrenal insufficiency, colitis, dyspnea, and pyrexia (3% each).
Keytruda was discontinued due to adverse reactions (Grade 1-4) in 19% of patients, regardless of action taken with Lenvima. The most common adverse reactions (≥2%) leading to discontinuation of Keytruda were adrenal insufficiency, colitis, pancreatitis, and muscular weakness (2% each). Permanent discontinuation due to adverse reactions (Grade 1-4) occurred in 21% of patients who received Keytruda plus Lenvima. The most common adverse reactions (≥2%) resulting in discontinuation of Lenvima were gastrointestinal perforation or fistula, muscular weakness, and pancreatitis (2% each).
Adverse reactions leading to interruption of Keytruda occurred in 49% of patients. The most common adverse reactions leading to interruption of Keytruda (≥2%) were fatigue (14%), diarrhea and decreased appetite (6% each), rash (5%), renal impairment, vomiting, increased lipase, and decreased weight (4% each), nausea, increased blood alkaline phosphatase, and skin ulcer (3% each), adrenal insufficiency, increased amylase, hypocalcemia, hypomagnesemia, hyponatremia, peripheral edema, musculoskeletal pain, pancreatitis, and syncope (2% each). Adverse reactions led to dose reduction or interruption in 88% of patients receiving Lenvima. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of Lenvima were fatigue (32%), hypertension (26%), diarrhea (18%), nausea, palmar-plantar erythrodysesthesia, and vomiting (13% each), decreased appetite (12%), musculoskeletal pain (11%), stomatitis (9%), abdominal pain, hemorrhages (7% each), renal impairment and decreased weight (6% each), rash, headache, increased lipase, and proteinuria (5% each).
The most common adverse reactions (≥20%) with the Keytruda plus Lenvima combination were fatigue, musculoskeletal pain, and hypertension (65% each), diarrhea (64%), decreased appetite (52%), hypothyroidism (51%), nausea (48%), stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal pain and headache (33% each), constipation (32%), urinary tract infection (31%), dysphonia (29%), hemorrhagic events (28%), hypomagnesemia (27%), palmar-plantar erythrodysesthesia syndrome (26%), dyspnea (24%), cough and rash (21% each).
Recommended Dosage for Endometrial Carcinoma
The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every three weeks in combination with Lenvima 20 mg orally once daily until disease progression, unacceptable toxicity, or for Keytruda, up to 24 months in patients without disease progression. Refer to the Lenvima prescribing information for recommended dosing information, as appropriate.
About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of Lenvima. Under the agreement, the companies will jointly develop, manufacture and commercialize Lenvima, both as monotherapy and in combination with Merck’s anti-PD-1 therapy Keytruda.
In addition to ongoing clinical studies evaluating the Keytruda plus Lenvima combination across several different tumor types, the companies will jointly initiate new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program, which will evaluate the combination to support 11 potential indications in six types of cancer. The LEAP clinical program also includes a new basket trial targeting six additional cancer types.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope 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 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 to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several 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.
For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Eisai is a leading global research and development-based pharmaceutical company headquartered in Japan, with approximately 10,000 employees worldwide. We define our corporate mission as “giving first thought to patients and their families and to increasing the benefits health care provides,” which we call our human health care (hhc) philosophy. We strive to realize our hhc philosophy by delivering innovative products in therapeutic areas with high unmet medical needs, including Oncology and Neurology. In the spirit of hhc, we take that commitment even further by applying our scientific expertise, clinical capabilities and patient insights to discover and develop innovative solutions that help address society’s toughest unmet needs, including neglected tropical diseases and the Sustainable Development Goals.
Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J. , USA
This news release of Merck & Co., Inc., Kenilworth, N.J., 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 and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. 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 and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care 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 of international economies and sovereign 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 be found in the company’s 2018 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (http://www.sec.gov).
Posted: September 2019
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