Carcinoma, Hepatocellular
Conditions
Keywords
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)
Brief 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).
Interventions
DRUGlenvatinib
Administered orally once a day
BIOLOGICALpembrolizumab
Administered as an IV infusion on Day 1 Q3W
DRUGsaline placebo
Administered as an IV infusion on Day 1 Q3W
Sponsors
Merck Sharp & Dohme LLC
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 41 months | 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. |
| Overall Survival (OS) | Up to approximately 41 months | OS was defined as the time from randomization until death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 41 months | 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. |
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 41 months | 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. |
| Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 41 months | 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 to Disease Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 41 months | 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. |
| Progression-free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Up to approximately 41 months | 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. |
| Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Up to approximately 41 months | 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. |
| Duration of Response (DOR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Up to approximately 41 months | 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. |
| Disease Control Rate (DCR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Up to approximately 41 months | 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 to Disease Progression (TTP) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Up to approximately 41 months | 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. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 68 months | 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 |
| Number of Participants Who Experienced an Serious Adverse Event (SAE) | Up to approximately 68 months | 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 |
| Number of Participants Who Experienced an Immune-related Adverse Event (irAE) of Clinical Interest | Up to approximately 41 months | Number of participants who experienced an AE representing an immunologic etiology and considered to be causally related to drug exposure |
| Number of Participants Who Experienced an Hepatic Event of Clinical Interest (HECI) | Up to approximately 68 months | Number of participants who experienced a hepatic ECI not due to disease progression as judged by the investigator. |
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | Up to approximately 68 months | Number of participants who discontinued study treatment due to an AE |
Countries
Australia, Canada, Chile, China, Colombia, France, Germany, Ireland, Italy, Japan, Mexico, New Zealand, Poland, Russia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Recruitment details
Participants with a radiologically, histologically- or cytologically-confirmed diagnosis of hepatocellular carcinoma (HCC) were recruited into this study.
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib + Pembrolizumab 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. | 395 |
| Lenvatinib + Placebo 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. | 399 |
| Total | 794 |
Baseline characteristics
| Characteristic | Lenvatinib + Placebo | Lenvatinib + Pembrolizumab | Total |
|---|---|---|---|
| Age, Continuous | 64.1 Years STANDARD_DEVIATION 12.1 | 64.2 Years STANDARD_DEVIATION 10.9 | 64.1 Years STANDARD_DEVIATION 11.5 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG = 0 | 271 Participants | 267 Participants | 538 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG = 1 | 126 Participants | 127 Participants | 253 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG = 2 | 0 Participants | 1 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 41 Participants | 48 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 349 Participants | 334 Participants | 683 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 13 Participants | 22 Participants |
| Geographic Region Asia without Japan | 123 Participants | 121 Participants | 244 Participants |
| Geographic Region Japan and Western regions | 276 Participants | 274 Participants | 550 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 8 Participants | 13 Participants | 21 Participants |
| Race (NIH/OMB) Asian | 173 Participants | 172 Participants | 345 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 5 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 12 Participants | 22 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 28 Participants | 18 Participants | 46 Participants |
| Race (NIH/OMB) White | 172 Participants | 173 Participants | 345 Participants |
| Sex: Female, Male Female | 72 Participants | 78 Participants | 150 Participants |
| Sex: Female, Male Male | 327 Participants | 317 Participants | 644 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 314 / 395 | 352 / 399 |
| other Total, other adverse events | 390 / 395 | 388 / 395 |
| serious Total, serious adverse events | 185 / 395 | 159 / 395 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization until death from any cause
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Overall Survival (OS) | 21.2 Months |
| Lenvatinib + Placebo | Overall Survival (OS) | 19.0 Months |
p-value: 0.022795% CI: [0.708, 0.997]Log Rank
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.
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 8.2 Months |
| Lenvatinib + Placebo | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 8.1 Months |
95% CI: [0.712, 0.978]
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.
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Disease Control Rate (DCR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 84.3 Percentage of Participants |
| Lenvatinib + Placebo | Disease Control Rate (DCR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 83.2 Percentage of Participants |
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.
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 81.3 Percentage of Participants |
| Lenvatinib + Placebo | Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 78.4 Percentage of Participants |
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.
Time frame: Up to approximately 41 months
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Duration of Response (DOR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 2.1 Months |
| Lenvatinib + Placebo | Duration of Response (DOR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 2.1 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.
Time frame: Up to approximately 41 months
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 4.1 Months |
| Lenvatinib + Placebo | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 4.0 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
Time frame: Up to approximately 68 months
Population: The analysis population consisted of all randomized participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 51 Participants |
| Lenvatinib + Placebo | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 41 Participants |
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
Time frame: Up to approximately 68 months
Population: The analysis population consisted of all randomized participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Number of Participants Who Experienced an Adverse Event (AE) | 394 Participants |
| Lenvatinib + Placebo | Number of Participants Who Experienced an Adverse Event (AE) | 392 Participants |
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.
Time frame: Up to approximately 68 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Number of Participants Who Experienced an Hepatic Event of Clinical Interest (HECI) | 71 Participants |
| Lenvatinib + Placebo | Number of Participants Who Experienced an Hepatic Event of Clinical Interest (HECI) | 77 Participants |
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
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Number of Participants Who Experienced an Immune-related Adverse Event (irAE) of Clinical Interest | 210 Participants |
| Lenvatinib + Placebo | Number of Participants Who Experienced an Immune-related Adverse Event (irAE) of Clinical Interest | 184 Participants |
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
Time frame: Up to approximately 68 months
Population: The analysis population consisted of all randomized participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Number of Participants Who Experienced an Serious Adverse Event (SAE) | 185 Participants |
| Lenvatinib + Placebo | Number of Participants Who Experienced an Serious Adverse Event (SAE) | 159 Participants |
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.
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 40.8 Percentage of Participants |
| Lenvatinib + Placebo | Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 34.1 Percentage of Participants |
95% CI: [0, 13.4]
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.
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 26.1 Percentage of Participants |
| Lenvatinib + Placebo | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 17.5 Percentage of Participants |
95% CI: [2.8, 14.2]
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.
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Progression-free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 8.4 Months |
| Lenvatinib + Placebo | Progression-free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 8.1 Months |
95% CI: [0.68, 0.94]
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.
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Time to Disease Progression (TTP) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 10.4 Months |
| Lenvatinib + Placebo | Time to Disease Progression (TTP) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | 8.3 Months |
95% CI: [0.61, 0.88]
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.
Time frame: Up to approximately 41 months
Population: The analysis population consisted of all randomized participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Time to Disease Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 8.3 Months |
| Lenvatinib + Placebo | Time to Disease Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 8.2 Months |
95% CI: [0.66, 0.93]