Carcinoma, Hepatocellular
Conditions
Keywords
receptor tyrosine kinase inhibitor, programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1)
Brief summary
The purpose of this study is to evaluate the efficacy and safety of lenvatinib and pembrolizumab in combination with TACE versus TACE plus oral and intravenous (IV) placebos in participants with incurable, non-metastatic hepatocellular carcinoma (HCC). The primary hypotheses are that pembrolizumab plus lenvatinib in combination with TACE is superior to placebo plus TACE with respect to progression-free survival (PFS) and overall survival (OS).
Interventions
DRUGLenvatinib
Administered at a dose of 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight \<60 kg) via oral capsules once a day during each 21-day cycle.
BIOLOGICALPembrolizumab
Administered via IV infusion at a dose of 400 mg once every 6 weeks (Q6W).
DRUGOral Placebo
Lenvatinib-matching placebo administered via oral capsules once a day during each 21-day cycle.
DRUGIV Placebo
Pembrolizumab-matching placebo administered via IV infusion once every 6 weeks (Q6W).
PROCEDURETACE
Conducted as a background procedure of chemotherapeutic and embolic agent(s).
Sponsors
Merck Sharp & Dohme LLC
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a diagnosis of HCC confirmed by radiology, histology, or cytology * Has HCC localized to the liver and not amenable to curative treatment * Participants with Hepatitis C virus (HCV) are eligible if treatment was completed at least 1 month prior to starting study intervention * Participants with Hepatitis B virus (HBV) are eligible * Has adequately controlled blood pressure with or without antihypertensive medications * Has adequate organ function
Exclusion criteria
* Is currently a candidate for liver transplantation * Has had gastric bleeding within the last 6 months * Has ascites that is not controlled with medication * Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as congestive heart failure * Has a serious nonhealing wound, ulcer, or bone fracture * Has received locoregional therapy to existing liver lesions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 43.5 Months | PFS was defined as the time from the first dose of study intervention to the first documented progressive disease (PD) per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1 adjusted for this study to allow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 as assessed by BICR was reported. |
| Overall Survival (OS) | Up to approximately 61.7 Months | OS was defined as the time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per mRECIST as Assessed by BICR | Up to approximately 61.7 Months | ORR was defined as the percentage of participants who achieve a confirmed complete response (CR) (disappearance of any intratumoral arterial enhancement in all target lesions) or a partial response (PR) (at least a 30% decrease in the SOD of viable \[contrast enhancement in the arterial phase\] target lesions, taking as reference the baseline SOD of target lesions) per mRECIST as assessed by BICR. mRECIST for HCC allows evaluation of treatment effects that are not reflected in simple total size changes of lesions. The percentage of participants who experienced CR or PR per mRECIST as assessed BICR was presented. |
| Disease Control Rate (DCR) Per mRECIST as Assessed by BICR | Up to approximately 61.7 Months | DCR was defined as the percentage of participants who have achieved a confirmed complete response (CR) (disappearance of any intratumoral arterial enhancement in all target lesions) or a partial response (PR) (at least a 30% decrease in the SOD of viable \[contrast enhancement in the arterial phase\] target lesions, taking as reference the baseline SOD of target lesions) per mRECIST as assessed by BICR. mRECIST for HCC allows evaluation of treatment effects that are not reflected in simple total size changes of lesions. PD was defined as at least a 20% increase in the SOD of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The percentage of participants who achieved CR, PR, or SD after ≥6 weeks per mRECIST assessed by BICR was presented. |
| Duration of Response (DOR) Per mRECIST as Assessed by BICR | Up to approximately 61.7 Months | For participants who demonstrated confirmed CR or PR per mRECIST assessed by BICR, DOR was defined as the time from the first documented evidence of a confirmed complete response (CR) (disappearance of any intratumoral arterial enhancement in all target lesions) or a partial response (PR) (at least a 30% decrease in the SOD of viable \[contrast enhancement in the arterial phase\] target lesions, taking as reference the baseline SOD of target lesions) per mRECIST as assessed by BICR. mRECIST for HCC allows evaluation of treatment effects that are not reflected in simple total size changes of lesions. PD was defined as at least a 20% increase in the SOD of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The DOR as assessed using mRECIST for all participants who experienced a confirmed CR or PR was presented. |
| Time-To-Progression (TTP) Per mRECIST as Assessed by BICR | Up to approximately 61.7 Months | TTP was defined as the time from the first dose of study intervention to the first documented PD per mRECIST assessed by BICR. mRECIST for HCC allows evaluation of treatment effects that are not reflected in simple total size changes of lesions. PD was defined as at least a 20% increase in the SOD of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. TTP per mRECIST as assessed by BICR was presented. |
| Number of Participants Who Experienced At Least One Adverse Event (AE) | Up to approximately 71.1 Months | An AE will be any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE will be reported. |
| Percentage of Participants Who Experience At Least One Serious Adverse Event (SAE) | Up to approximately 71.1 Months | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was another important medical event. The number of participants with an SAE was reported. |
| Number of Participants Who Experience At Least One Hepatic Event of Clinical Interest (ECI) | Up to approximately 71.1 Months | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Hepatic events of clinical interest (ECIs) included any of the following events if the event was considered not due to disease progression as judged by the investigator: among participants with Baseline ALT \<2 × ULN: ALT ≥5 × ULN; among participants with Baseline ALT ≥2 × ULN: ALT \>3 × the Baseline level; ALT \>500 U/L regardless of baseline level; total bilirubin \>3.0 mg/dL; hepatic decompensation diagnosed clinically (regardless of laboratory values) including new onset clinically detectable ascites requiring intervention for \>3 days, hepatic encephalopathy, or gastrointestinal bleeding suggestive of portal hypertension. The number of participants with a hepatic AE of clinical interest was reported. |
| ORR Per RECIST 1.1 as Assessed by BICR | Up to approximately 61.7 Months | ORR was defined as the percentage of participants who achieve a confirmed Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters \[SOD\] of target lesions) per RECIST 1.1 adjusted for this study to allow a maximum of 10 target lesions in total and 5 per organ, and assessed by BICR. The percentage of participants who experienced CR or PR per RECIST 1.1 as assessed BICR was presented. |
| DCR Per RECIST 1.1 as Assessed by BICR | Up to approximately 61.7 Months | DCR was defined as the percentage of participants who have achieved CR (disappearance of all target lesions), PR (at least a 30% decrease in the SOD of target lesions), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD) after ≥6 weeks (the start of the window for the first scheduled scan) per RECIST 1.1 assessed by BICR. Per RECIST 1.1 adjusted for this study to allow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, PD was defined as at least a 20% increase in the SOD of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The percentage of participants who achieved CR, PR, or SD after ≥6 weeks per RECIST 1.1 assessed by BICR was presented. |
| DOR Per RECIST 1.1 as Assessed by BICR | Up to approximately 61.7 Months | For participants who demonstrated confirmed CR or PR per RECIST 1.1 assessed by BICR, DOR was defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the SOD of target lesions) until progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 adjusted for this study to allow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, PD was defined as at least a 20% increase in the SOD of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The DOR as assessed using RECIST 1.1 for all participants who experienced a confirmed CR or PR was presented. |
| Number of Participants Who Discontinue Study Treatment Due to an AE | Up to approximately 71.1 Months | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants that discontinued study treatment due to an AE was reported. |
| TTP Per RECIST 1.1 as Assessed by BICR | Up to approximately 61.7 Months | TTP was defined as the time from the first dose of study intervention to the first documented PD per RECIST 1.1 assessed by BICR. Per RECIST 1.1 adjusted for this study to allow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, PD was defined as at least a 20% increase in the SOD of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. TTP per RECIST 1.1 as assessed by BICR was presented. |
| PFS Per Modified RECIST (mRECIST) as Assessed by BICR | Up to approximately 61.7 Months | PFS was defined as the time from the first dose of study intervention to the first documented PD per mRECIST by BICR or death due to any cause, whichever occurs first. mRECIST for hepatocellular carcinoma (HCC) allows evaluation of treatment effects that are not reflected in simple total size changes of lesions. Per mRECIST, PD was defined as an increase of at least 20% in the SODs of viable target lesions, taking as reference the smallest SODs of viable target lesions recorded since the treatment started. PFS per mRECIST as assessed by BICR was reported. |
Countries
Australia, Brazil, Chile, China, Colombia, Denmark, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Netherlands, New Zealand, Norway, Portugal, Puerto Rico, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
480 participants were enrolled. Of the 480 enrolled participants 1 participant was enrolled in the study in error and did not receive study treatment and 1 participant withdrew from the study and subsequently died without receiving study treatment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 63.8 Years STANDARD_DEVIATION 10.7 |
| Alpha Fetoprotein at Screening Lab ≤ 400 ng/mL | 200 Participants |
| Alpha Fetoprotein at Screening Lab > 400 ng/mL | 37 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline ECOG= 0 | 216 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline ECOG= 1 | 30 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 199 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 24 Participants |
| Geographic Region Asia without Japan | 272 Participants |
| Geographic Region Non-Asia with Japan | 102 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 347 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 98 Participants |
| Serum Albumin (ALBI) Grade Grade 1 | 345 Participants |
| Serum Albumin (ALBI) Grade Grade 2 | 134 Participants |
| Serum Albumin (ALBI) Grade Missing | 1 Participants |
| Sex: Female, Male Female | 82 Participants |
| Sex: Female, Male Male | 206 Participants |
| Tumor Burden Stratum per Investigator > 12 | 15 Participants |
| Tumor Burden Stratum per Investigator ≤ 6 | 116 Participants |
| Tumor Burden Stratum per Investigator > 6 and ≤ 12 | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 126 / 237 | 127 / 243 |
| other Total, other adverse events | 234 / 237 | 229 / 241 |
| serious Total, serious adverse events | 122 / 237 | 62 / 241 |
Outcome results
None listed