N.J. and NUTLEY, N.J. - Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai announced that the Phase 3 LEAP-002 trial investigating KEYTRUDA, Merck's anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, versus LENVIMA monotherapy did not meet its dual primary endpoints of overall survival (OS) and progression-free survival (PFS) as a first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). There were trends toward improvement in OS and PFS for patients who received KEYTRUDA plus LENVIMA versus LENVIMA monotherapy; however, these results did not meet statistical significance per the pre-specified statistical plan. The median OS of the LENVIMA monotherapy arm in LEAP-002 was longer than that observed in previously reported clinical trials evaluating LENVIMA monotherapy in uHCC. The safety profile of KEYTRUDA plus LENVIMA was consistent with previously reported data on the combination. Merck and Eisai plan to present these data at an upcoming medical conference.

'Our joint clinical development program for KEYTRUDA plus LENVIMA is designed to address unmet needs for some of the most challenging-to-treat types of cancer, like hepatocellular carcinoma,' said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories. 'We remain confident in the potential of this combination based on the body of evidence we've seen to date and will continue to investigate its role across multiple types of cancer.'

'Aiming for further improvement in the treatment of patients with unresectable HCC, we selected LENVIMA monotherapy, a standard of care option, as the control arm of the LEAP-002 trial,' said Corina Dutcus, M.D., Senior Vice President, Clinical Research, Oncology at Eisai Inc. 'While results evaluating the combination are not what we had hoped for, we will continue to contribute to the care of patients with unresectable HCC by applying valuable knowledge from the LEAP-002 trial.'

LENVIMA monotherapy is approved for the first-line treatment of patients with uHCC in the U.S., Europe, and China, and for patients with uHCC in Japan. The approval of LENVIMA was based on results of the Phase 3 REFLECT trial which evaluated the efficacy and safety of LENVIMA versus sorafenib for the first-line treatment of patients with uHCC.

In the U.S., KEYTRUDA plus LENVIMA is approved for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation and for adult patients with advanced renal cell carcinoma (RCC) in the first-line setting. In Europe, KEYTRUDA plus LENVIMA (marketed as KISPLYX for RCC in the EU) is approved for adult patients with advanced or recurrent endometrial carcinoma who have disease progression on or following prior treatment with a platinum containing therapy in any setting and are not candidates for curative surgery or radiation and for adults with advanced RCC in the first-line setting. The KEYTRUDA plus LENVIMA combination is also approved in Japan for patients with radically unresectable or metastatic RCC and patients with unresectable, advanced or recurrent endometrial carcinoma that progressed after cancer chemotherapy. Results from the LEAP-002 trial do not affect the current approved indications for the KEYTRUDA plus LENVIMA combination.

Merck and Eisai are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in more than 10 different tumor types (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, biliary tract cancer, colorectal cancer, gastric cancer, esophageal cancer, glioblastoma and pancreatic cancer) across more than 15 clinical trials.

About LEAP-002

LEAP-002 is a multicenter, randomized, double-blinded, active-controlled Phase 3 trial (ClinicalTrials.gov, NCT03713593) evaluating KEYTRUDA plus LENVIMA versus LENVIMA monotherapy for the first-line treatment of adult patients with uHCC. The dual primary endpoints are PFS, as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors Version (RECIST) v1.1 (RECIST v1.1 has been modified for this study to follow a maximum of 10 target lesions in total and a maximum of 5 target lesions per organ), and OS. The secondary endpoints include ORR, as assessed by BICR per RECIST v1.1, and DOR. The study enrolled 794 patients who were randomized 1:1 to receive:

KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle) plus LENVIMA (12 mg orally once daily [for patients with screening body weight of at least 60 kg] or 8 mg orally once daily [for patients with screening body weight less than 60 kg]); or

LENVIMA (12 mg orally once daily [for patients with screening body weight of at least 60 kg] or 8 mg orally once daily [for patients with screening body weight less than 60 kg]) plus saline placebo (IV administered on Day 1 of each three-week cycle).

LENVIMA was administered until progressive disease or unacceptable toxicity. KEYTRUDA /placebo was administered for up to 35 cycles (approximately two years).

About hepatocellular carcinoma (HCC)

Hepatocellular carcinoma is the most common type of primary liver cancer and the most rapidly increasing cause of cancer deaths in the United States. Hepatocellular carcinoma accounts for approximately 90% of primary liver cancers. It is estimated there were more than 905,000 new cases of liver cancer and more than 830,000 deaths from the disease globally in 2020, making it the sixth most frequently diagnosed cancer worldwide and one of the leading causes of cancer deaths around the world. In the United States, it is estimated there will be over 41,000 new cases of liver cancer and over 30,000 deaths from this disease in 2022. Risk factors for liver cancer include gender, ethnicity, chronic viral hepatitis (Hep-B or Hep-C) infection, cirrhosis, alcohol use and metabolic syndrome. Hepatocellular carcinoma, which is often diagnosed at an advanced stage, has a five-year survival rate of approximately 20% in the U.S.

About KEYTRUDA (pembrolizumab) injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing 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 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry's largest immuno-oncology clinical research program. There are currently more than 1,700 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand 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.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval 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 trials.

See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti-PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

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