Hepatocellular Carcinoma
Conditions
Keywords
hepatocellular carcinoma, E7080, lenvatinib, pembrolizumab, Japan
Brief summary
This is an open-label Phase 1b study designed to evaluate the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with hepatocellular carcinoma (HCC). The study will evaluate objective response rate and duration of response by modified Response Evaluation Criteria In Solid Tumors (mRECIST) for HCC and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) based on independent imaging review (IIR).
Interventions
DRUGlenvatinib
4 mg capsules
DRUGpembrolizumab (200 mg)
30-minute intravenous infusion
Sponsors
Merck Sharp & Dohme LLC
Eisai Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of hepatocellular carcinoma (HCC) * HCC for which no other appropriate therapy is available. Note: Expansion Part: No prior systemic therapy for advanced/unresectable HCC * Stage B (not applicable for transarterial chemoembolization \[TACE\]), or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system * At least 1 measurable target lesion according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) * Child-Pugh score A * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1 * Total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within normal limits. (control by thyroid replacement therapy is acceptable.) Participants with T3, free T3 or free T4 abnormalities at screening who are asymptomatic can be eligible * Adequately controlled blood pressure * Adequate renal function * Adequate bone marrow function * Adequate blood coagulation function * Adequate liver function * Males or females age ≥ 18 years at the time of informed consent * Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol
Exclusion criteria
* Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent * Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 36 months * Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial * Active infection (any infection requiring systemic treatment). Hepatitis B or C \[HBV/HCV\] is allowed * Participants with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy \[WBRT\], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From first dose until 120 days after the last dose (up to 50.2 months) | 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). |
| Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From first dose until 120 days after the last dose (up to 50.2 months) | A TEAE was defined as an AE that emerged during the time from the first dose of study drug to 120 days (if participant initiated new anticancer therapy) following last dose of study drug, was absent at pretreatment (Baseline) or reemerged during treatment, was at pretreatment (Baseline) but stopped before treatment or worsened in severity during treatment relative to the pretreatment state, when AE was continuous. An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening (that is, participant was at immediate risk of death from AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). |
| DLT Part: Number of Participants With Dose Limiting Toxicities (DLTs) | From first dose of study drug up to Cycle 1 Day 21 (Cycle length= 21 days) | 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. |
| DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST Version (v) 1.1 Assessed by Independent Imaging Review (IIR) | 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) | 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. |
| DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR | 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 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). |
| DLT+Expansion Part: Duration of Response (DOR) Based on RECIST v1.1 Assessed by IIR | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by Investigator Review | 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. |
| DLT+Expansion Part: Overall Survival (OS) | From the date of first dose of study drug until date of death from any cause (up to 48.1 months) | 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. |
| DLT+Expansion Part, Cmax: Maximum Observed Plasma Concentration for Lenvatinib | Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days) | 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. |
| DLT+Expansion Part, Tmax: Time to Reach the Cmax for Lenvatinib | 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. |
| DLT+Expansion Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib | Cycle 1 Day 1: 0-24 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. |
| 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 Days 1 and 15: 0-8 hours post-dose (Cycle length=21 days) | 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. |
| DLT+Expansion Part, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib | 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. |
| DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | 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. |
| DLT+Expansion Part, CL/F: Apparent Total Clearance for Lenvatinib | 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. |
| DLT+Expansion Part, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib | 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. |
| DLT+Expansion Part, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib | 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. |
| DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review | 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) | 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. |
| DLT+Expansion Part, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib | 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. |
| DLT+Expansion Part, AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib | 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. |
| DLT+Expansion Part, Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib | 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. |
| DLT+Expansion Part, Css,Av: Average Steady State Plasma Concentration for Lenvatinib | 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. |
| DLT+Expansion Part, Vz,ss/F: Apparent Terminal Volume of Distribution at Steady State for Lenvatinib | 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. |
| DLT+Expansion Part, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib | 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. |
| DLT+Expansion Part, Rac (AUC0-8 Hour): Accumulation Ratio of AUC(0-8 Hour) for Lenvatinib | 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. |
| DLT+Expansion Part, %PTF: Percent (%) Peak-trough Fluctuation for Lenvatinib | 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. |
| DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab | Cycles 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36: Pre-dose (each Cycle length=21 days) | Ctrough was defined as trough (pre-dose) serum concentration for pembrolizumab at steady state. |
| DLT+Expansion Part: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status | Cycles 1 and 6 Day 1: Pre-dose (each cycle length=21 days) | 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. |
| DLT+Expansion Part, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib | 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. |
| DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review | 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) 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). |
| 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 | From the first study dose date to the date of first documentation of PD or death, whichever occurred first (up to 46.2 months) | 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). |
| 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 | From date of first dose of study drug until PD (up to 46.2 months) | 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). |
| DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by IIR | 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. |
| DLT+Expansion Part: Time-to-Response (TTR) Based on RECIST v1.1 Assessed by IIR | 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. |
Countries
France, Italy, Japan, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| 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. | 98 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 27 |
| Overall Study | Clinical Disease Progression | 0 | 10 |
| Overall Study | Other | 0 | 8 |
| Overall Study | Radiological Disease Progression | 0 | 52 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg | Total | DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg |
|---|---|---|---|
| Age, Continuous | 66.2 years STANDARD_DEVIATION 8.16 | 66.1 years STANDARD_DEVIATION 8.23 | 65.2 years STANDARD_DEVIATION 10.11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 84 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants | 17 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 26 Participants | 32 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 19 Participants | 0 Participants |
| Race (NIH/OMB) White | 51 Participants | 51 Participants | 0 Participants |
| Sex: Female, Male Female | 19 Participants | 20 Participants | 1 Participants |
| Sex: Female, Male Male | 79 Participants | 84 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 67 / 98 |
| other Total, other adverse events | 6 / 6 | 97 / 98 |
| serious Total, serious adverse events | 4 / 6 | 73 / 98 |
Outcome results
Primary
DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR | 16.7 months |
Primary
DLT+Expansion Part: Duration of Response (DOR) Based on RECIST v1.1 Assessed by IIR
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Duration of Response (DOR) Based on RECIST v1.1 Assessed by IIR | NA months |
Primary
DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST Version (v) 1.1 Assessed by Independent Imaging Review (IIR)
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
Primary
DLT Part: Number of Participants With Dose Limiting Toxicities (DLTs)
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT Part: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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).
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 6 Participants |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
Primary
Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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).
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 97 Participants |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 73 Participants |
Secondary
DLT+Expansion Part, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib
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.
Time frame: Cycle 1 Days 1 and 15: 0-24 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 | — |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | 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 | 1900 ng*h/mL | Geometric Coefficient of Variation 31.8 |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | 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 | — |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | 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 | 1540 ng*h/mL | Geometric Coefficient of Variation 16.6 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | 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 | 2530 ng*h/mL | — |
Secondary
DLT+Expansion Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib
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.
Time frame: 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 (with concentration data within the limit of quantification).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib | 1230 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 7.61 |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib | 1690 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 23.7 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib | 1950 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 39.2 |
Secondary
DLT+Expansion Part, AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib | 4150 ng*h/mL | — |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib | 2330 ng*h/mL | Geometric Coefficient of Variation 16.5 |
Secondary
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
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | 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 | 868 ng*h/mL | Geometric Coefficient of Variation 25.9 |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | 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 | 1020 ng*h/mL | Geometric Coefficient of Variation 57.4 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | 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 | 736 ng*h/mL | Geometric Coefficient of Variation 42.2 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | 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 | 1120 ng*h/mL | Geometric Coefficient of Variation 18.2 |
Secondary
DLT+Expansion Part, CL/F: Apparent Total Clearance for Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, CL/F: Apparent Total Clearance for Lenvatinib | 5.98 liter per hour (L/h) | — |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, CL/F: Apparent Total Clearance for Lenvatinib | 6.32 liter per hour (L/h) | Geometric Coefficient of Variation 31.6 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, CL/F: Apparent Total Clearance for Lenvatinib | 7.79 liter per hour (L/h) | Geometric Coefficient of Variation 16.7 |
Secondary
DLT+Expansion Part, Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib | 2.89 L/h | — |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib | 5.14 L/h | Geometric Coefficient of Variation 16.4 |
Secondary
DLT+Expansion Part, Cmax: Maximum Observed Plasma Concentration for Lenvatinib
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, Cmax: Maximum Observed Plasma Concentration for Lenvatinib | 127 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 37.7 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg | DLT+Expansion Part, Cmax: Maximum Observed Plasma Concentration for Lenvatinib | 98.3 nanogram per milliliter (ng/mL) | — |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Cmax: Maximum Observed Plasma Concentration for Lenvatinib | 168 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 29.7 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Cmax: Maximum Observed Plasma Concentration for Lenvatinib | 145 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 30.9 |
Secondary
DLT+Expansion Part, Css,Av: Average Steady State Plasma Concentration for Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Css,Av: Average Steady State Plasma Concentration for Lenvatinib | 173 ng/mL | — |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Css,Av: Average Steady State Plasma Concentration for Lenvatinib | 97.2 ng/mL | Geometric Coefficient of Variation 16.4 |
Secondary
DLT+Expansion Part, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib | 154 ng/mL | Geometric Coefficient of Variation 25.1 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg | DLT+Expansion Part, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib | 145 ng/mL | — |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib | 201 ng/mL | Geometric Coefficient of Variation 53.5 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib | 193 ng/mL | Geometric Coefficient of Variation 17.8 |
Secondary
DLT+Expansion Part, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib | 42.9 ng/mL | Geometric Coefficient of Variation 24.7 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg | DLT+Expansion Part, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib | 14.3 ng/mL | — |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib | 33.4 ng/mL | Geometric Coefficient of Variation 48.1 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib | 34.3 ng/mL | Geometric Coefficient of Variation 51.3 |
Secondary
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab
Ctrough was defined as trough (pre-dose) serum concentration for pembrolizumab at steady state.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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
DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review | 17.1 months |
Secondary
DLT+Expansion Part: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status | Cycle 1 Day 1: Pre-dose | 3 Participants |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status | Cycle 6 Day 1: Pre-dose | 0 Participants |
Secondary
DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review | 43.0 percentage of participants |
Secondary
DLT+Expansion Part: Overall Survival (OS)
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Overall Survival (OS) | 20.4 months |
Secondary
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
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
Secondary
DLT+Expansion Part, %PTF: Percent (%) Peak-trough Fluctuation for Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, %PTF: Percent (%) Peak-trough Fluctuation for Lenvatinib | 161 percentage fluctuation | — |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, %PTF: Percent (%) Peak-trough Fluctuation for Lenvatinib | 161 percentage fluctuation | Geometric Coefficient of Variation 34 |
Secondary
DLT+Expansion Part, Rac (AUC0-8 Hour): Accumulation Ratio of AUC(0-8 Hour) for Lenvatinib
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.
Time frame: 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Rac (AUC0-8 Hour): Accumulation Ratio of AUC(0-8 Hour) for Lenvatinib | 1.32 ratio | Geometric Coefficient of Variation 44.8 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Rac (AUC0-8 Hour): Accumulation Ratio of AUC(0-8 Hour) for Lenvatinib | 1.83 ratio | Geometric Coefficient of Variation 66.8 |
Secondary
DLT+Expansion Part, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib
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.
Time frame: Cycle 1 Days 1 and 15: 0-24 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib | 1.07 ratio | Geometric Coefficient of Variation 28.6 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg | DLT+Expansion Part, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib | 1.48 ratio | — |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib | 1.17 ratio | Geometric Coefficient of Variation 33.9 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib | 1.38 ratio | Geometric Coefficient of Variation 41.7 |
Secondary
DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib
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.
Time frame: Cycle 1 Days 1 and 15: 0-24 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | Cycle 1 Day 1: 0-24 hours post-dose | 7.71 hours | — |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | Cycle 1 Day 1: 0-24 hours post-dose | 6.64 hours | Geometric Coefficient of Variation 16 |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | Cycle 1 Day 15: 0-24 hours post-dose | 7.33 hours | — |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | Cycle 1 Day 1: 0-24 hours post-dose | 5.75 hours | Geometric Coefficient of Variation 3.07 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | Cycle 1 Day 15: 0-24 hours post-dose | 6.48 hours | — |
Secondary
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
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | 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 |
Secondary
DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by IIR
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.
Time frame: From date of first dose of study drug until CR or PR (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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by IIR | 2.5 months |
Secondary
DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by Investigator Review
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.
Time frame: From date of first dose of study drug until CR or PR (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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by Investigator Review | 2.7 months |
Secondary
DLT+Expansion Part: Time-to-Response (TTR) Based on RECIST v1.1 Assessed by IIR
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.
Time frame: From date of first dose of study drug until CR or PR (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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part: Time-to-Response (TTR) Based on RECIST v1.1 Assessed by IIR | 2.8 months |
Secondary
DLT+Expansion Part, Tmax: Time to Reach the Cmax for Lenvatinib
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, Tmax: Time to Reach the Cmax for Lenvatinib | 3.90 hours |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg | DLT+Expansion Part, Tmax: Time to Reach the Cmax for Lenvatinib | 4.00 hours |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Tmax: Time to Reach the Cmax for Lenvatinib | 3.92 hours |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Tmax: Time to Reach the Cmax for Lenvatinib | 4.00 hours |
Secondary
DLT+Expansion Part, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib | 6.01 hours |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 8 mg | DLT+Expansion Part, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib | 4.02 hours |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib | 3.89 hours |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib | 4.00 hours |
Secondary
DLT+Expansion Part, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib
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.
Time frame: Cycle 1 Day 1: 0-24 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg | DLT+Expansion Part, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib | 66.6 liter | — |
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib | 60.6 liter | Geometric Coefficient of Variation 23.2 |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib | 64.7 liter | Geometric Coefficient of Variation 19.8 |
Secondary
DLT+Expansion Part, Vz,ss/F: Apparent Terminal Volume of Distribution at Steady State for Lenvatinib
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.
Time frame: Cycle 1 Day 15: 0-24 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| DLT+Expansion Part, Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Vz,ss/F: Apparent Terminal Volume of Distribution at Steady State for Lenvatinib | 30.6 liter |
| DLT+Expansion Part, Non-Japanese Participants: Lenvatinib 12 mg | DLT+Expansion Part, Vz,ss/F: Apparent Terminal Volume of Distribution at Steady State for Lenvatinib | 48.5 liter |