An Open-Label, 2-Cohort, Multicenter, Study of Lenvatinib in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma

ORR, (ORR = CR + PR) was defined as the percentage of participants in each cohort who had a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans and independent radiologic review (IRR). A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than (<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death from any cause (whichever occurred first), as determined by IRR and Investigator based on RECIST v1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% confidence interval (CI) when an adequate number of at risk participants warranted the estimates in the table below.

OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date for each cohort. OS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% CI when an adequate number of at risk participants warranted the estimates in the table below.

DCR, (DCR = CR + PR + SD) was defined as the percentage of participants who had a BOR of CR or PR or stable disease (SD) based on RECIST v1.1 for target lesions assessed by MRI/CT and IRR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to <10 mm.; PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR. SD defined as reduction in tumor volume of < 30% or an increase in the volume of 1 or more measurable lesions of < 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to disease progression. BOR of SD, time from first administration of study drug until date of documented SD needed to be >=7 weeks based on IRR and Investigator's assessment.

CBR, (CBR = CR + PR + durable SD rate) was defined as the percentage of participants who had a BOR of CR or PR or durable SD (dSD, SD lasting >=23 weeks) based on RECIST v1.1 for target lesions assessed by MRI/CT, IRR and Investigator's assessment. A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; OR = CR + PR. A BOR of dSD, the time from the first administration of study drug until the date of documented dSD needed to be ≥23 weeks based on IRR and Investigator's assessment.

Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECGs), and multi-gated acquisition (MUGA) scans or echocardiogram.

Blood samples were drawn at specific time points. Utilizing a standard protocol, the deoxyribonucleic acid (DNA) from whole blood was extracted and analyzed for specific biomarkers of absorption, distribution, metabolism, and excretion of lenvatinib. Some of the biomarkers analyzed included; Angiopoietin, Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), FMS Like Tyrosine Kinase 3 Ligand (Flt3l) Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macro Colony Stimulating Factor (GM-CSF), Interleukin 1 Receptor Antagonist (IL-1RA), Interferon (IFN), Macrophage Inflammatory Protein (MIP) 1 alpha, Platelet Derived Growth Factor (PDGF), Stromal Cell Derived Factor (SDF) 1 alpha, Interleukin (IL), Transforming Growth Factor (TGF), Tumor Necrosis Factor (TNF), Vascular Endothelial Growth Factor (VEGF).

Blood samples for the quantification of lenvatinib in plasma were obtained and processed using a standardized protocol. The lower limit of quantification was 0.25 ng/mL. Pharmacokinetic (PK) analysis was conducted using nonlinear mixed effects modeling. Descriptive statistics were used to summarize lenvatinib plasma concentration data.