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)

Carcinoma, Hepatocellular Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03713593
• Other study ID #: 7902-002
• Secondary ID: MK-7902-002E7080
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 31, 2018
• Est. completion date: August 29, 2024

Study information

• Verified date: January 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 794
• Est. completion date: August 29, 2024
• Est. primary completion date: June 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular

Intervention

Drug:
• lenvatinib
Administered orally once a day

Biological:
• pembrolizumab
Administered as an IV infusion on Day 1 Q3W

Drug:
• saline placebo
Administered as an IV infusion on Day 1 Q3W

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital ( Site 0001)	Camperdown	New South Wales
Australia	Monash Health-Monash Medical Centre ( Site 0004)	Clayton	Victoria
Australia	St Vincents Hospital Melbourne ( Site 0003)	Fitzroy	Victoria
Australia	Liverpool Hospital. ( Site 0002)	Liverpool
Australia	Princess Alexandra Hospital ( Site 0007)	Wooloongabba	Queensland
Canada	London Health Sciences Centre ( Site 0053)	London	Ontario
Canada	McGill University Health Centre ( Site 0052)	Montreal	Quebec
Canada	Princess Margaret Cancer Centre ( Site 0050)	Toronto	Ontario
Canada	Sunnybrook Research Institute ( Site 0055)	Toronto	Ontario
Canada	BC Cancer-Vancouver Center ( Site 0056)	Vancouver	British Columbia
Chile	Fundacion Arturo Lopez Perez ( Site 0064)	Santiago	Region Metropolitana De Santiago
Chile	Pontificia Universidad Catolica de Chile ( Site 0070)	Santiago	Region Metropolitana De Santiago
Chile	Clinica Universidad Catolica del Maule ( Site 0065)	Talca	Region Del Maule
Chile	Instituto Clinico Oncologico del Sur ( Site 0067)	Temuco
China	Beijing Cancer Hospital ( Site 0088)	Beijing	Beijing
China	Cancer Hospital Chinese Academy of Medical Sciences ( Site 0100)	Beijing	Beijing
China	Hunan Cancer Hospital ( Site 0094)	Changsha	Hunan
China	The Third Xiangya Hospital of Central South University ( Site 0093)	Changsha	Hunan
China	West China Hospital of Sichuan University ( Site 0087)	Chengdu	Sichuan
China	900 Hospital of the Joint ( Site 0091)	Fuzhou	Fujian
China	Guangdong General Hospital ( Site 0092)	Guangzhou	Guangdong
China	Southern Medical University Nanfang Hospital ( Site 0102)	Guangzhou	Guangdong
China	Sir Run Run Shaw Hospital ( Site 0110)	Hangzhou	Zhejiang
China	The First Affiliated Hospital of Zhejiang University ( Site 0097)	Hangzhou	Zhejiang
China	Zhejiang Cancer Hospital ( Site 0101)	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital ( Site 0089)	Harbin	Heilongjiang
China	First Affiliated Hospital of Anhui Medical University ( Site 0095)	Hefei	Anhui
China	The 81st Hospital of PLA ( Site 0085)	Nanjing	Jiangsu
China	Fudan University Shanghai Cancer Center ( Site 0086)	Shanghai	Shanghai
China	Zhongshan Hospital Fudan University ( Site 0096)	Shanghai
China	Affiliated Tumor Hospital of Xinjiang Medical University ( Site 0109)	Urumqi	Xinjiang
China	Wuhan Union hospital Cancer Center ( Site 0105)	Wuhan	Hubei
China	The First Affiliated Hospital of Xi an Jiaotong University ( Site 0090)	XI An	Shanxi
Colombia	Biomelab S A S ( Site 0145)	Barranquilla	Atlantico
Colombia	Administradora Country SA - Clinica del Country ( Site 0146)	Bogota	Distrito Capital De Bogota
Colombia	Instituto Nacional de Cancerologia E.S.E ( Site 0142)	Bogota	Distrito Capital De Bogota
Colombia	Centro Medico Imbanaco de Cali S.A ( Site 0139)	Cali	Valle Del Cauca
Colombia	Fundacion Valle del Lili ( Site 0140)	Cali	Valle Del Cauca
Colombia	Fundacion Centro de Investigacion Clinica CIC ( Site 0141)	Medellin	Antioquia
Colombia	Hospital General de Medellin Luz Castro de Gutierrez ( Site 0137)	Medellin	Antioquia
Colombia	Hospital Pablo Tobon Uribe ( Site 0144)	Medellin	Antioquia
France	Institut Sainte Catherine ( Site 0167)	Avignon
France	Hopital Beaujon ( Site 0160)	Clichy
France	CHU Henri Mondor ( Site 0162)	Creteil
France	CHRU de Lille - Hopital Claude Huriez ( Site 0159)	Lille
France	Hopital de la Croix Rousse ( Site 0157)	Lyon
France	Hopital Saint Joseph ( Site 0166)	Marseille
France	Centre Hospitalier Regional du Orleans ( Site 0169)	Orleans
France	Centre Eugene Marquis ( Site 0158)	Rennes
France	CHU de Nancy Hopital Brabois Adultes ( Site 0164)	Vandoeuvre les Nancy
Germany	Klinikum der Universitaet Aachen - RWTH ( Site 0185)	Aachen
Germany	Universitaetsklinikum Carl Gustav Carus der TU Dresden ( Site 0178)	Dresden
Germany	Universitaetsklinikum Essen ( Site 0188)	Essen
Germany	Universitaetsklinikum Frankfurt ( Site 0180)	Frankfurt am Main
Germany	Universitaetsklinikum Hamburg-Eppendorf ( Site 0184)	Hamburg
Germany	Universitaetsklinik Koeln ( Site 0189)	Koeln
Germany	Universitaetsklinikum Leipzig ( Site 0187)	Leipzig
Germany	Otto-Von-Guericke-Universitaet Magdeburg ( Site 0182)	Magdeburg
Germany	Universitaetsklinikum Tuebingen ( Site 0179)	Tuebingen
Germany	Universitaetsklinikum Wuerzburg ( Site 0186)	Wuerzburg
Ireland	Mater Misericordiae University Hospital ( Site 0241)	Dublin
Ireland	St Vincents University Hospital ( Site 0242)	Dublin
Italy	Centro di Riferimento Oncologico de Aviano Istituto Nazionale Tumori ( Site 0292)	Aviano
Italy	Policlinico S. Orsola-Malpighi ( Site 0286)	Bologna
Italy	Ospedale Sacro Cuore - Don Calabria ( Site 0289)	Negrar	VR
Italy	Istituto Oncologico Veneto ( Site 0287)	Padova
Italy	Az Osp Univ Policlin Paolo Giaccone ( Site 0284)	Palermo
Italy	Fondazione Salvatore Maugeri IRCCS. ( Site 0290)	Pavia
Italy	Azienda Ospedaliero-Univers. Pisana Ospedale S. Chiara ( Site 0291)	Pisa
Italy	Policlinico Universitario Campus Biomedico ( Site 0288)	Roma
Japan	Chiba University Hospital ( Site 0305)	Chiba
Japan	National Hospital Organization Kyushu Medical Center ( Site 0321)	Fukuoka
Japan	Hiroshima University Hospital ( Site 0320)	Hiroshima
Japan	Kanazawa University Hospital ( Site 0315)	Kanazawa	Ishikawa
Japan	National Cancer Center Hospital East ( Site 0306)	Kashiwa	Chiba
Japan	Toranomon Hospital Kajigaya ( Site 0312)	Kawasaki	Kanagawa
Japan	Kagawa University Hospital ( Site 0324)	Kita-gun	Kagawa
Japan	Kurume University Hospital ( Site 0322)	Kurume	Fukuoka
Japan	Kyorin University Hospital ( Site 0309)	Mitaka	Tokyo
Japan	Musashino Red Cross Hospital ( Site 0310)	Musashino	Tokyo
Japan	Aichi Cancer Center Hospital ( Site 0316)	Nagoya	Aichi
Japan	Osaka Red Cross Hospital ( Site 0317)	Osaka
Japan	Kindai University Hospital ( Site 0319)	Osakasayama	Osaka
Japan	Saga-Ken Medical Centre Koseikan ( Site 0323)	Saga
Japan	Hokkaido P.W.F.A.C Sapporo-Kosei General Hospital ( Site 0304)	Sapporo	Hokkaido
Japan	Kagawa Prefectural Central Hospital ( Site 0325)	Takamatsu	Kagawa
Japan	National Cancer Center Hospital ( Site 0307)	Tokyo
Japan	The University of Tokyo Hospital ( Site 0308)	Tokyo
Japan	Toranomon Hospital ( Site 0311)	Tokyo
Japan	Wakayama Medical University Hospital ( Site 0318)	Wakayama
Japan	Kanagawa Cancer Center ( Site 0314)	Yokohama	Kanagawa
Japan	Yokohama City University Medical Center ( Site 0313)	Yokohama	Kanagawa
Korea, Republic of	Seoul National University Bundang Hospital ( Site 0464)	Seongnam-si	Kyonggi-do
Korea, Republic of	Asan Medical Center ( Site 0460)	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Samsung Medical Center ( Site 0461)	Seoul
Korea, Republic of	Seoul National University Hospital ( Site 0462)	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Yonsei University Severance Hospital ( Site 0463)	Seoul	Seoul-teukbyeolsi [Seoul]
Mexico	Centro de Investigacion Medica Aguascalientes ( Site 0355)	Aguascalientes
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran ( Site 0363)	Ciudad de Mexico	Cdmx
Mexico	Hospital Civil de Guadalajara Fray Antonio Alcalde ( Site 0365)	Guadalajara	Jalisco
Mexico	Medical Care and Research S.A. de C.V. ( Site 0359)	Merida
Mexico	CRYPTEX Investigacion Clinica S.A. de C.V. ( Site 0362)	Mexico City
Mexico	Oaxaca Site Management Organization S.C. ( Site 0366)	Oaxaca
Mexico	Unidad Medica Oncologica ( Site 0369)	Puebla
New Zealand	Auckland City Hospital ( Site 0376)	Auckland
New Zealand	Christchurch Hospital ( Site 0377)	Christchurch
Poland	Wojewodzki Szpital Specjalistyczny nr 4 w Bytomiu ( Site 0419)	Bytom	Slaskie
Poland	Szpital Wojewodzki w Koszalinie im. Mikolaja Kopernika ( Site 0421)	Koszalin	Zachodniopomorskie
Poland	ID Clinic ( Site 0431)	Myslowice
Poland	Ars Medical Sp. z o.o. ( Site 0433)	Pila
Poland	MTZ Clinical Research Sp. z o. o. ( Site 0427)	Warsaw
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie ( Site 0418)	Warszawa
Russian Federation	Krasnoyarsk Regional Clinical Oncological Dispensary ( Site 0450)	Krasnoyarsk
Russian Federation	First Moscow State Medical University n.a. I.M.Sechenov ( Site 0453)	Moscow	Moskva
Russian Federation	N.N. Blokhin NMRCO ( Site 0439)	Moscow	Moskva
Russian Federation	Pyatigorsk Oncology Dispensary ( Site 0441)	Pyatigorsk
Russian Federation	City Clinical Oncology Center ( Site 0446)	Saint Petersburg	Sankt-Peterburg
Russian Federation	Railway Hospital of OJSC ( Site 0447)	Saint Petersburg	Sankt-Peterburg
Spain	Hospital Universitari Vall d Hebron ( Site 0508)	Barcelona	Barcelona [Barcelona]
Spain	Hospital General Universitario Gregorio Maranon ( Site 0504)	Madrid
Spain	Hospital Universitario La Paz ( Site 0510)	Madrid
Spain	Hospital Universitario Ramon y Cajal ( Site 0514)	Madrid
Spain	Hospital Universitario Puerta de Hierro ( Site 0513)	Majadahonda	Madrid
Spain	Complejo Hospitalario Universitario de Santiago ( Site 0506)	Santiago de Compostela
Spain	Hospital Universitario Virgen del Rocio ( Site 0509)	Sevilla
Spain	Hospital Universitario y Politecnico La Fe de Valencia ( Site 0505)	Valencia
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital ( Site 0529)	Kaoshiung
Taiwan	China Medical University Hospital ( Site 0527)	Taichung
Taiwan	Taichung Veterans General Hospital ( Site 0526)	Taichung
Taiwan	National Cheng Kung University Hospital ( Site 0528)	Tainan
Taiwan	National Taiwan University Hospital ( Site 0523)	Taipei
Taiwan	Taipei Veterans General Hospital ( Site 0524)	Taipei
Taiwan	Chang Gung Medical Foundation. Linkou ( Site 0525)	Taoyuan
Thailand	Siriraj Hospital. Mahidol Univerisity ( Site 0213)	Bangkok Noi	Bangkok
Thailand	Chiang Mai University Maharaj Nakorn Chiang Mai Hospital ( Site 0211)	Chiang Mai
Thailand	Songklanagarind Hospital ( Site 0214)	HatYai	Songkhla
Turkey	Adana Sehir Hastanesi ( Site 0549)	Adana
Turkey	Abdurrahman Yurtaslan Onkoloji Hastanesi ( Site 0551)	Ankara
Turkey	Hacettepe Uni. Tip Fakultesi ( Site 0553)	Ankara
Turkey	Akdeniz Universitesi Tip Fakultesi ( Site 0548)	Antalya
Turkey	Trakya Universitesi Tip Fakultesi ( Site 0544)	Edirne
Turkey	Erzurum Ataturk University Faculty of Medicine ( Site 0546)	Erzurum
Turkey	Bezmi Alem Universitesi Tip Fakultesi ( Site 0547)	Istanbul
Turkey	Necmettin Erbakan Universitesi Meram Tip Fakultesi ( Site 0550)	Konya
Turkey	Inonu Universitesi Medical Fakultesi ( Site 0545)	Malatya
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust ( Site 0573)	Birkenhead
United Kingdom	The Beatson West of Scotland Cancer Centre ( Site 0566)	Glasgow
United Kingdom	Kings College Hospital NHS Foundation Trust ( Site 0565)	London	London, City Of
United Kingdom	Royal Free London NHS Foundation Trust ( Site 0567)	London	London, City Of
United Kingdom	The Christie NHS Foundation Trust ( Site 0575)	Manchester
United Kingdom	Nottingham University Hospitals NHS Trust ( Site 0569)	Nottingham
United States	Emory University Winship Cancer Institute ( Site 0639)	Atlanta	Georgia
United States	Beth Israel Deaconess Medical Center ( Site 0716)	Boston	Massachusetts
United States	Massachusetts General Hospital ( Site 0603)	Boston	Massachusetts
United States	City of Hope Comprehensive Cancer Center ( Site 0587)	Duarte	California
United States	Scripps Health ( Site 0644)	La Jolla	California
United States	University of Miami, Sylvester Comprehensive Cancer Center ( Site 0596)	Miami	Florida
United States	Icahn School of Medicine at Mount Sinai ( Site 0611)	New York	New York
United States	University of Oklahoma Health Science Center ( Site 0625)	Oklahoma City	Oklahoma
United States	Advent Health ( Site 0595)	Orlando	Florida
United States	Eastern Regional Medical Center, Inc. ( Site 0626)	Philadelphia	Pennsylvania
United States	Oregon Health & Science University ( Site 0645)	Portland	Oregon
United States	University of Rochester ( Site 0613)	Rochester	New York
United States	Pacific Hematology Oncology Associates ( Site 0588)	San Francisco	California
United States	UCLA ( Site 0589)	Santa Monica	California
United States	Cancer Care Northwest ( Site 0636)	Spokane	Washington
United States	Stony Brook University Medical Center - Cancer Center ( Site 0612)	Stony Brook	New York
United States	Tampa General Medical Group ( Site 0629)	Tampa	Florida
United States	Central Texas Veterans Healthcare System ( Site 0617)	Temple	Texas
United States	The University of Arizona Cancer Center - North Campus ( Site 0621)	Tucson	Arizona
United States	Georgetown University ( Site 0594)	Washington	District of Columbia
United States	University of Kansas Cancer Center ( Site 0600)	Westwood	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC	Eisai Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Chile,  China,  Colombia,  France,  Germany,  Ireland,  Italy,  Japan,  Korea, Republic of,  Mexico,  New Zealand,  Poland,  Russian Federation,  Spain,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

References & Publications (1)

Llovet JM, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, Xu R, Edeline J, Ryoo BY, Ren Z, Masi G, Kwiatkowski M, Lim HY, Kim JH, Breder V, Kumada H, Cheng AL, Galle PR, Kaneko S, Wang A, Mody K, Dutcus C, Dubrovsky L, Siegel AB, Finn RS; LEAP-002 Investigator — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Overall Survival (OS)	OS was defined as the time from randomization until death from any cause	Up to approximately 41 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Merck Clinical Trials Information