Trial Outcomes & Findings for A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma (NCT NCT03006926)

Last Updated: 2023-12-13

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

104 participants

Primary outcome timeframe

From first dose until 120 days after the last dose (up to 50.2 months)

Results posted on

2023-12-13

Participant Flow

Participants took part in the study at 24 investigative sites in the United States, Japan, United Kingdom, France, Italy, Spain, and Russian Federation from 13 February 2017 to 22 November 2022.

A total of 104 participants were enrolled and received treatment. Of these, 6 participants were enrolled in Dose Limiting Toxicity (DLT) part and 98 were enrolled in the expansion part.

Participant milestones

Participant milestones
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg 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.	Expansion 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.
Overall Study STARTED	6	98
Overall Study Japanese Population	6	16
Overall Study Non-Japanese Population	0	82
Overall Study COMPLETED	6	0
Overall Study NOT COMPLETED	0	98

Reasons for withdrawal

Reasons for withdrawal
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg 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.	Expansion 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.
Overall Study Adverse Event	0	27
Overall Study Withdrawal by Subject	0	1
Overall Study Radiological Disease Progression	0	52
Overall Study Clinical Disease Progression	0	10
Overall Study Other	0	8

Baseline Characteristics

A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=6 Participants 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.	Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg n=98 Participants 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.	Total n=104 Participants Total of all reporting groups
Age, Continuous	65.2 years STANDARD_DEVIATION 10.11 • n=5 Participants	66.2 years STANDARD_DEVIATION 8.16 • n=7 Participants	66.1 years STANDARD_DEVIATION 8.23 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	19 Participants n=7 Participants	20 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	79 Participants n=7 Participants	84 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	78 Participants n=7 Participants	84 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	17 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants	26 Participants n=7 Participants	32 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	51 Participants n=7 Participants	51 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	19 Participants n=7 Participants	19 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first dose until 120 days after the last dose (up to 50.2 months)

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

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=6 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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 Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	6 Participants	—	—	—
DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	4 Participants	—	—	—

PRIMARY outcome

Timeframe: From first dose until 120 days after the last dose (up to 50.2 months)

Population: The safety analysis set included all participants who had received at least 1 dose of 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).

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=98 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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.
Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	97 Participants	—	—	—
Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	73 Participants	—	—	—

PRIMARY outcome

Timeframe: From first dose of study drug up to Cycle 1 Day 21 (Cycle length= 21 days)

Population: 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 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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=6 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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 Part: Number of Participants With Dose Limiting Toxicities (DLTs)	0 Participants	—	—	—

PRIMARY outcome

Timeframe: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 46.2 months)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=100 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Objective Response Rate (ORR) Based on mRECIST and RECIST Version (v) 1.1 Assessed by Independent Imaging Review (IIR) RECIST v1.1	38.0 percentage of participants Interval 28.5 to 48.3	—	—	—
DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST Version (v) 1.1 Assessed by Independent Imaging Review (IIR) mRECIST	46.0 percentage of participants Interval 36.0 to 56.3	—	—	—

PRIMARY outcome

Timeframe: From date of first documented confirmed CR or PR until date of first documentation of PD or death, whichever occurred first (up to 46.2 months)

Population: 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.

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).

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=46 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Duration of Response (DOR) Based on mRECIST Assessed by IIR	16.7 months Interval 8.6 to Upper limit of confidence interval could not be estimated due to an insufficient number of events.	—	—	—

PRIMARY outcome

Timeframe: From date of first documented confirmed CR or PR until date of first documentation of PD or death, whichever occurred first (up to 46.2 months)

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).

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=38 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Duration of Response (DOR) Based on RECIST v1.1 Assessed by IIR	NA months Interval 12.6 to Median and upper limit of confidence interval could not be estimated due to an insufficient number of events.	—	—	—

SECONDARY outcome

Timeframe: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 46.2 months)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=100 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review	43.0 percentage of participants Interval 33.1 to 53.3	—	—	—

SECONDARY outcome

Timeframe: From date of first documented confirmed CR or PR until date of first documentation of PD or death, whichever occurred first (up to 46.2 months)

Population: 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.

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).

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=43 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review	17.1 months Interval 6.9 to 19.3	—	—	—

SECONDARY outcome

Timeframe: From the first study dose date to the date of first documentation of PD or death, whichever occurred first (up to 46.2 months)

Population: 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.

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).

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=100 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Progression-free Survival (PFS) Based on mRECIST and RECIST v1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review mRECIST: IIR	9.6 months Interval 5.6 to 11.8	—	—	—
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 RECIST v1.1: IIR	9.6 months Interval 7.6 to 10.8	—	—	—
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 mRECIST: Investigator Review	9.3 months Interval 7.4 to 9.8	—	—	—

SECONDARY outcome

Timeframe: From date of first dose of study drug until PD (up to 46.2 months)

Population: 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.

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).

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=100 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Time-to-Progression (TTP) Based on mRECIST and RECIST v1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review mRECIST: IIR	9.9 months Interval 9.3 to 20.0	—	—	—
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 RECIST v1.1: IIR	10.8 months Interval 9.6 to 24.3	—	—	—
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 mRECIST: Investigator Review	9.8 months Interval 7.7 to 15.9	—	—	—

SECONDARY outcome

Timeframe: From date of first dose of study drug until CR or PR (up to 46.2 months)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=46 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Time-to-Response (TTR) Based on mRECIST Assessed by IIR	2.5 months Interval 1.2 to 7.6	—	—	—

SECONDARY outcome

Timeframe: From date of first dose of study drug until CR or PR (up to 46.2 months)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=38 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Time-to-Response (TTR) Based on RECIST v1.1 Assessed by IIR	2.8 months Interval 1.2 to 13.8	—	—	—

SECONDARY outcome

Timeframe: From date of first dose of study drug until CR or PR (up to 46.2 months)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=43 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Time-to-Response (TTR) Based on mRECIST Assessed by Investigator Review	2.7 months Interval 1.2 to 15.7	—	—	—

SECONDARY outcome

Timeframe: From the date of first dose of study drug until date of death from any cause (up to 48.1 months)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=100 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Overall Survival (OS)	20.4 months Interval 14.4 to 25.9	—	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=7 Participants 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+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg n=1 Participants 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, Japanese Participants: Lenvatinib 12 mg n=11 Participants 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 n=9 Participants 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, Cmax: Maximum Observed Plasma Concentration for Lenvatinib	127 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 37.7	98.3 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	168 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 29.7	145 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 30.9

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=7 Participants 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+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg n=1 Participants 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, Japanese Participants: Lenvatinib 12 mg n=11 Participants 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 n=9 Participants 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, Tmax: Time to Reach the Cmax for Lenvatinib	3.90 hours Interval 1.0 to 7.97	4.00 hours Full Range (minimum and maximum) could not be calculated for a single participant.	3.92 hours Interval 0.82 to 7.92	4.00 hours Interval 2.0 to 8.8

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=7 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=11 Participants 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 n=4 Participants 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, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib	1230 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 7.61	—	1690 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 23.7	1950 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 39.2

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=21 days)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=7 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=11 Participants 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 n=6 Participants 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, 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: 0-8 hours post-dose	673 ng*h/mL Geometric Coefficient of Variation 29.3	—	868 ng*h/mL Geometric Coefficient of Variation 25.9	736 ng*h/mL Geometric Coefficient of Variation 42.2
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 15: 0-8 hours post-dose	793 ng*h/mL Geometric Coefficient of Variation 36.0	—	1020 ng*h/mL Geometric Coefficient of Variation 57.4	1120 ng*h/mL Geometric Coefficient of Variation 18.2

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=1 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=5 Participants 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 n=2 Participants 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, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib Cycle 1 Day 1: 0-24 hours post-dose	1340 ng*h/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	—	1900 ng*h/mL Geometric Coefficient of Variation 31.8	1540 ng*h/mL Geometric Coefficient of Variation 16.6
DLT+Expansion Part, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib Cycle 1 Day 15: 0-24 hours post-dose	—	—	4690 ng*h/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	2530 ng*h/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=1 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=5 Participants 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 n=2 Participants 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, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib Cycle 1 Day 1: 0-24 hours post-dose	7.71 hours Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	—	6.64 hours Geometric Coefficient of Variation 16.0	5.75 hours Geometric Coefficient of Variation 3.07
DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib Cycle 1 Day 15: 0-24 hours post-dose	—	—	7.33 hours Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	6.48 hours Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=1 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=5 Participants 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 n=2 Participants 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, CL/F: Apparent Total Clearance for Lenvatinib	5.98 liter per hour (L/h) Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	—	6.32 liter per hour (L/h) Geometric Coefficient of Variation 31.6	7.79 liter per hour (L/h) Geometric Coefficient of Variation 16.7

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=1 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=5 Participants 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 n=2 Participants 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, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib	66.6 liter Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	—	60.6 liter Geometric Coefficient of Variation 23.2	64.7 liter Geometric Coefficient of Variation 19.8

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=4 Participants 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+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg n=1 Participants 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, Japanese Participants: Lenvatinib 12 mg n=8 Participants 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 n=5 Participants 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, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib	154 ng/mL Geometric Coefficient of Variation 25.1	145 ng/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	201 ng/mL Geometric Coefficient of Variation 53.5	193 ng/mL Geometric Coefficient of Variation 17.8

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=4 Participants 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+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg n=1 Participants 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, Japanese Participants: Lenvatinib 12 mg n=8 Participants 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 n=5 Participants 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, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib	42.9 ng/mL Geometric Coefficient of Variation 24.7	14.3 ng/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	33.4 ng/mL Geometric Coefficient of Variation 48.1	34.3 ng/mL Geometric Coefficient of Variation 51.3

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=4 Participants 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+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg n=1 Participants 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, Japanese Participants: Lenvatinib 12 mg n=8 Participants 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 n=5 Participants 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, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib	6.01 hours Interval 4.0 to 8.0	4.02 hours Full Range (minimum and maximum) could not be calculated for a single participant.	3.89 hours Interval 2.02 to 7.77	4.00 hours Interval 1.98 to 4.42

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=1 Participants 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 n=3 Participants 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, AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib	—	—	4150 ng*h/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	2330 ng*h/mL Geometric Coefficient of Variation 16.5

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=1 Participants 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 n=3 Participants 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, Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib	—	—	2.89 L/h Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	5.14 L/h Geometric Coefficient of Variation 16.4

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=1 Participants 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 n=3 Participants 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, Css,Av: Average Steady State Plasma Concentration for Lenvatinib	—	—	173 ng/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	97.2 ng/mL Geometric Coefficient of Variation 16.4

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=1 Participants 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 n=1 Participants 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, Vz,ss/F: Apparent Terminal Volume of Distribution at Steady State for Lenvatinib	—	—	30.6 liter Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	48.5 liter Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=4 Participants 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+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg n=1 Participants 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, Japanese Participants: Lenvatinib 12 mg n=8 Participants 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 n=5 Participants 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, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib	1.07 ratio Geometric Coefficient of Variation 28.6	1.48 ratio Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	1.17 ratio Geometric Coefficient of Variation 33.9	1.38 ratio Geometric Coefficient of Variation 41.7

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=4 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=6 Participants 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 n=3 Participants 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, Rac (AUC0-8 Hour): Accumulation Ratio of AUC(0-8 Hour) for Lenvatinib	1.07 ratio Geometric Coefficient of Variation 21.2	—	1.32 ratio Geometric Coefficient of Variation 44.8	1.83 ratio Geometric Coefficient of Variation 66.8

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 mg n=1 Participants 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 n=3 Participants 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, %PTF: Percent (%) Peak-trough Fluctuation for Lenvatinib	—	—	161 percentage fluctuation Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.	161 percentage fluctuation Geometric Coefficient of Variation 34.0

SECONDARY outcome

Timeframe: Cycles 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36: Pre-dose (each Cycle length=21 days)

Population: 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.

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

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=101 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 1: Pre-dose	0.00 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 0.00	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 2: Pre-dose	12.3 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 40.7	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 4: Pre-dose	21.9 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 56.6	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 6: Pre-dose	25.0 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 64.7	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 8: Pre-dose	26.6 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 86.1	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 12: Pre-dose	27.9 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 57.7	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 16: Pre-dose	33.6 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 39.3	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 20: Pre-dose	27.9 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 50.1	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 24: Pre-dose	29.0 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 69.9	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 28: Pre-dose	32.4 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 49	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 32: Pre-dose	30.7 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 34.3	—	—	—
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab Cycle 36: Pre-dose	34.6 microgram per milliliter (mcg/mL) Geometric Coefficient of Variation 40.2	—	—	—

SECONDARY outcome

Timeframe: Cycles 1 and 6 Day 1: Pre-dose (each cycle length=21 days)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg n=81 Participants 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+Expansion Part, Non-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, Japanese Participants: Lenvatinib 12 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, Non-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: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status Cycle 1 Day 1: Pre-dose	3 Participants	—	—	—
DLT+Expansion Part: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status Cycle 6 Day 1: Pre-dose	0 Participants	—	—	—

Adverse Events

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

Serious events: 4 serious events

Other events: 6 other events

Deaths: 5 deaths

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

Serious events: 73 serious events

Other events: 97 other events

Deaths: 67 deaths

Serious adverse events

Other adverse events

Additional Information

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Principal investigator is a sponsor employee
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