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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)

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ClinicalTrials.gov Identifier: NCT03713593
Recruitment Status : Active, not recruiting
First Posted : October 22, 2018
Results First Posted : July 24, 2023
Last Update Posted : January 10, 2024
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Carcinoma, Hepatocellular
Interventions Drug: lenvatinib
Biological: pembrolizumab
Drug: saline placebo
Enrollment 794
Recruitment Details Participants with a radiologically, histologically- or cytologically-confirmed diagnosis of hepatocellular carcinoma (HCC) were recruited into this study.
Pre-assignment Details  
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity. Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Period Title: Overall Study
Started 395 399
Completed 0 0
Not Completed 395 399
Reason Not Completed
Participants Ongoing             140             114
Withdrawal by Subject             3             6
Death             252             279
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo Total
Hide Arm/Group Description Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity. Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 395 399 794
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 395 participants 399 participants 794 participants
64.2  (10.9) 64.1  (12.1) 64.1  (11.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 395 participants 399 participants 794 participants
Female
78
  19.7%
72
  18.0%
150
  18.9%
Male
317
  80.3%
327
  82.0%
644
  81.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 395 participants 399 participants 794 participants
Hispanic or Latino
48
  12.2%
41
  10.3%
89
  11.2%
Not Hispanic or Latino
334
  84.6%
349
  87.5%
683
  86.0%
Unknown or Not Reported
13
   3.3%
9
   2.3%
22
   2.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 395 participants 399 participants 794 participants
American Indian or Alaska Native
13
   3.3%
8
   2.0%
21
   2.6%
Asian
172
  43.5%
173
  43.4%
345
  43.5%
Native Hawaiian or Other Pacific Islander
2
   0.5%
0
   0.0%
2
   0.3%
Black or African American
5
   1.3%
8
   2.0%
13
   1.6%
White
173
  43.8%
172
  43.1%
345
  43.5%
More than one race
12
   3.0%
10
   2.5%
22
   2.8%
Unknown or Not Reported
18
   4.6%
28
   7.0%
46
   5.8%
Eastern Cooperative Oncology Group (ECOG) Performance Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 395 participants 399 participants 794 participants
ECOG = 0
267
  67.6%
271
  67.9%
538
  67.8%
ECOG = 1
127
  32.2%
126
  31.6%
253
  31.9%
ECOG = 2
1
   0.3%
0
   0.0%
1
   0.1%
Missing
0
   0.0%
2
   0.5%
2
   0.3%
[1]
Measure Description: Randomization of participants in the study was stratified by an ECOG Performance Status of 0 (Fully active, able to carry on all pre-disease performance without restriction) or 1 (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature) or 2 (Ambulatory but unable to work). The number of participants with missing ECOG performance status is indicated for each treatment arm.
Geographic Region   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 395 participants 399 participants 794 participants
Asia without Japan
121
  30.6%
123
  30.8%
244
  30.7%
Japan and Western regions
274
  69.4%
276
  69.2%
550
  69.3%
[1]
Measure Description: Randomization of participants in this study was stratified by geographic region of the enrolling site (Asia without Japan versus Japan and Western regions).
1.Primary Outcome
Title Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Median (95% Confidence Interval)
Unit of Measure: Months
8.2
(6.3 to 8.3)
8.1
(6.3 to 8.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lenvatinib + Pembrolizumab, Lenvatinib + Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments Descriptive assessment
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.834
Confidence Interval (2-Sided) 95%
0.712 to 0.978
Estimation Comments Based on Cox model with Efron's method of tie handling with treatment as a covariate stratified by geographic region, MPVI or extrahepatic spread or both, AFP and ECOG PS.
2.Primary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from randomization until death from any cause
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Median (95% Confidence Interval)
Unit of Measure: Months
21.2
(19.0 to 23.6)
19.0
(17.2 to 21.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lenvatinib + Pembrolizumab, Lenvatinib + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0227
Comments [Not Specified]
Method Log Rank
Comments Onesided p-value based on logrank test stratified by geographic region, portal vein invasion/extrahepatic spread/both AFP status,ECOG status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.840
Confidence Interval (2-Sided) 95%
0.708 to 0.997
Estimation Comments Based on Cox model with Efron's method of tie handling with treatment as a covariate stratified by geographic region, MPVI or extrahepatic spread or both, AFP and ECOG PS.
3.Secondary Outcome
Title Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
26.1
(21.8 to 30.7)
17.5
(13.9 to 21.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lenvatinib + Pembrolizumab, Lenvatinib + Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments Descriptive assessment
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 8.5
Confidence Interval (2-Sided) 95%
2.8 to 14.2
Estimation Comments Based on Miettinen & Nurminen method stratified by geographic region, MPVI or extrahepatic spread or both, AFP and ECOG PS.
4.Secondary Outcome
Title Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed based on the population of responders (participants that achieved complete or partial response).
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 103 70
Median (Full Range)
Unit of Measure: Months
4.1
(1.3 to 25.3)
4.0
(0.3 to 18.6)
5.Secondary Outcome
Title Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
81.3
(77.1 to 85.0)
78.4
(74.1 to 82.4)
6.Secondary Outcome
Title Time to Disease Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Median (95% Confidence Interval)
Unit of Measure: Months
8.3
(8.1 to 10.3)
8.2
(7.0 to 8.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lenvatinib + Pembrolizumab, Lenvatinib + Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments Descriptive assessment
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.66 to 0.93
Estimation Comments Based on Cox model with Efron's method of tie handling with treatment as a covariate stratified by geographic region, MPVI or extrahepatic spread or both, AFP and ECOG PS.
7.Secondary Outcome
Title Progression-free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Median (95% Confidence Interval)
Unit of Measure: Months
8.4
(8.2 to 10.2)
8.1
(6.5 to 8.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lenvatinib + Pembrolizumab, Lenvatinib + Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments Descriptive assessment
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.68 to 0.94
Estimation Comments Based on Cox model with Efron's method of tie handling with treatment as a covariate stratified by geographic region, MPVI or extrahepatic spread or both, AFP and ECOG PS.
8.Secondary Outcome
Title Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
40.8
(35.9 to 45.8)
34.1
(29.4 to 39.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lenvatinib + Pembrolizumab, Lenvatinib + Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments Descriptive assessment
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 6.7
Confidence Interval (2-Sided) 95%
0.0 to 13.4
Estimation Comments Based on Miettinen & Nurminen method stratified by geographic region, MPVI or extrahepatic spread or both, AFP and ECOG PS.
9.Secondary Outcome
Title Duration of Response (DOR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants who received at least 1 dose of study treatment. Participants were analyzed based on the population of responders (participants that achieved complete or partial response).
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 151 136
Median (Full Range)
Unit of Measure: Months
2.1
(1.2 to 16.6)
2.1
(0.2 to 14.5)
10.Secondary Outcome
Title Disease Control Rate (DCR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
84.3
(80.3 to 87.7)
83.2
(79.2 to 86.7)
11.Secondary Outcome
Title Time to Disease Progression (TTP) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
Hide Description 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.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 399
Median (95% Confidence Interval)
Unit of Measure: Months
10.4
(8.5 to 11.7)
8.3
(8.1 to 8.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lenvatinib + Pembrolizumab, Lenvatinib + Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments Descriptive assessment
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 95%
0.61 to 0.88
Estimation Comments BBased on Cox model with Efron's method of tie handling with treatment as a covariate stratified by geographic region, MPVI or extrahepatic spread or both, AFP and ECOG PS.
12.Secondary Outcome
Title Number of Participants Who Experienced an Adverse Event (AE)
Hide Description 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
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants who received at least 1 dose of study intervention.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 395
Measure Type: Count of Participants
Unit of Measure: Participants
394
  99.7%
392
  99.2%
13.Secondary Outcome
Title Number of Participants Who Experienced an Serious Adverse Event (SAE)
Hide Description 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
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants who received at least 1 dose of study intervention.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 395
Measure Type: Count of Participants
Unit of Measure: Participants
181
  45.8%
154
  39.0%
14.Secondary Outcome
Title Number of Participants Who Experienced an Immune-related Adverse Event (irAE) of Clinical Interest
Hide Description Number of participants who experienced an AE representing an immunologic etiology and considered to be causally related to drug exposure
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants who received at least 1 dose of study intervention.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 395
Measure Type: Count of Participants
Unit of Measure: Participants
208
  52.7%
180
  45.6%
15.Secondary Outcome
Title Number of Participants Who Experienced an Hepatic Event of Clinical Interest (HECI)
Hide Description Number of participants who experienced a hepatic ECI not due to disease progression as judged by the investigator.
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 395
Measure Type: Count of Participants
Unit of Measure: Participants
71
  18.0%
77
  19.5%
16.Secondary Outcome
Title Number of Participants Who Discontinued Study Drug Due to an Adverse Event
Hide Description Number of participants who discontinued study treatment due to an AE
Time Frame Up to approximately 41 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all randomized participants who received at least 1 dose of study intervention.
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description:
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
Overall Number of Participants Analyzed 395 395
Measure Type: Count of Participants
Unit of Measure: Participants
113
  28.6%
71
  18.0%
Time Frame For AEs: Up to ~41 months. All-cause mortality (ACM): Up to ~41 months.
Adverse Event Reporting Description All-cause mortality includes all randomized participants. Safety includes participants who received ≥1 dose of study treatment. Per protocol, disease progression was not considered an AE, unless related to study treatment. Thus, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study treatment were excluded as AEs.
 
Arm/Group Title Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Hide Arm/Group Description Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity. Participants received 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 was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
All-Cause Mortality
Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   252/395 (63.80%)      282/399 (70.68%)    
Hide Serious Adverse Events
Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   181/395 (45.82%)      154/395 (38.99%)    
Blood and lymphatic system disorders     
Agranulocytosis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Anaemia † 1  5/395 (1.27%)  5 1/395 (0.25%)  1
Immune thrombocytopenia † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Neutropenia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Cardiac disorders     
Acute myocardial infarction † 1  3/395 (0.76%)  3 2/395 (0.51%)  2
Angina pectoris † 1  2/395 (0.51%)  3 0/395 (0.00%)  0
Angina unstable † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Atrial fibrillation † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Atrioventricular block † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Atrioventricular block complete † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Atrioventricular block second degree † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Cardiac failure † 1  0/395 (0.00%)  0 2/395 (0.51%)  2
Cardio-respiratory arrest † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Coronary artery disease † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Myocardial infarction † 1  3/395 (0.76%)  3 2/395 (0.51%)  2
Myocardial injury † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Myocarditis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Sinus node dysfunction † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Tachycardia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Ventricular tachycardia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Endocrine disorders     
Adrenal insufficiency † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Hyperthyroidism † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Hypophysitis † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Thyroiditis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Eye disorders     
Cataract † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Diabetic retinopathy † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Glaucoma † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Pterygium † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Gastrointestinal disorders     
Abdominal distension † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Abdominal hernia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Abdominal pain † 1  7/395 (1.77%)  7 4/395 (1.01%)  4
Abdominal pain upper † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Anal fistula † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Ascites † 1  5/395 (1.27%)  5 10/395 (2.53%)  10
Colitis † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Constipation † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Diarrhoea † 1  13/395 (3.29%)  13 5/395 (1.27%)  5
Duodenal ulcer † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Duodenal ulcer haemorrhage † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Duodenal ulcer perforation, obstructive † 1  1/395 (0.25%)  2 0/395 (0.00%)  0
Dysphagia † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Enteritis † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Enterocolitis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Gastric haemorrhage † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Gastric ulcer haemorrhage † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Gastric varices haemorrhage † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Gastritis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Gastrointestinal haemorrhage † 1  3/395 (0.76%)  3 1/395 (0.25%)  1
Gastrointestinal inflammation † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Haemoperitoneum † 1  0/395 (0.00%)  0 2/395 (0.51%)  2
Haemorrhoidal haemorrhage † 1  3/395 (0.76%)  3 1/395 (0.25%)  1
Haemorrhoids † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Ileus † 1  0/395 (0.00%)  0 2/395 (0.51%)  2
Inguinal hernia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Intestinal ischaemia † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Intestinal obstruction † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Lower gastrointestinal haemorrhage † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Mechanical ileus † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Melaena † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Mesenteric vein thrombosis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Nausea † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Oesophageal haemorrhage † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Oesophageal ulcer haemorrhage † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Oesophageal varices haemorrhage † 1  0/395 (0.00%)  0 5/395 (1.27%)  5
Pancreatitis † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Pancreatitis acute † 1  0/395 (0.00%)  0 2/395 (0.51%)  2
Pneumatosis intestinalis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Proctitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Small intestinal perforation † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Stomatitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Subileus † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Upper gastrointestinal haemorrhage † 1  1/395 (0.25%)  1 4/395 (1.01%)  5
Varices oesophageal † 1  1/395 (0.25%)  2 0/395 (0.00%)  0
Vomiting † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
General disorders     
Asthenia † 1  3/395 (0.76%)  3 0/395 (0.00%)  0
Death † 1  4/395 (1.01%)  4 3/395 (0.76%)  3
Drowning † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Fatigue † 1  3/395 (0.76%)  3 2/395 (0.51%)  2
General physical health deterioration † 1  7/395 (1.77%)  8 0/395 (0.00%)  0
Hyperthermia malignant † 1  1/395 (0.25%)  2 0/395 (0.00%)  0
Mucosal inflammation † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Multiple organ dysfunction syndrome † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Oedema peripheral † 1  1/395 (0.25%)  1 2/395 (0.51%)  2
Pyrexia † 1  3/395 (0.76%)  3 4/395 (1.01%)  5
Stent-graft endoleak † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Hepatobiliary disorders     
Bile duct stone † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Biliary obstruction † 1  0/395 (0.00%)  0 2/395 (0.51%)  2
Cholangitis † 1  1/395 (0.25%)  1 2/395 (0.51%)  6
Cholangitis acute † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Cholecystitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Cholecystitis chronic † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Hepatic cirrhosis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Hepatic failure † 1  4/395 (1.01%)  5 8/395 (2.03%)  8
Hepatic function abnormal † 1  1/395 (0.25%)  1 3/395 (0.76%)  3
Hepatic haemorrhage † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Hepatic necrosis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Hepatic pain † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Hepatitis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Hepatorenal syndrome † 1  2/395 (0.51%)  3 2/395 (0.51%)  2
Immune-mediated hepatitis † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Jaundice cholestatic † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Liver injury † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Portal vein thrombosis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Infections and infestations     
Abdominal infection † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Abdominal sepsis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Anal abscess † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Anorectal infection † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Appendicitis † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Appendicitis perforated † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Bacteraemia † 1  0/395 (0.00%)  0 3/395 (0.76%)  3
Biliary tract infection † 1  0/395 (0.00%)  0 2/395 (0.51%)  3
Bronchitis † 1  0/395 (0.00%)  0 3/395 (0.76%)  3
COVID-19 † 1  5/395 (1.27%)  5 3/395 (0.76%)  3
COVID-19 pneumonia † 1  3/395 (0.76%)  3 1/395 (0.25%)  1
Cellulitis † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Clostridium difficile colitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Cryptococcosis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Cystitis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Cytomegalovirus colitis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Encephalitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Endocarditis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Enterocolitis infectious † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Escherichia bacteraemia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Fungaemia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Gastroenteritis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Infection † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Infectious pleural effusion † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Large intestine infection † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Liver abscess † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Lower respiratory tract infection † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Osteomyelitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Periodontitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Peritonitis † 1  1/395 (0.25%)  2 2/395 (0.51%)  2
Peritonitis bacterial † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Pneumonia † 1  7/395 (1.77%)  7 7/395 (1.77%)  7
Pneumonia aspiration † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Pneumonia cryptococcal † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Pneumonia klebsiella † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Postoperative wound infection † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Prostatic abscess † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Pulmonary tuberculosis † 1  1/395 (0.25%)  1 2/395 (0.51%)  2
Salmonellosis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Sepsis † 1  3/395 (0.76%)  5 2/395 (0.51%)  2
Septic shock † 1  3/395 (0.76%)  3 2/395 (0.51%)  2
Spinal cord infection † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Staphylococcal sepsis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Streptococcal sepsis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Subcutaneous abscess † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Urinary tract infection † 1  4/395 (1.01%)  5 1/395 (0.25%)  1
Urosepsis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Viral infection † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Injury, poisoning and procedural complications     
Contusion † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Fall † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Femoral neck fracture † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Femur fracture † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Hip fracture † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Infusion related reaction † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Joint injury † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Ligament rupture † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Limb injury † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Lumbar vertebral fracture † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Pelvic fracture † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Rib fracture † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Wound dehiscence † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Investigations     
Alanine aminotransferase increased † 1  4/395 (1.01%)  4 1/395 (0.25%)  1
Amylase increased † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Aspartate aminotransferase increased † 1  3/395 (0.76%)  3 1/395 (0.25%)  1
Blood bilirubin increased † 1  5/395 (1.27%)  5 1/395 (0.25%)  1
Blood creatinine increased † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Blood glucose decreased † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Blood thyroid stimulating hormone decreased † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
False positive investigation result † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Gamma-glutamyltransferase increased † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Platelet count decreased † 1  2/395 (0.51%)  2 2/395 (0.51%)  2
Troponin T increased † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Metabolism and nutrition disorders     
Decreased appetite † 1  2/395 (0.51%)  2 3/395 (0.76%)  3
Dehydration † 1  2/395 (0.51%)  2 4/395 (1.01%)  4
Diabetes mellitus † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Diabetic ketoacidosis † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Electrolyte imbalance † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Hyperglycaemia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Hyperkalaemia † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Hypervolaemia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Hypoglycaemia † 1  3/395 (0.76%)  4 0/395 (0.00%)  0
Hypokalaemia † 1  3/395 (0.76%)  3 1/395 (0.25%)  1
Hyponatraemia † 1  2/395 (0.51%)  2 2/395 (0.51%)  2
Metabolic acidosis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Tumour lysis syndrome † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Type 1 diabetes mellitus † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  0/395 (0.00%)  0 1/395 (0.25%)  2
Arthritis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Back pain † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Fistula † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Intervertebral disc degeneration † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Muscular weakness † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Musculoskeletal pain † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Osteoarthritis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Osteolysis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Osteonecrosis of jaw † 1  0/395 (0.00%)  0 2/395 (0.51%)  2
Pain in extremity † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Pathological fracture † 1  0/395 (0.00%)  0 2/395 (0.51%)  2
Tenosynovitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Basal cell carcinoma † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Cancer pain † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Liver carcinoma ruptured † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Malignant neoplasm of unknown primary site † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Prostate cancer † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Skin squamous cell carcinoma recurrent † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Squamous cell carcinoma † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Tumour haemorrhage † 1  3/395 (0.76%)  3 2/395 (0.51%)  2
Tumour pain † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Nervous system disorders     
Cerebral infarction † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Cerebrovascular accident † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Depressed level of consciousness † 1  3/395 (0.76%)  3 0/395 (0.00%)  0
Embolic stroke † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Hepatic encephalopathy † 1  21/395 (5.32%)  27 11/395 (2.78%)  12
Ischaemic stroke † 1  2/395 (0.51%)  2 1/395 (0.25%)  1
Myasthenia gravis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Posterior reversible encephalopathy syndrome † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Ruptured cerebral aneurysm † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Seizure † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Transient global amnesia † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Psychiatric disorders     
Completed suicide † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Confusional state † 1  1/395 (0.25%)  1 1/395 (0.25%)  2
Delirium † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Renal and urinary disorders     
Acute kidney injury † 1  3/395 (0.76%)  3 2/395 (0.51%)  2
Chronic kidney disease † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Nephritis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Nephrotic syndrome † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Prerenal failure † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
Renal failure † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Renal infarct † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Renal tubular necrosis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Reproductive system and breast disorders     
Benign prostatic hyperplasia † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Prostatitis † 1  1/395 (0.25%)  2 0/395 (0.00%)  0
Scrotal inflammation † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Respiratory, thoracic and mediastinal disorders     
Chronic respiratory failure † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Dyspnoea † 1  3/395 (0.76%)  3 0/395 (0.00%)  0
Epistaxis † 1  0/395 (0.00%)  0 1/395 (0.25%)  2
Haemoptysis † 1  0/395 (0.00%)  0 2/395 (0.51%)  3
Hiccups † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Idiopathic pulmonary fibrosis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Lower respiratory tract congestion † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Lung disorder † 1  1/395 (0.25%)  2 0/395 (0.00%)  0
Oropharyngeal spasm † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Pleurisy † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Pneumonitis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Pulmonary embolism † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Respiratory arrest † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Respiratory failure † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Skin and subcutaneous tissue disorders     
Henoch-Schonlein purpura † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Hidradenitis † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Lichenoid keratosis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Palmar-plantar erythrodysaesthesia syndrome † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Parapsoriasis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Pemphigoid † 1  2/395 (0.51%)  2 0/395 (0.00%)  0
Psoriasis † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Rash † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Skin ulcer † 1  1/395 (0.25%)  1 0/395 (0.00%)  0
Vascular disorders     
Aortic aneurysm † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Hypertension † 1  3/395 (0.76%)  3 2/395 (0.51%)  2
Hypertensive crisis † 1  0/395 (0.00%)  0 2/395 (0.51%)  2
Peripheral arterial occlusive disease † 1  0/395 (0.00%)  0 1/395 (0.25%)  1
Vasculitis † 1  1/395 (0.25%)  1 1/395 (0.25%)  1
1
Term from vocabulary, MedDRA 25.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lenvatinib + Pembrolizumab Lenvatinib + Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   390/395 (98.73%)      388/395 (98.23%)    
Blood and lymphatic system disorders     
Anaemia † 1  48/395 (12.15%)  55 62/395 (15.70%)  85
Neutropenia † 1  19/395 (4.81%)  45 22/395 (5.57%)  32
Endocrine disorders     
Hyperthyroidism † 1  30/395 (7.59%)  31 17/395 (4.30%)  20
Hypothyroidism † 1  167/395 (42.28%)  203 156/395 (39.49%)  197
Gastrointestinal disorders     
Abdominal distension † 1  27/395 (6.84%)  31 18/395 (4.56%)  20
Abdominal pain † 1  73/395 (18.48%)  87 73/395 (18.48%)  88
Abdominal pain upper † 1  43/395 (10.89%)  49 39/395 (9.87%)  52
Ascites † 1  27/395 (6.84%)  34 29/395 (7.34%)  34
Constipation † 1  67/395 (16.96%)  80 71/395 (17.97%)  79
Diarrhoea † 1  184/395 (46.58%)  352 165/395 (41.77%)  346
Dry mouth † 1  20/395 (5.06%)  20 14/395 (3.54%)  14
Dyspepsia † 1  33/395 (8.35%)  41 13/395 (3.29%)  17
Nausea † 1  89/395 (22.53%)  122 81/395 (20.51%)  119
Stomatitis † 1  41/395 (10.38%)  53 35/395 (8.86%)  47
Toothache † 1  24/395 (6.08%)  27 17/395 (4.30%)  22
Vomiting † 1  53/395 (13.42%)  88 60/395 (15.19%)  92
General disorders     
Asthenia † 1  73/395 (18.48%)  90 60/395 (15.19%)  84
Fatigue † 1  125/395 (31.65%)  147 98/395 (24.81%)  126
Malaise † 1  20/395 (5.06%)  24 30/395 (7.59%)  35
Mucosal inflammation † 1  24/395 (6.08%)  29 19/395 (4.81%)  25
Oedema peripheral † 1  62/395 (15.70%)  79 50/395 (12.66%)  63
Pyrexia † 1  45/395 (11.39%)  53 45/395 (11.39%)  66
Infections and infestations     
Urinary tract infection † 1  34/395 (8.61%)  46 39/395 (9.87%)  60
Investigations     
Alanine aminotransferase increased † 1  92/395 (23.29%)  156 86/395 (21.77%)  144
Amylase increased † 1  38/395 (9.62%)  56 18/395 (4.56%)  28
Aspartate aminotransferase increased † 1  116/395 (29.37%)  186 102/395 (25.82%)  163
Blood alkaline phosphatase increased † 1  49/395 (12.41%)  63 33/395 (8.35%)  47
Blood bilirubin increased † 1  101/395 (25.57%)  202 106/395 (26.84%)  210
Blood creatinine increased † 1  38/395 (9.62%)  56 22/395 (5.57%)  35
Gamma-glutamyltransferase increased † 1  64/395 (16.20%)  75 56/395 (14.18%)  70
Lipase increased † 1  56/395 (14.18%)  78 36/395 (9.11%)  57
Neutrophil count decreased † 1  34/395 (8.61%)  68 39/395 (9.87%)  85
Platelet count decreased † 1  100/395 (25.32%)  157 110/395 (27.85%)  187
Weight decreased † 1  119/395 (30.13%)  135 88/395 (22.28%)  101
White blood cell count decreased † 1  28/395 (7.09%)  64 44/395 (11.14%)  103
Metabolism and nutrition disorders     
Decreased appetite † 1  146/395 (36.96%)  182 119/395 (30.13%)  166
Hyperglycaemia † 1  23/395 (5.82%)  31 24/395 (6.08%)  44
Hyperkalaemia † 1  13/395 (3.29%)  20 20/395 (5.06%)  25
Hypertriglyceridaemia † 1  23/395 (5.82%)  49 31/395 (7.85%)  61
Hypoalbuminaemia † 1  60/395 (15.19%)  83 60/395 (15.19%)  95
Hypokalaemia † 1  37/395 (9.37%)  72 35/395 (8.86%)  59
Hypomagnesaemia † 1  25/395 (6.33%)  42 28/395 (7.09%)  56
Hyponatraemia † 1  42/395 (10.63%)  68 39/395 (9.87%)  64
Hypophosphataemia † 1  19/395 (4.81%)  24 22/395 (5.57%)  36
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  86/395 (21.77%)  109 76/395 (19.24%)  92
Back pain † 1  56/395 (14.18%)  68 44/395 (11.14%)  49
Myalgia † 1  25/395 (6.33%)  27 14/395 (3.54%)  15
Pain in extremity † 1  19/395 (4.81%)  22 23/395 (5.82%)  27
Nervous system disorders     
Dizziness † 1  25/395 (6.33%)  29 28/395 (7.09%)  30
Dysgeusia † 1  21/395 (5.32%)  25 19/395 (4.81%)  21
Headache † 1  49/395 (12.41%)  63 42/395 (10.63%)  57
Psychiatric disorders     
Insomnia † 1  35/395 (8.86%)  40 42/395 (10.63%)  48
Renal and urinary disorders     
Haematuria † 1  26/395 (6.58%)  43 24/395 (6.08%)  46
Proteinuria † 1  130/395 (32.91%)  247 148/395 (37.47%)  255
Respiratory, thoracic and mediastinal disorders     
Cough † 1  53/395 (13.42%)  63 43/395 (10.89%)  49
Dysphonia † 1  83/395 (21.01%)  94 79/395 (20.00%)  92
Dyspnoea † 1  42/395 (10.63%)  44 24/395 (6.08%)  32
Epistaxis † 1  25/395 (6.33%)  28 29/395 (7.34%)  42
Oropharyngeal pain † 1  21/395 (5.32%)  22 14/395 (3.54%)  16
Skin and subcutaneous tissue disorders     
Palmar-plantar erythrodysaesthesia syndrome † 1  133/395 (33.67%)  149 124/395 (31.39%)  140
Pruritus † 1  67/395 (16.96%)  79 44/395 (11.14%)  57
Rash † 1  63/395 (15.95%)  79 35/395 (8.86%)  45
Vascular disorders     
Hypertension † 1  179/395 (45.32%)  245 199/395 (50.38%)  255
1
Term from vocabulary, MedDRA 25.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation.

Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.

Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme LLC
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Publications of Results:
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 Investigators. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1399-1410. doi: 10.1016/S1470-2045(23)00469-2. Erratum In: Lancet Oncol. 2024 Apr;25(4):e137.
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT03713593    
Other Study ID Numbers: 7902-002
MK-7902-002 ( Other Identifier: Merck Protocol Number )
E7080-G000-311 ( Other Identifier: Eisai Protocol Number )
LEAP-002 ( Other Identifier: Merck )
194590 ( Registry Identifier: JAPIC-CTI )
2018-002983-26 ( EudraCT Number )
First Submitted: October 18, 2018
First Posted: October 22, 2018
Results First Submitted: June 8, 2023
Results First Posted: July 24, 2023
Last Update Posted: January 10, 2024