Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Lenvatinib as First-line Therapy in Participants With Advanced Hepatocellular Carcinoma (MK-7902-002/E7080-G000-311/LEAP-002)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3745) versus lenvatinib in combination with placebo as first-line therapy for the treatment of advanced hepatocellular carcinoma in adult participants. The primary hypotheses of this study are that lenvatinib plus pembrolizumab is superior to lenvatinib plus placebo with respect to progression-free survival (PFS) and overall survival (OS).

Official Title
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A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Lenvatinib in First-line Therapy of Participants With Advanced Hepatocellular Carcinoma (LEAP-002)

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: lenvatinib
* Biological: pembrolizumab
* Drug: saline placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is male or female and ≥18 years of age at the time of signing the informed consent Has a diagnosis of hepatocellular carcinoma confirmed by radiology, histology, or cytology Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach Has a Child-Pugh class A liver score Has a predicted life expectancy of >3 months Has at least one measurable hepatocellular carcinoma (HCC) lesion based on RECIST 1.1 as confirmed by BICR Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1 Participants with hepatitis B will be eligible as long as their virus is well controlled Exclusion Criteria: Has had esophageal or gastric variceal bleeding within the last 6 months Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib Has a preexisting Grade ≥3 gastrointestinal or non-gastrointestinal fistula Has clinically significant hemoptysis from any source or tumor bleeding within 2 weeks prior to the first dose of study intervention Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability Has had major surgery to the liver within 4 weeks prior to the first dose of study intervention Has had a minor surgery (ie, simple excision) within 7 days prior to the first dose of study intervention Has serious non-healing wound, ulcer, or bone fracture Has received any systemic chemotherapy for HCC or chemotherapy for any malignancy in the past 3 years Has received prior therapy with an anti-programmed cell death 1 (ant-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti- programmed cell death ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, or CD137) Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exceptions of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that has undergone potentially curative therapy Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by local site investigator Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of their excipients Has an active autoimmune disease that has required systemic treatment in past 2 years Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis Has urine protein ≥1 grams/24 hours Prolongation of corrected QT (QTc) interval to >480 milliseconds (corrected by Fridericia Formula) Has left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO) Has an active infection requiring systemic therapy with the exceptions of hepatitis B virus (HBV) or hepatitis C virus (HCV) Has a known history of human immunodeficiency virus (HIV) infection Has known active tuberculosis (Bacillus tuberculosis) Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention Has had an allogenic tissue/solid organ transplant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lenvatinib plus pembrolizumab<br>Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity. | Drug: lenvatinib<br>* Administered orally once a day<br>* Other names: LENVIMA®;Biological: pembrolizumab<br>* Administered as an IV infusion on Day 1 Q3W<br>* Other names: KEYTRUDA®;|
| Active Comparator: lenvatinib plus placebo<br>Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity. | Drug: lenvatinib<br>* Administered orally once a day<br>* Other names: LENVIMA®;Drug: saline placebo<br>* Administered as an IV infusion on Day 1 Q3W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | PFS was defined as the time from the date of the first documentation of disease progression, as determined by blinded independent central review (BICR) per RECIST 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method. | Up to approximately 41 months | 
| Overall Survival (OS) | OS was defined as the time from randomization until death from any cause | Up to approximately 41 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | ORR was defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. | Up to approximately 41 months | 
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | DOR was determined by disease assessment and is defined as the time from the first documented evidence of a response of CR or PR, per RECIST 1.1 as assessed by BICR, until the first documented disease progression or death due to any cause, whichever occurred first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. | Up to approximately 41 months | 
| Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | DCR was defined as the percentage of participants who have a best overall response of CR, PR, or stable disease (SD) per RECIST 1.1 as assessed by BICR. SD must be achieved at ≥6 weeks after randomization to be considered best overall response. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. | Up to approximately 41 months | 
| Time to Disease Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | TTP was defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by BICR. RECIST 1.1 was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed. | Up to approximately 41 months | 
| Progression-free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | PFS was defined as the time from the first dose of study intervention to the first documented progressive disease (PD) per mRECIST by BICR or death due to any cause, whichever occurred first. mRECIST for HCC allowed evaluation of treatment effects that were not reflected in simple total size changes of lesions. Per mRECIST, PD was defined as an increase of at least 20% in the sum of diameters (SODs) of viable (enhancing) target lesions, taking as reference the smallest SODs of viable (enhancing) target lesions recorded since the treatment started. | Up to approximately 41 months | 
| Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | ORR wass defined as the percentage of participants who have a confirmed complete response (CR: disappearance of any intratumoral arterial enhancement in all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of viable [enhancement in the arterial phase] target lesions, taking as reference the baseline sum of the diameters of target lesions) per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed. | Up to approximately 41 months | 
| Duration of Response (DOR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | DOR was determined by disease assessment and is defined as the time from the first documented evidence of a response of CR or PR, per mRECIST as assessed by BICR, until the first documented disease progression or death due to any cause, whichever occurs first. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed. | Up to approximately 41 months | 
| Disease Control Rate (DCR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | DCR was defined as the percentage of participants who have a best overall response of CR, PR, or SD per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. SD must be achieved at ≥6 weeks after randomization to be considered best overall response. A maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed. | Up to approximately 41 months | 
| Time to Disease Progression (TTP) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | TTP was defined as the time from randomization to the first documented disease progression per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed. | Up to approximately 41 months | 
| Number of Participants Who Experienced an Adverse Event (AE) | Number of participants who experienced an AE defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study treatment | Up to approximately 41 months | 
| Number of Participants Who Experienced an Serious Adverse Event (SAE) | Number of participants who experienced a SAE defined as an AE that resulted in death, was life threatening, resulting in persistent or significant disability or incapacity, resulting in or prolonged a hospitalization, was a congenital anomaly or birth defect, was a cancer, was associated with an overdose, or was another important medical event | Up to approximately 41 months | 
| Number of Participants Who Experienced an Immune-related Adverse Event (irAE) of Clinical Interest | Number of participants who experienced an AE representing an immunologic etiology and considered to be causally related to drug exposure | Up to approximately 41 months | 
| Number of Participants Who Experienced an Hepatic Event of Clinical Interest (HECI) | Number of participants who experienced a hepatic ECI not due to disease progression as judged by the investigator. | Up to approximately 41 months | 
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | Number of participants who discontinued study treatment due to an AE | Up to approximately 41 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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receptor tyrosine kinase inhibitor, programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1), programmed cell death ligand 2 (PD-L2, PDL2)