Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Lenvatinib

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants will receive oral lenvatinib at a starting dose of 8 or 12 milligrams (mg) once a day (QD) in combination with intravenous pembrolizumab 200 mg every 3 weeks (Q3W) on a 21-day treatment cycle. The starting dose of lenvatinib will be based on Baseline body weight. Participants weighing greater than or equal to 60 kilograms (kg) will receive 12 mg QD; participants weighing less than 60 kg will receive 8 mg QD.

lenvatinib

pembrolizumab (200 mg)

This is an open-label Phase 1b study designed to evaluate the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with hepatocellular carcinoma (HCC). The study will evaluate objective response rate and duration of response by modified Response Evaluation Criteria In Solid Tumors (mRECIST) for HCC and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) based on independent imaging review (IIR).

A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma

An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects With Hepatocellular Carcinoma

A TEAE was defined as an adverse event (AE) that emerged during the time from the first dose of study drug to 120 days (if participant initiated new anticancer therapy) following last dose of study drug, was absent at pretreatment (Baseline) or reemerged during treatment, was at pretreatment (Baseline) but stopped before treatment or worsened in severity during treatment relative to the pretreatment state, when AE was continuous. An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening (that is, participant was at immediate risk of death from AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).

A TEAE was defined as an AE that emerged during the time from the first dose of study drug to 120 days (if participant initiated new anticancer therapy) following last dose of study drug, was absent at pretreatment (Baseline) or reemerged during treatment, was at pretreatment (Baseline) but stopped before treatment or worsened in severity during treatment relative to the pretreatment state, when AE was continuous. An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening (that is, participant was at immediate risk of death from AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).

DLT was graded according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). DLT was defined as any of the following: (1) any of the hematological or nonhematological toxicities considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1; (2) failure to administer \>=75 percent (%) of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1; (3) participants who discontinued treatment due to treatment-related toxicity in Cycle 1; (4) greater than (\>) 2 week delay in starting pembrolizumab in Cycle 2 because of a treatment-related toxicity, even if the toxicity did not meet DLT criteria.

ORR was defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 assessed by IIR analysis. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is \<10 millimeter \[mm\] if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the long diameter (LD) (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.

DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on mRECIST assessed by IIR analysis. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is \<10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).

DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on RECIST v1.1 assessed by IIR analysis. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is \<10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).

ORR was defined as the percentage of participants who had BOR of CR or PR based on mRECIST assessed by investigator review. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is \<10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.

DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) based on mRECIST assessed by investigator review. CR defined as disappearance of all target and non-target lesions (a short diameter is \<10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).

PFS was defined as the time from the first study dose date to the date of first documentation of PD or death (whichever occurred first) based on mRECIST and RECIST v1.1 assessed by IIR, and mRECIST assessed by investigator review. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).

TTP was defined as the time from the first study dose date to the date of first documentation of PD, based on mRECIST and RECIST v1.1 assessed by IIR and mRECIST assessed by an investigator review. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).

TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to mRECIST assessed by IIR. CR defined as disappearance of all target and non-target lesions (a short diameter is \<10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.

TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to RECIST v1.1 assessed by IIR. CR defined as disappearance of all target and non-target lesions (a short diameter is \<10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.

TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to mRECIST assessed by investigator review. CR defined as disappearance of all target and non-target lesions (a short diameter is \<10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.

OS was measured from the date of first dose of study drug until date of death from any cause. Participants who were lost to follow-up or who were alive at the date of data cutoff were censored at the date the participants were last known alive, whichever came earlier.

Cmax was defined as the maximum plasma concentration for lenvatinib. Cmax was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). As per pharmacokinetic (PK) planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Tmax was defined as the time to reach maximum observed plasma concentration (Cmax) for lenvatinib. Tmax was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 time to last measurable point for lenvatinib. AUC(0-t) was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

AUC(0-ti) was defined as the area under the plasma concentration-time curve from 0 to a given sampling time for lenvatinib. AUC(0-ti) was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

AUC(0-Inf) was defined as the area under the plasma concentration-time curve from 0 to infinity for lenvatinib. AUC(0-Inf) was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

t1/2 was defined as the terminal elimination phase half-life for lenvatinib. t1/2 was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as (Dose/AUC(0-inf))/F. Where AUC(0-inf) is the area under the plasma concentration-time curve from zero to infinity and F is the bioavailability of the drug. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was calculated as (CL/F)/Lambda Z. Where, CL/F is the apparent total clearance and lambda Z is the apparent terminal elimination rate constant. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Css,max was defined as the maximum plasma concentration at steady state for lenvatinib. Css,max was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Css,min is the minimum plasma concentration at steady state for lenvatinib. Css,min was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Tss,Max was defined as the time to reach maximum observed plasma concentration of lenvatinib at steady state. Tss,Max was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

AUC(0-tau) was defined as the area under the plasma concentration-time curve over dosing interval for lenvatinib. AUC(0-tau) was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Clearance of a drug at steady state is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CLss/F was calculated as (Dose/AUC(0-tau))/F. Where, AUC(0-tau) is the area under the plasma concentration-time curve over the dosing interval and F is the bioavailability of the drug. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Css,Av was defined as the average plasma concentration at steady state for lenvatinib. Css,Av was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. Css,Av was calculated as AUC(0-tau)/tau. Where, AUC(0-tau) is the area under the plasma concentration-time curve over the dosing interval and tau is the length of dosing interval. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz,ss/F was calculated as (CLss/F)/Lambda Z. Where, CLss/F is the apparent total clearance following oral administration at steady state and lambda Z is the apparent terminal elimination rate constant. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Rac(Cmax) was calculated as Css,max at Cycle 1 Day 15/Cmax at Cycle 1 Day 1. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Rac(AUC0-8 hour) was calculated as AUC(0-8 hour) at Cycle 1 Day 15/AUC(0-8 hour) at Cycle 1 Day 1. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

The PTF within complete dosing interval at steady state, calculated as PTF (%) = (\[Css,max - Css,min\]/Css,Av)\* 100. Where, Css,max is the maximum observed plasma concentration at steady state and Css,min is the minimum observed plasma concentration at steady state and Css,Av average steady state plasma concentration. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.

Ctrough was defined as trough (pre-dose) serum concentration for pembrolizumab at steady state.

ADA positive was defined as participants with at least one pre-treatment or post-dose sample positive in the confirmatory assay for antibodies against pembrolizumab. ADA was assessed using a validated electrochemiluminescence (ECL) immunoassay.

Merck Sharp & Dohme LLC

Eisai Co., Ltd.

The safety analysis set included all participants who had received at least 1 dose of study drug.

In the DLT part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in Cycle 1 of a 21-day treatment cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg; participants with body weight \<60 kg, received lenvatinib 8 mg. Participants who discontinued treatment in Cycle 1, entered the follow-up phase. Participants who were still receiving treatment at the end of Cycle 1, continued to receive same treatment until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Upon confirmation of the tolerability of the tested combination regimen of lenvatinib plus pembrolizumab in Cycle 1, expansion part was opened for participant's enrollment.

DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg

In the Expansion part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight \>=60 kg received lenvatinib 12 mg; participants with body weight \<60 kg, received lenvatinib 8 mg.

Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

The efficacy analysis set included all participants who had received at least 1 dose of study drug.

Eisai Inquiry Service

TEAEs

SAEs

DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

The DLT analysis set included all participants (except for the Expansion part) who had completed Cycle 1 without major protocol deviation with at least 75% of study drug compliance and assessed for DLT, and participants who had experienced DLT during Cycle 1.

DLT Part: Number of Participants With Dose Limiting Toxicities (DLTs)

RECIST v1.1

mRECIST

Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight \>=60 kg received lenvatinib 12 mg; participants with body weight \<60 kg, received lenvatinib 8 mg.

HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg

All participants with hepatocellular carcinoma (HCC) who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as first line (1L) therapy, with no prior systemic therapy. In DLT part, 4 participants had received prior systemic therapy with sorafenib; therefore, they were excluded from analysis for this measure.

DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST Version (v) 1.1 Assessed by Independent Imaging Review (IIR)

All participants with HCC who received at least 1 dose of combination of lenvatinib and pembrolizumab as 1L therapy with no prior systemic therapy. In DLT part, 4 participants who received prior systemic therapy with sorafenib were excluded from analysis for this measure. Overall number analyzed were the participants who had CR or PR.

DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR

DLT+Expansion Part: Duration of Response (DOR) Based on RECIST v1.1 Assessed by IIR

HCC 1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as 1L therapy, with no prior systemic therapy. In DLT part of the study, 4 participants had received prior sorafenib; therefore, they were excluded from analysis for this measure.

DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as 1L therapy, with no prior systemic therapy. In DLT part of study, 4 participants had received prior sorafenib; therefore, they were excluded. "Overall Number of Participants Analyzed": participants who had CR or PR.

DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review

mRECIST: IIR

RECIST v1.1: IIR

mRECIST: Investigator Review

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as 1L therapy, with no prior systemic therapy. In DLT part of the study, 4 participants had received prior systemic therapy with sorafenib; therefore, they were excluded from analysis for this measure.

DLT+Expansion Part: Progression-free Survival (PFS) Based on mRECIST and RECIST v1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as 1L therapy, with no prior systemic therapy. In DLT part of the study, 4 participants had received prior systemic therapy with sorafenib; therefore, they were excluded from analysis of this measure.

DLT+Expansion Part: Time-to-Progression (TTP) Based on mRECIST and RECIST v1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review

DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by IIR

DLT+Expansion Part: Time-to-Response (TTR) Based on RECIST v1.1 Assessed by IIR

DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by Investigator Review

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as 1L therapy, with no prior systemic therapy. In DLT part of study, 4 participants had received prior systemic therapy with sorafenib; therefore, they were excluded from analysis of this measure.

DLT+Expansion Part: Overall Survival (OS)

Japanese participants who received lenvatinib 8 mg capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor.

DLT+Expansion Part, Japanese Participants: Lenvatinib 8 mg

Non-Japanese participants who received lenvatinib 8 mg capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor.

DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg

Japanese participants who received lenvatinib 12 mg capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor.

DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg

Non-Japanese participants who received lenvatinib 12 mg capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor.

DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg

PK Analysis Set included all participants who had received at least 1 dose of lenvatinib and pembrolizumab and had evaluable concentration data (data within the limit of quantification). "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

DLT+Expansion Part, Cmax: Maximum Observed Plasma Concentration for Lenvatinib

DLT+Expansion Part, Tmax: Time to Reach the Cmax for Lenvatinib

PK Analysis Set included all participants who had received at least 1 dose of lenvatinib and pembrolizumab and had evaluable concentration data (data within the limit of quantification). "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure (with concentration data within the limit of quantification).

DLT+Expansion Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib

Cycle 1 Day 1: 0-8 hours post-dose

Cycle 1 Day 15: 0-8 hours post-dose

PK Analysis Set included all participants who received at least 1 dose of lenvatinib and pembrolizumab and have evaluable concentration data (data within the limit of quantification). "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure (with concentration data within the limit of quantification) and "number analyzed" signifies participants who were evaluable for specified timepoints.

DLT+Expansion Part, AUC(0-ti): Area Under The Plasma Concentration-time Curve From Zero (Pre-Dose) to a Given Sampling Time (ti) for Lenvatinib

Cycle 1 Day 1: 0-24 hours post-dose

Cycle 1 Day 15: 0-24 hours post-dose

DLT+Expansion Part, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib

DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib

PK Analysis Set included all participants who received at least 1 dose of lenvatinib and pembrolizumab and have evaluable concentration data (data within the limit of quantification). "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure (with concentration data within the limit of quantification).

DLT+Expansion Part, CL/F: Apparent Total Clearance for Lenvatinib

DLT+Expansion Part, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib

PK Analysis Set included all participants who received at least 1 dose of lenvatinib and pembrolizumab and have evaluable concentration data (data within the limit of quantification). "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

DLT+Expansion Part, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib

DLT+Expansion Part, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib

DLT+Expansion Part, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib

DLT+Expansion Part, AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib

DLT+Expansion Part, Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib

DLT+Expansion Part, Css,Av: Average Steady State Plasma Concentration for Lenvatinib

DLT+Expansion Part, Vz,ss/F: Apparent Terminal Volume of Distribution at Steady State for Lenvatinib

DLT+Expansion Part, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib

DLT+Expansion Part, Rac (AUC0-8 Hour): Accumulation Ratio of AUC(0-8 Hour) for Lenvatinib

DLT+Expansion Part, %PTF: Percent (%) Peak-trough Fluctuation for Lenvatinib

Cycle 1: Pre-dose

Cycle 2: Pre-dose

Cycle 4: Pre-dose

Cycle 6: Pre-dose

Cycle 8: Pre-dose

Cycle 12: Pre-dose

Cycle 16: Pre-dose

Cycle 20: Pre-dose

Cycle 24: Pre-dose

Cycle 28: Pre-dose

Cycle 32: Pre-dose

Cycle 36: Pre-dose

Participants received pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor.

DLT+Expansion Part: Pembrolizumab 200 mg

PK Analysis Set included all participants who had received at least 1 dose of pembrolizumab and had evaluable concentration data. "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure and "number analyzed" signifies participants who were evaluable for specified timepoints. As per PK planned analysis for pembrolizumab, the combined PK data for pembrolizumab was collected and analyzed for participants of DLT and Expansion part.

DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab

Cycle 1 Day 1: Pre-dose

Cycle 6 Day 1: Pre-dose

All participants with HCC who received at least 1 dose of combination of lenvatinib and pembrolizumab as 1L therapy with no prior systemic therapy. Here, "overall number of participants analyzed" signifies participants with at least one ADA sample available after treatment with pembrolizumab.

DLT+Expansion Part: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status

In the DLT part, participants received lenvatinib 12 milligram (mg) or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in Cycle 1 of a 21-day treatment cycle. Participants with body weight greater than or equal to (\>=) 60 kilogram (kg) received lenvatinib 12 mg; participants with body weight less than (\<) 60 kg, received lenvatinib 8 mg. Participants who discontinued treatment in Cycle 1, entered the follow-up phase. Participants who were still receiving treatment at the end of Cycle 1, continued to receive same treatment until progressive disease (PD), development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Upon confirmation of the tolerability of the tested combination regimen of lenvatinib plus pembrolizumab in Cycle 1, expansion part was opened for participant's enrollment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma	NCT03006926	Hepatocellular ...	lenvatinib pembrolizumab (...	18 Years -	Eisai Inc.
A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma	NCT03006926	Hepatocellular ...	lenvatinib pembrolizumab (...	18 Years -	Eisai Inc.
A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma	NCT03006926	Hepatocellular ...	lenvatinib pembrolizumab (...	18 Years -	Eisai Inc.

Spots Global Cancer Trial Database for pembrolizumab (200 mg)