Trial Outcomes & Findings for Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Participants With Selected Solid Tumors (NCT NCT03006887)

Last Updated: 2021-05-20

Results Overview

A TEAE was defined as an adverse event (AE) that emerged during the time from the first dose of study drug to 30 days following the last dose of study drug, having been absent at pretreatment (Baseline) or reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. A Serious AE is any untoward medical occurrence that at any dose: resulted in death; was life threatening (that is, the participant was at immediate risk of death from the AE as it occurred; this does 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 or is medically important due to other reasons than the above mentioned criteria.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

6 participants

Primary outcome timeframe

From the first dose until 30 days after the last dose (approximately 2 years 7 months)

Results posted on

2021-05-20

Participant Flow

Participants took part in the study at 1 investigative site in Japan from 12 Jan 2017 to 15 Apr 2020.

A total of 11 participants were screened, of which 5 were screen failures and 6 received study treatment.

Participant milestones

Participant milestones
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 milligram (mg), capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing Dose limiting toxicities (DLTs). In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Overall Study STARTED	6
Overall Study COMPLETED	5
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 milligram (mg), capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing Dose limiting toxicities (DLTs). In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Overall Study Adverse Event	1

Baseline Characteristics

Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Participants With Selected Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Age, Continuous	55.0 years STANDARD_DEVIATION 13.39 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: From the first dose until 30 days after the last dose (approximately 2 years 7 months)

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

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	6 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	4 Participants

PRIMARY outcome

Timeframe: Cycle 1 (Cycle length=21 days)

Population: The DLT set included all participants who completed Cycle 1 without major protocol deviation with at least 75% of study drug compliance and were assessed for DLT, and participants who experienced DLT during Cycle 1.

A DLT is defined as any of the following: any of the hematological or nonhematological toxicities specified in the protocol that are considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1; failed to administer greater than or equal to 75 percent (%) of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1; participants who discontinued due to treatment-related toxicity in Cycle 1; greater than a 2-week delay in starting pembrolizumab in Cycle 2 because of a treatment-related toxicity, even if the toxicity does not meet DLT criteria.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Number of Participants With Dose-limiting Toxicities	0 Participants

SECONDARY outcome

Timeframe: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 7 months

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

ORR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) for target and non-target lesions. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The tumor assessment was done using number of lesions based on modified RECIST 1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1	33.3 percentage of participants

SECONDARY outcome

Timeframe: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 7 months.

Population: The efficacy analysis set included all participants who received at least 1 dose of study drug. Here overall number analyzed "N" included the participants who had CR or PR.

DOR was defined as time from the first documented of CR or PR to the date of first documentation of disease progression (PD) (based on modified RECIST 1.1) or death (whichever occurs first). CR was defined as the disappearance of all target lesions and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD for target lesion, was defined as a minimum 20% increase and a minimum 5 mm absolute increase in sum of diameters compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir was defined as lowest measure sum of diameters of target lesions at any time point from baseline onward. The tumor assessment was done using number of lesions based on modified RECIST 1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ. DOR = Date of PD/death (whichever occurs first) - Date of first CR or PR + 1.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=2 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Duration of Response (DOR) Based on Modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1	NA months Interval 16.79 to Median and upper limit of 95%CI was not estimable due to lesser number of participants with events.

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Cmax: Maximum Plasma Concentration of Lenvatinib in Combination With Pembrolizumab	325 nanogram per milliliter (ng/mL) Standard Deviation 233

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Lenvatinib in Combination With Pembrolizumab	3.85 hours Interval 1.78 to 7.02

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data. Here overall number analyzed "N" included the participants who were evaluable for the outcome measure.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=2 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
T1/2: Terminal Half-life of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 1	5.62 hours Interval 5.52 to 5.71
T1/2: Terminal Half-life of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 15	7.26 hours Interval 6.95 to 7.57

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 1	3040 nanogramhour per milliliter (ngh/mL) Standard Deviation 1780
AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 15	4280 nanogramhour per milliliter (ngh/mL) Standard Deviation 2600

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=2 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Lenvatinib in Combination With Pembrolizumab	3880 ng*h/mL Standard Deviation 2090

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=2 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Vz/F: Apparent Volume of Distribution at Terminal Phase of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 1	41.8 liter (L) Standard Deviation 23.5
Vz/F: Apparent Volume of Distribution at Terminal Phase of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 15	26.1 liter (L) Standard Deviation 0.636

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data. Here, overall number analyzed "N" are the participants who were evaluable for the outcome measure.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=2 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
CL/F: Apparent Total Clearance Following Oral Dosing of Lenvatinib in Combination With Pembrolizumab	5.15 liter per hour (L/hr) Standard Deviation 2.78

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=2 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
MRT: Mean Residence Time of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 1	9.06 hours Standard Deviation 0.983
MRT: Mean Residence Time of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 15	11.8 hours Standard Deviation 0.141

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Css,Max: Maximum Observed Plasma Concentration at Steady State of Lenvatinib in Combination With Pembrolizumab	355 ng/mL Standard Deviation 319

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Css,Min: Minimum Observed Plasma Concentration at Steady State of Lenvatinib in Combination With Pembrolizumab	60.1 ng/mL Standard Deviation 24.6

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State of Lenvatinib in Combination With Pembrolizumab	7.14 hours Interval 2.07 to 7.83

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=3 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval of Lenvatinib in Combination With Pembrolizumab	6780 ng*h/mL Standard Deviation 1820

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=3 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Clss/F: Apparent Total Clearance Following Oral Administration at Steady State of Lenvatinib in Combination With Pembrolizumab	2.95 L/h Standard Deviation 0.932

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=3 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Css,Av: Average Steady State Plasma Concentration of Lenvatinib in Combination With Pembrolizumab	283 ng/mL Standard Deviation 75.8

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours and Cycle 1 Day 15: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Rac (Cmax) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Rac (Cmax) = Css,max on Cycle 1 Day 15 / Cmax on Cycle 1 Day 1

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Rac (Cmax): Accumulation Index of Cmax for Lenvatinib in Combination With Pembrolizumab	1.14 ratio Standard Deviation 0.376

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours and Cycle 1 Day 15: 0-24 hours

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Rac (AUC) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Rac (AUC) = AUC(0-t) on Cycle 1 Day 15 / AUC(0-t) on Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Rac (AUC): Accumulation Index of AUC for Lenvatinib in Combination With Pembrolizumab	1.46 ratio Standard Deviation 0.450

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 15: 0-24 hours

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=2 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Lambda z: Terminal Phase Elimination Rate Constant of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 1	0.123 1/hour Standard Deviation 0.00354
Lambda z: Terminal Phase Elimination Rate Constant of Lenvatinib in Combination With Pembrolizumab Cycle 1 Day 15	0.0956 1/hour Standard Deviation 0.00573

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours

The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=3 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
PTF: Peak-trough Fluctuation Ratio of Lenvatinib in Combination With Pembrolizumab	194 Percentage fluctuation Standard Deviation 48.8

SECONDARY outcome

Timeframe: Day 1 of Cycles 1, 2, 4, 6, and 8 and every 4 cycles thereafter; within 30 days after discontinuation or until the initiation of other anticancer treatment, whichever is earlier (Cycle length=21 days); up to 31 months

Population: The PK analysis set included all participants who received at least 1 dose of lenvatinib and pembrolizumab, and had evaluable concentration data.

Outcome measures

Outcome measures
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 Participants Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status for Pembrolizumab	0 Participants

Adverse Events

Lenvatinib 20 mg Plus Pembrolizumab 200 mg

Serious events: 4 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 participants at risk Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Gastrointestinal disorders Subileus	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Hepatobiliary disorders Bile duct stenosis	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Pneumonitis	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Infections and infestations Aspergillus infection	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)

Other adverse events

Other adverse events
Measure	Lenvatinib 20 mg Plus Pembrolizumab 200 mg n=6 participants at risk Participants with selected solid tumors received oral lenvatinib at a starting dose of 20 mg, capsule, once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks on a 21-day treatment cycle to confirm the dose tolerability by assessing DLTs. In case of dose intolerability in Cycle 1, lenvatinib dose was reduced from 20 mg to 14 mg once daily, in combination with 200 mg pembrolizumab every 3 weeks administered up to maximum of 45 cycles or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study (31 months).
Blood and lymphatic system disorders Anaemia	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Ear and labyrinth disorders Tinnitus	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Endocrine disorders Hypothyroidism	83.3% 5/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Endocrine disorders Hyperthyroidism	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Gastrointestinal disorders Nausea	66.7% 4/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Gastrointestinal disorders Abdominal pain	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Gastrointestinal disorders Constipation	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Gastrointestinal disorders Diarrhoea	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Gastrointestinal disorders Stomatitis	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Gastrointestinal disorders Vomiting	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Gastrointestinal disorders Haemorrhoids	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Gastrointestinal disorders Odynophagia	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
General disorders Fatigue	83.3% 5/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
General disorders Malaise	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
General disorders Oedema	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
General disorders Oedema peripheral	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
General disorders Performance status decreased	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Hepatobiliary disorders Gallbladder enlargement	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Infections and infestations Nasopharyngitis	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Infections and infestations Bronchopulmonary aspergillosis	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Infections and infestations Conjunctivitis	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Infections and infestations Hordeolum	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Infections and infestations Tooth infection	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Infections and infestations Upper respiratory tract infection	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Injury, poisoning and procedural complications Post procedural haemorrhage	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Injury, poisoning and procedural complications Thermal burn	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Aspartate aminotransferase increased	100.0% 6/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Alanine aminotransferase increased	83.3% 5/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Gamma-glutamyltransferase increased	50.0% 3/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Lipase increased	50.0% 3/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Platelet count decreased	50.0% 3/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations White blood cell count decreased	50.0% 3/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Blood bilirubin increased	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Lymphocyte count decreased	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Neutrophil count decreased	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Weight decreased	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Amylase increased	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Blood alkaline phosphatase increased	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Blood cholesterol increased	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Blood creatinine increased	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Investigations Electrocardiogram ST-T change	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Metabolism and nutrition disorders Decreased appetite	66.7% 4/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Metabolism and nutrition disorders Hypoalbuminaemia	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Metabolism and nutrition disorders Hyperphosphataemia	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Metabolism and nutrition disorders Hypozincaemia	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Musculoskeletal and connective tissue disorders Periarthritis	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Nervous system disorders Headache	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Nervous system disorders Peripheral sensory neuropathy	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Psychiatric disorders Insomnia	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Renal and urinary disorders Proteinuria	66.7% 4/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Epistaxis	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Dysphonia	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Dyspnoea	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Haemoptysis	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Pneumonitis	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	50.0% 3/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Skin and subcutaneous tissue disorders Rash	33.3% 2/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Skin and subcutaneous tissue disorders Dry skin	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Skin and subcutaneous tissue disorders Pruritus	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Skin and subcutaneous tissue disorders Purpura	16.7% 1/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)
Vascular disorders Hypertension	100.0% 6/6 • Baseline up to 30 days after last dose of study drug (approximately 2 years 7 months)

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