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Lenvatinib

Benzocaine

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Cadexomer iodine

Protein Kinase Inhibitors

Enzyme Inhibitors

Tannic Acid

Participants will receive 24 mg once daily (QD) as the starting dose. Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, or 8 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.

Participants will receive 18mg QD as the starting dose. Dose reductions will occur in succession based on the previous dose level (18,14, 10, 8, or 4 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.

Lenvatinib matching placebo

This is a multicenter, randomized, double-blind study being conducted as a postmarketing requirement to the US Food and Drug Administration (FDA) to evaluate whether there is a lower starting dosage of lenvatinib 24 mg once daily (QD) that provides comparable efficacy but has a better safety profile in participants with radioiodine-refractory differentiated thyroid cancer RR-DTC with radiographic evidence of disease progression within the prior 12 months.

This study consists of 2 phases, the Prerandomization Phase and the Randomization Phase. The Prerandomization Phase will last no longer than 28 days and will include a Screening Period to establish protocol eligibility and a Baseline Period to confirm eligibility and establish disease characteristics prior to randomization and treatment.

The Randomization Phase will consist of a Treatment Period and a Follow-up Period. It will begin at the time of randomization of the first participant and will consist of 28-day blinded study treatment cycles. The data cutoff for the primary analysis will occur at the end of the Randomization Phase, which is defined as when the last participant enrolled completes the Week 24 tumor assessments or discontinues study treatment if before Week 24.

Participants on treatment at the time of data cutoff for the primary analysis will remain on blinded investigational product until the primary analysis has been completed, after which they will transition to commercial lenvatinib outside the study. The last participant's last assessment (Off-treatment visit) will be the End of Study.

Participants will be randomly assigned to treatment with 1 of 2 blinded starting dosages of lenvatinib in a 1:1 ratio to receive lenvatinib 18 mg or 24 mg orally once daily (QD). Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, and 8 mg QD, or 18, 14, 10, 8, and 4 mg QD, respectively). Once the dose has been reduced, it may not be increased at a later date.

A Trial of Lenvatinib (E7080) in Subjects With Iodine-131 Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 Milligram (mg) Daily Will Provide Comparable Efficacy to a 24 mg Starting Dose, But Have a Better Safety Profile

A Multicenter, Randomized, Double-Blind Phase 2 Trial of Lenvatinib (E7080) in Subjects With 131I-Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 mg Daily Will Provide Comparable Efficacy to a 24-mg Starting Dose, But Have a Better Safety Profile

ORR as of Week 24 was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) as of the Week 24 time point or earlier, as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.

This outcome measure reports TEAEs in the first 24 weeks only. A TEAE was defined as any adverse event (AE) that had an onset date on or after the first dose of study drug up to 28 days following the last dose of study drug, or a worsening in severity from Baseline (pretreatment). In addition, if an AE reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, it was also counted as a TEAE. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.

PFS, defined as the time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurs first, as measured by RECIST V1.1. PD: 20% increase in the sum of the pertinent diameters (SOD) of target lesions, taking as reference the smallest sum SOD recorded since the treatment started or the appearance of one or more new lesions. PFS was analyzed using the Kaplan-Meier method. As planned, data for this endpoint was analyzed and collected till Primary completion date.

PFS2, defined as the time from randomization to PD on next-line treatment, or death from any cause, whichever occurred first, as measured by RECIST V1.1. PD: 20% increase in the SOD of target lesions, taking as reference the smallest sum SOD recorded since the treatment started or the appearance of one or more new lesions. PFS was analyzed using the Kaplan-Meier method. As planned, data for this endpoint was analyzed and collected till Primary completion date.

TEAEs were defined as those AEs that occurred (or worsened, if present at Baseline) after the first dose of study drug through 28 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. SAE was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect.

Time to Treatment Discontinuation due to an AE (such as abdominal distention, appendicitis perforated, arthralgia, anemia, etc) was analyzed using the Kaplan-Meier method. As planned, data for this endpoint was analyzed and collected till Primary completion date.

Number of dose reduction was reported as number of participants who underwent one or more number of dose reductions. As planned, data for this endpoint was analyzed and collected till Primary completion date.

Time to First Dose Reduction was analyzed using the Kaplan-Meier method. As planned, data for this endpoint was analyzed and collected till Primary completion date.

Sparse pharmacokinetic (PK) samples (approximately 9 per participant) were collected and analyzed using a population PK approach to estimate PK parameters. Lenvatinib total plasma concentration data were pooled with data from studies E7080-G000-303 (NCT01321554) and E7080-G000-201 (NCT00784303), and a population PK model was applied to the pooled dataset. Individual predicted CL/F for lenvatinib was then derived from the PK model by starting dose.

Sparse PK samples (approximately 9 per participant) were collected and analyzed using a population PK approach to estimate PK parameters. Lenvatinib total plasma concentration data were pooled with data from studies E7080-G000-303 (NCT01321554) and E7080-G000-201 (NCT00784303), and a population PK model was applied to the pooled dataset. Individual predicted AUC for lenvatinib was then derived from the PK model by starting dose.

The relationship between exposure to lenvatinib and change from baseline in thyroglobulin was planned to be analyzed using a model-based approach.

The relationship between exposure to lenvatinib and change from baseline in TSH was planned to be analyzed using a model-based approach.

Per the planned population PK/PD analysis for this endpoint, Arms/Groups were combined and lenvatinib total plasma concentration and serum biomarker data for VEGF, Ang-2, soluble Tie-2, and FGF23 from this study were combined with data from study E7080-G000-303 (NCT01321554). The relationship between lenvatinib exposure at the time of measurement of biomarker was described using PK/PD modelling. Initially, PK/PD models were developed individually for each biomarker and then combined into a single combined model. Changes in biomarker levels over time related to lenvatinib exposure were best described by an indirect response, sigmoidal Emax model. For the final combined model, baseline level estimates were determined separately for each biomarker. The data presented are the model predicted baseline estimates, with Measure Type "Number." They are population PK/PD model predictions and have been estimated using non-linear mixed effects modelling.

Per the planned population PK/PD analysis for this endpoint, Arms/Groups were combined and lenvatinib total plasma concentration and serum biomarker data for VEGF, Ang-2, soluble Tie-2, and FGF23 from this study were combined with data from study E7080-G000-303 (NCT01321554). The relationship between lenvatinib exposure at the time of measurement of biomarker was described using PK/PD modelling. Initially, PK/PD models were developed individually for each biomarker and then combined into a single combined model. Changes in biomarker levels over time related to lenvatinib exposure were best described by an indirect response, sigmoidal Emax model. For the final combined model, MRT estimates were determined separately for each biomarker. The data presented are the model predicted MRT estimates, with Measure Type "Number." They are population PK/PD model predictions and have been estimated using non-linear mixed effects modelling.

Per the planned population PK/PD analysis for this endpoint, Arms/Groups were combined and lenvatinib total plasma concentration and serum biomarker data for VEGF, Ang-2, soluble Tie-2, and FGF23 from this study were combined with data from study E7080-G000-303 (NCT01321554). The relationship between lenvatinib exposure at the time of measurement of biomarker was described using PK/PD modelling. Initially, PK/PD models were developed individually for each biomarker and then combined into a single combined model. Changes in biomarker levels over time related to lenvatinib exposure were best described by an indirect response, sigmoidal Emax model. For the final combined model, Hill Coefficient estimates were determined separately for each biomarker. The data presented are the model predicted Hill Coefficient estimates, with Measure Type "Number." They are population PK/PD model predictions and (\&) have been estimated using non-linear mixed effects modelling.

Per the planned analysis, Arms/Groups were combined \& tumor-growth inhibition models based on lenvatinib \& placebo data from this study combined with study NCT01321554. Effects of tumor growth rate, drug effects, tumor resistance, \& tumor size reduction related to biomarker response were assessed. Longitudinal data of sum of the longest diameter for target lesion by investigator assessment in this study \& independent reviewer assessment in study NCT01321554 were used. Changes in Ang-2 \& soluble Tie-2 were evaluated, individually \& in combination for their impact on tumor size. The concomitant use of lenvatinib \& biomarker changes due to drug effects as predictors of tumor size were also evaluated. The final integrated model for tumor growth \& biomarkers included effects of lenvatinib exposure \& tumor growth reduction related to Tie-2 \& Ang-2 biomarkers as significant predictors. Data presented are the parameters defining this non-linear mixed effects model, with Measure Type "Number."

Per the planned analysis, Arms/Groups were combined \& tumor-growth inhibition models based on lenvatinib \& placebo data from this study combined with study NCT01321554. Effects of tumor growth rate, drug effects, tumor resistance, \& tumor size reduction related to biomarker response were assessed. Longitudinal data of the sum of the longest diameter for target lesion by investigator assessment in this study \& independent reviewer assessment in study NCT01321554 were used. Changes in Ang-2 \& soluble Tie-2 were evaluated, individually \& in combination for their impact on tumor size. The concomitant use of lenvatinib \& biomarker changes due to drug effects as predictors of tumor size were also evaluated. The final integrated model for tumor growth \& biomarkers included effects of lenvatinib exposure \& tumor growth reduction related to Tie-2 \& Ang-2 biomarkers as significant predictors. Data presented are EC50 estimated using non-linear mixed effects modeling, with Measure Type "Number."

Per planned analysis, Arms/Groups were combined \& PK/PD analysis for PFS was based on lenvatinib \& placebo data from this study combined with NCT01321554. Relationship between lenvatinib exposure \& PFS was assessed using Kaplan-Meier plots. A parametric survival model (proportional hazard model) with Weibull distribution structure was developed to estimate the probability distribution of time from study start to progression, as a function of covariates including baseline disease characteristics, demographics, lenvatinib exposure, changes in biomarker time profiles, model predicted change from baseline in tumor size \& change in tumor size time-profiles. Significant (p\<0.01) covariates from the univariate analysis were added to the model simultaneously \& significant predictors were retained according to backward exclusion criteria (log likelihood ratio test, p-value of 0.001). Data presented are scale factor estimated using non-linear mixed effects modeling, with Measure Type "Number."

Per planned analysis, Arms/Groups were combined \& PK/PD analysis for PFS was based on lenvatinib \& placebo data from this study combined with NCT01321554. Relationship between lenvatinib exposure \& PFS was assessed using Kaplan-Meier plots. A parametric survival model (proportional hazard model) with Weibull distribution structure was developed to estimate the probability distribution of time from study start to progression, as a function of covariates including baseline disease characteristics, demographics, lenvatinib exposure, changes in biomarker time profiles, model predicted change from baseline in tumor size \& change in tumor size time-profiles. Significant (p\<0.01) covariates from the univariate analysis were added to the model simultaneously \& significant predictors were retained according to backward exclusion criteria (log likelihood ratio test, p-value of 0.001). Data presented are shape factor estimated using non-linear mixed effects modeling, with Measure Type "Number."

Per planned analysis, Arms/Groups were combined \& PK/PD analysis for PFS was based on lenvatinib \& placebo data from this study combined with NCT01321554. Relationship between lenvatinib exposure \& PFS was assessed using Kaplan-Meier plots. A parametric survival model (proportional hazard model) with Weibull distribution structure was developed to estimate probability distribution of time from study start to progression, as a function of covariates including baseline disease characteristics, demographics, lenvatinib exposure, changes in biomarker time profiles, model predicted change from baseline in tumor size \& change in tumor size time-profiles. Significant (p\<0.01) covariates from the univariate analysis were added to the model simultaneously \& significant predictors retained according to backward exclusion criteria (log likelihood ratio test, p-value of 0.001). Data presented are AUC exposure effect estimated using non-linear mixed effects modeling, with Measure Type "Number."

Per planned analysis, Arms/Groups were combined \& PK/PD analysis for PFS based on lenvatinib \& placebo data from this study combined with NCT01321554. Relationship between lenvatinib exposure \& PFS was assessed using Kaplan-Meier plots. A parametric survival model (proportional hazard model) with Weibull distribution structure was developed to estimate probability distribution of time from study start to progression, as a function of covariates including baseline disease characteristics, demographics, lenvatinib exposure, changes in biomarker time profiles, model predicted change from baseline tumor size \& change in tumor size time-profiles. Significant (p\<0.01) covariates from univariate analysis were added to the model simultaneously \& significant predictors retained according to backward exclusion criteria (log likelihood ratio test, p-value = 0.001). Data presented are the predicted change in tumor size estimated using non-linear mixed effects modeling, with Measure Type "Number."

Per planned analysis Arms/Groups were combined \& PK/PD analysis for PFS was based on lenvatinib \& placebo data from this study combined with E7080-G000-303(NCT01321554).Relationship between lenvatinib exposure \& PFS was assessed using Kaplan-Meier plots.Parametric survival model(proportional hazard model)with Weibull distribution structure was developed to estimate probability distribution of time from study start to progression as function of covariates including baseline disease characteristics,demographics,lenvatinib exposure,changes in biomarker time profiles,model predicted change from baseline tumor size \& change in tumor size time-profiles.Significant(p\<0.01)covariates from univariate analysis were added to model simultaneously \& significant predictors retained as per backward exclusion criteria(log likelihood ratio test,p-value of 0.001).Data presented are predicted baseline tumor size from the model with Measure Type "Number"estimated using non-linear mixed effects modelling.

Per the planned analysis, Arms/Groups were combined and population PK/PD analysis for blood pressure was based on lenvatinib and placebo pooled data from this study combined with study E7080-G000-201 (NCT00784303) \& study E7080-G000-303 (NCT01321554). The effect of lenvatinib exposure (AUC) at the time of blood pressure assessment on systolic and diastolic blood pressure was tested as a simultaneous indirect model where lenvatinib AUC was linked to the input rate of the indirect effect model by a linear slope factor function. Based on the results from model development, an indirect PK/PD model with a linear effect of lenvatinib exposure on both systolic and diastolic blood pressure was selected as the base model for subsequent univariate analysis. The data presented are the input rate indirect effect model estimate, with Measure Type "Number." They are population PK/PD model predictions and have been estimated using mixed effects non-linear modeling.

Per the planned analysis, Arms/Groups were combined and population PK/PD analysis for blood pressure was based on lenvatinib and placebo pooled data from this study combined with study E7080-G000-201 (NCT00784303) \& study E7080-G000-303 (NCT01321554). The effect of lenvatinib exposure (AUC) at the time of blood pressure assessment on systolic and diastolic blood pressure was tested as a simultaneous indirect model where lenvatinib AUC was linked to the input rate of the indirect effect model by a linear slope factor function. Based on the results from model development, an indirect PK/PD model with a linear effect of lenvatinib exposure on both systolic and diastolic blood pressure was selected as the base model for subsequent univariate analysis. The data presented are the input rate indirect effect model estimate, with Measure Type "Number." They are population PK/PD model predictions and have been estimated using non-linear mixed effects modeling.

Per the planned analysis for this endpoint, Arms/Groups were combined and a population PK/PD analysis of the relationship between lenvatinib exposure and occurrence of the TEAE weight decreased was based on placebo and lenvatinib pooled data from this study combined with study E7080-G000-201 (NCT00784303) and study E7080-G000-303 (NCT01321554). The relationship of occurrence probability of different grades of the TEAE weight decreased and lenvatinib exposure were evaluated by logistic regression model. The logit model was of the form: sum of intercept, of lenvatinib exposure, effects of covariates were explored, and random effects were used to describe between participant variability. Lenvatinib exposure was AUC based on the dose at the time of event. For each TEAE, probabilities of having no TEAE and a CTCAE Version 4.03 Grade 1 (Mild), Grade 2 (Moderate) or Grade 3 (severe or medically significant) TEAE were estimated as a function of lenvatinib or exposure.

Per the planned analysis for this endpoint, Arms/Groups were combined \& a population PK/PD analysis of the relationship between lenvatinib exposure \& occurrence of the TEAE hypertension was based on placebo \& lenvatinib pooled data from this study combined with study E7080-G000-201 (NCT00784303) \& study E7080-G000-303 (NCT01321554). The relationship of occurrence probability of different grades of the TEAE hypertension \& lenvatinib exposure were evaluated by logistic regression model. The logit model was of the form: sum of intercept, of lenvatinib exposure, effects of covariates were explored, \& random effects were used to describe between participant variability. Lenvatinib exposure was AUC based on the dose at the time of event. For each TEAE, probabilities of having no TEAE \& a CTCAE Version 4.03 Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (severe or medically significant) or Grade 4 (life-threatening consequences) TEAE were estimated as a function of lenvatinib or exposure.

Per the planned analysis for this endpoint, Arms/Groups were combined and a population PK/PD analysis of the relationship between lenvatinib exposure and occurrence of the TEAE proteinuria was based on placebo and lenvatinib pooled data from this study combined with study E7080-G000-201 (NCT00784303) and study E7080-G000-303 (NCT01321554). The relationship of occurrence probability of different grades of the TEAE proteinuria and lenvatinib exposure were evaluated by logistic regression model. The logit model was of the form: sum of intercept, of lenvatinib exposure, effects of covariates were explored, and random effects were used to describe between participant variability. Lenvatinib exposure was AUC based on the dose at the time of event. For each TEAE, probabilities of having no TEAE and a CTCAE Version 4.03 Grade 1 (Mild), Grade 2 (Moderate), or Grade 3 (severe or medically significant) TEAE were estimated as a function of lenvatinib or exposure.

Per the planned analysis for this endpoint, Arms/Groups were combined and a population PK/PD analysis of the relationship between lenvatinib exposure and occurrence of the TEAE fatigue was based on placebo and lenvatinib pooled data from this study combined with study E7080-G000-201 (NCT00784303) and study E7080-G000-303 (NCT01321554). The relationship of occurrence probability of different grades of the TEAE fatigue and lenvatinib exposure were evaluated by logistic regression model. The logit model was of the form: sum of intercept, of lenvatinib exposure, effects of covariates were explored, and random effects were used to describe between participant variability. Lenvatinib exposure was AUC based on the dose at the time of event. For each TEAE, probabilities of having no TEAE and a CTCAE Version 4.03 Grade 1 (Mild), Grade 2 (Moderate) or Grade 3 (severe or medically significant) TEAE were estimated as a function of lenvatinib or exposure.

Per the planned analysis for this endpoint, Arms/Groups were combined and a population PK/PD analysis of the relationship between lenvatinib exposure and occurrence of the TEAE diarrhea was based on placebo and lenvatinib pooled data from this study combined with study E7080-G000-201 (NCT00784303) and study E7080-G000-303 (NCT01321554). The relationship of occurrence probability of different grades of the TEAE diarrhea and lenvatinib exposure were evaluated by logistic regression model. The logit model was of the form: sum of intercept, of lenvatinib exposure, effects of covariates were explored, and random effects were used to describe between participant variability. Lenvatinib exposure was AUC based on the dose at the time of event. For each TEAE, probabilities of having no TEAE and a CTCAE Version 4.03 Grade 1 (Mild), Grade 2 (Moderate) or Grade 3 (severe or medically significant) TEAE were estimated as a function of lenvatinib or exposure.

Per the planned analysis for this endpoint, Arms/Groups were combined and a population PK/PD analysis of the relationship between lenvatinib exposure and occurrence of the TEAE nausea was based on placebo and lenvatinib pooled data from this study combined with study E7080-G000-201 (NCT00784303) and study E7080-G000-303 (NCT01321554). The relationship of occurrence probability of different grades of the TEAE nausea and lenvatinib exposure were evaluated by logistic regression model. The logit model was of the form: sum of intercept, of lenvatinib exposure, effects of covariates were explored, and random effects were used to describe between participant variability. Lenvatinib exposure was AUC based on the dose at the time of event. For each TEAE, probabilities of having no TEAE and a CTCAE Version 4.03 Grade 1 (Mild), Grade 2 (Moderate) or Grade 3 (severe or medically significant) TEAE were estimated as a function of lenvatinib or exposure.

Per the planned analysis for this endpoint, Arms/Groups were combined and a population PK/PD analysis of the relationship between lenvatinib exposure and occurrence of the TEAE vomiting was based on placebo and lenvatinib pooled data from this study combined with study E7080-G000-201 (NCT00784303) and study E7080-G000-303 (NCT01321554). The relationship of occurrence probability of different grades of the TEAE vomiting and lenvatinib exposure were evaluated by logistic regression model. The logit model was of the form: sum of intercept, of lenvatinib exposure, effects of covariates were explored, and random effects were used to describe between participant variability. Lenvatinib exposure was AUC based on the dose at the time of event. For each TEAE, probabilities of having no TEAE and a CTCAE Version 4.03 Grade 1 (Mild), Grade 2 (Moderate) or Grade 3 (severe or medically significant) TEAE were estimated as a function of lenvatinib or exposure.

The EQ-5D-3L is a health profile questionnaire assessing quality of life along 5 dimensions. Participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 5-15 with "5" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also included an EQ visual analogue scale (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best). EQ-5D-3L also included an EQ health utilities index (HUI) where 1 indicated full health while a score of 0 indicated worst health/death.

The FACT-G is a 27-item questionnaire that measures the effect of cancer treatment on quality of life that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being). Each item has a 5-point scale response set (0: not at all; 1: a little bit; 2: somewhat; 3: quite a bit; and 4: very much). The FACT-G total score ranges between 0 and 108. Higher score indicates better quality of life.

Merck Sharp & Dohme LLC

Eisai Inc.

Participants received lenvatinib 24 mg, capsule, orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first (up to 35 months). To maintain blinded treatment assignment, participants received a total of 4 capsules in the form of two 10-mg capsules and one 4-mg capsule containing lenvatinib and one 4-mg placebo capsule.

Lenvatinib 24 mg

Participants received lenvatinib 18 mg, capsule, orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first (up to 35 months). To maintain blinded treatment assignment, participants received a total of 4 capsules in the form of one 10-mg capsule and two 4-mg capsules containing lenvatinib and one 10-mg placebo capsule.

Lenvatinib 18 mg

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Full analysis set (FAS) included all participants randomly assigned to treatment.

Eisai Medical Information

FAS included all participants randomly assigned to treatment.

Objective Response Rate (ORR) as of Week 24 (ORR24wk)

Safety analysis set included all participants randomly assigned to treatment and who received at least 1 dose of study drug.

Percentage of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) in the First 24 Weeks

Progression-free Survival (PFS)

PFS After Next Line of Treatment (PFS2)

TEAE

Number of Participants With TEAE and Serious Adverse Events (SAEs)

Time to Treatment Discontinuation Due to an Adverse Event (AE)

Safety analysis set included all participants randomly assigned to treatment and who received at least 1 dose of study drug. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Number of Dose Reductions

Time to First Dose Reduction

All participants received lenvatinib 24 mg, capsule orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first in studies E7080-G000-303 (NCT01321554), E7080-G000-201 (NCT00784303) and this current study (E7080-G000-211).

Participants received lenvatinib 18 mg, capsule, orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first (up to 35 months) in this current study E7080-G000-211. To maintain blinded treatment assignment, participants received a total of 4 capsules in the form of one 10-mg capsule and two 4-mg capsules containing lenvatinib and one 10-mg placebo capsule.

PK Analysis Set included all participants who received at least one dose of study drug and who had evaluable lenvatinib plasma concentration data. Population for Lenvatinib 24 mg arm for this outcome measure included participants from study E7080-G000-303 (NCT01321554), E7080-G000-201 (NCT00784303) and from this current study E7080-G000-211. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Model Predicted Apparent Total Clearance (CL/F) Following Oral Dosing of Lenvatinib

Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib

PK/PD modeling of the effect of lenvatinib exposure on thyroglobulin levels could not be achieved due to the high variability in change from baseline data and hence data was not collected and reported.

Parameter Estimates From the Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Thyroglobulin Levels

PK/PD modeling of the effect of lenvatinib exposure on TSH levels could not be achieved due to the high variability in change from baseline data and hence data was not collected and reported.

Parameter Estimates From the Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Thyroid-Stimulating Hormone (TSH) Levels

VEGF

Tie-2

Ang-2

FGF23

All participants who received lenvatinib 24 mg or 18 mg or placebo, capsule, orally, once daily in a 28-day treatment cycles until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first in studies E7080-G000-303 (NCT01321554) and this current study (E7080-G000-211).

Lenvatinib or Placebo - All Participants

PK/PD analysis was performed for differentiated thyroid cancer (DTC) participants who received lenvatinib or placebo in study E7080-G000-303 (NCT01321554) and current study E7080-G000-211 and provided both PK data for lenvatinib and baseline and post-dose serum biomarkers samples. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure and "number analyzed" signifies participants who were evaluable for given categories.

Baseline Level Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Vascular Endothelial Growth Factor (VEGF), Soluble Tie-2, Angiopoietin-2 (Ang-2) and Fibroblast Growth Factor-23 (FGF23) Levels

PK/PD analysis was performed for DTC participants who received lenvatinib or placebo in study E7080-G000-303 (NCT01321554) and current study E7080-G000-211 and provided both PK data for lenvatinib and baseline and post-dose serum biomarkers samples. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure and "number analyzed" signifies participants who were evaluable for given categories.

Mean Residence Time (MRT) Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and VEGF, Soluble Tie-2, Ang-2 and FGF23 Levels

Hill Coefficient Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and VEGF, Soluble Tie-2, Ang-2 and FGF23 Levels

Tumor growth rate

Maximum effect of lenvatinib on tumor suppression (Emax)

Resistance term

Tumor size reduction rate constant for Tie-2

Tumor size reduction rate constant for Ang-2

PK/PD analysis was performed for DTC participants who received lenvatinib or placebo in study E7080-G000-303 (NCT01321554) and this current study E7080-G000-211 who had PK data and at least one post-baseline tumor evaluation. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Parameter Estimates From the PK/PD Model for Tumor Growth Inhibition and Serum Biomarkers Tie-2 and Ang-2

Lenvatinib Mean AUC Resulting in 50% of the Emax (EC50) Estimate From the PK/PD Model for Tumor Growth Inhibition and Serum Biomarkers Tie-2 and Ang-2

Scale factor

Scale factor drop out

All participants received lenvatinib 24 mg or 18 mg or placebo, capsule orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first in studies E7080-G000-303 (NCT01321554) and this current study (E7080-G000-211).

PK/PD analysis for PFS was performed for DTC participants who received lenvatinib or placebo in study E7080-G000-303 (NCT01321554) and this current study E7080-G000-211. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Scale Factor Estimate for Final Parametric Time to Event PK/PD Model for PFS

Shape factor

Shape factor drop out

Shape Factor Estimate for Final Parametric Time to Event PK/PD Model for PFS

All participants initially received lenvatinib 24 mg or 18 mg or placebo, capsule orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first in studies E7080-G000-303 (NCT01321554) and this current study (E7080-G000-211).

Lenvatinib AUC Exposure Effect Estimate for Final Parametric Time to Event PK/PD Model for PFS

Predicted Percent Change in Tumor Size Estimate for Final Parametric Time to Event PK/PD Model for PFS

Baseline Tumor Size Estimate for Final Parametric Time to Event PK/PD Model for PFS

All participants who received lenvatinib 24 mg or 18 mg or placebo, capsule, orally, once daily in a 28-day treatment cycles until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first in studies E7080-G000-303 (NCT01321554), E7080-G000-201 (NCT00784303) and this current study (E7080-G000-211).

For PK/PD analyses of blood pressure, participants received lenvatinib in studies E7080-G000-211, E7080-G000-201 (NCT00784303) and E7080-G000-303 (NCT01321554), with PK information and who had at least one post-baseline evaluation, and participants received placebo in study E7080-G000-303 were included. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Input Rate Indirect Effect Model Estimate From Base/Final PK/PD Blood Pressure Model

Drug effect on systolic input rate

Drug effect on diastolic input rate

Drug Effect on Systolic and Diastolic Input Rate Estimates From Base/Final PK/PD Blood Pressure Model

AUC Q1; None

AUC Q1; Grade 1

AUC Q1; Grade 2

AUC Q1; Grade 3

AUC Q2; None

AUC Q2; Grade 1

AUC Q2; Grade 2

AUC Q2; Grade 3

AUC Q3; None

AUC Q3; Grade 1

AUC Q3; Grade 2

AUC Q3; Grade 3

AUC Q4; None

AUC Q4; Grade 1

AUC Q4; Grade 2

AUC Q4; Grade 3

All participants received lenvatinib 24 mg or 18 mg or placebo, capsule orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first in studies E7080-G000-303 (NCT01321554), E7080-G000-201 (NCT00784303) and this current study (E7080-G000-211) with available pharmacokinetic data.

For PK/PD analysis of the TEAE weight decreased,participants with DTC who received lenvatinib and placebo from studies E7080-G000-211,E7080-G000-201(NCT00784303)and E7080-G000-303 (NCT01321554)with PK information and who had at least 1 postbaseline safety evaluation were included in analysis.Overall number of participants analyzed signifies participants who were evaluable for outcome measure.Number analyzed signifies participants who were evaluable for this outcome measure for given categories.

Number of Participants With Weight Decrease Stratified by AUC Quartile (Q) Group

AUC Q1; Grade 4

AUC Q2; Grade 4

AUC Q3; Grade 4

AUC Q4; Grade 4

For PK/PD analysis of the TEAE hypertension,participants with DTC who received lenvatinib and placebo from studies E7080-G000-211,E7080-G000-201(NCT00784303)and E7080-G000-303 (NCT01321554)with PK information and who had at least 1 postbaseline safety evaluation were included in analysis.Overall number of participants analyzed signifies participants who were evaluable for outcome measure.Number analyzed signifies participants who were evaluable for this outcome measure for given categories.

Number of Participants With Hypertension Stratified by AUC Quartile (Q) Group

For PK/PD analysis of the TEAE proteinuria,participants with DTC who received lenvatinib and placebo from studies E7080-G000-211,E7080-G000-201(NCT00784303)and E7080-G000-303 (NCT01321554)with PK information and who had at least 1 postbaseline safety evaluation were included in analysis.Overall number of participants analyzed signifies participants who were evaluable for outcome measure.Number analyzed signifies participants who were evaluable for this outcome measure for given categories.

Number of Participants With Proteinuria Stratified by AUC Quartile (Q) Group

For PK/PD analysis of the TEAE fatigue,participants with DTC who received lenvatinib and placebo from studies E7080-G000-211,E7080-G000-201(NCT00784303)and E7080-G000-303 (NCT01321554)with PK information and who had at least 1 postbaseline safety evaluation were included in analysis.Overall number of participants analyzed signifies participants who were evaluable for outcome measure.Number analyzed signifies participants who were evaluable for this outcome measure for given categories.

Number of Participants With Fatigue Stratified by AUC Quartile (Q) Group

For PK/PD analysis of the TEAE diarrhea,participants with DTC who received lenvatinib and placebo from studies E7080-G000-211,E7080-G000-201(NCT00784303)and E7080-G000-303 (NCT01321554)with PK information and who had at least 1 postbaseline safety evaluation were included in analysis.Overall number of participants analyzed signifies participants who were evaluable for outcome measure.Number analyzed signifies participants who were evaluable for this outcome measure for given categories.

Number of Participants With Diarrhea Stratified by AUC Quartile (Q) Group

For PK/PD analysis of the TEAE nausea,participants with DTC who received lenvatinib and placebo from studies E7080-G000-211,E7080-G000-201(NCT00784303)and E7080-G000-303 (NCT01321554)with PK information and who had at least 1 postbaseline safety evaluation were included in analysis.Overall number of participants analyzed signifies participants who were evaluable for outcome measure.Number analyzed signifies participants who were evaluable for this outcome measure for given categories.

Number of Participants With Nausea Stratified by AUC Quartile (Q) Group

For PK/PD analysis of the TEAE vomiting, participants with DTC who received lenvatinib and placebo from studies E7080-G000-211,E7080-G000-201(NCT00784303)and E7080-G000-303 (NCT01321554)with PK information and who had at least 1 postbaseline safety evaluation were included in analysis. Overall number of participants analyzed signifies participants who were evaluable for outcome measure. Number analyzed signifies participants who were evaluable for this outcome measure for given categories.

Number of Participants With Vomiting Stratified by AUC Quartile (Q) Group

EQ-HUI; Baseline

EQ-HUI; Change at week 8

EQ-HUI; Change at week 16

EQ-HUI; Change at week 24

EQ-VAS; Baseline

EQ-VAS; Change at week 8

EQ-VAS; Change at week 16

EQ-VAS; Change at week 24

Participants initially received lenvatinib 18 mg, capsule, orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first (up to 35 months). To maintain blinded treatment assignment, participants received a total of 4 capsules in the form of one 10-mg capsule and two 4-mg capsules containing lenvatinib and one 10-mg placebo capsule.

Change From Baseline in the Health-Related Quality of Life (HRQoL) Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS)

At Baseline

Change at Week 8

Change at Week 16

Change at Week 24

Participants initially received lenvatinib 24 mg, capsule, orally, once daily in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first (up to 35 months). To maintain blinded treatment assignment, participants received a total of 4 capsules in the form of two 10-mg capsules and one 4-mg capsule containing lenvatinib and one 4-mg placebo capsule.

Spots Global Cancer Trial Database for lenvatinib matching placebo