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

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01136967
• Collaborator: (none)
• Enrollment: 182
• Locations: 95
• Arms: 2
• Actual Duration (Months): 51
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the objective response rate of lenvatinib in previously treated participants with American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV melanoma and disease progression.

Condition or Disease	Intervention/Treatment	Phase
Unresectable Stage III; Stage IV Melanoma	Drug: Lenvatinib	Phase 2

Detailed Description

This was a Phase 2, multicenter, open-label, 2-cohort, 2-stage study that assessed the ORR of lenvatinib in previously treated participants with AJCC unresectable Stage III or Stage IV melanoma and disease progression. Cohort 1 enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma, and is referred to as Cohort 1 or V600E BRAF negative. Other less common BRAF activating mutations were allowed as long as the participant did not receive a BRAF-targeted therapy. Cohort 2 enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy, and is referred to as Cohort 2 or V600E BRAF positive. Eligible participants had measurable disease according to RECIST 1.1.

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, 2-Cohort, Multicenter, Phase 2 Study of E7080 (Lenvatinib) in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma
• Actual Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 (V600E BRAF negative) Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma.	Drug: Lenvatinib; Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.; Other Names: E7080
Experimental: Cohort 2 (V600E BRAF positive) Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy.	Drug: Lenvatinib; Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.; Other Names: E7080

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) [From date of treatment start until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to end of Cycle 6 (up to 24 weeks)]

   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.

Secondary Outcome Measures

1. Progression Free Survival (PFS) [From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months]

   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.

2. Overall Survival (OS) [From date of treatment start until date of death from any cause or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months]

   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.

3. Disease Control Rate (DCR) [From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months]

   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.

4. Clinical Benefit Rate (CBR) [From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months]

   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.

5. Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib [From date of treatment start up to 30 days after the last dose, or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 9 months]

   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.

6. Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood [Cycle 1 Day 15 (C1 D15), Cycle 2 Day 1 (C2 D1), Cycle 3 Day 1 (C3 D1), Off-Treatment/Phase Visit 98 (V98)]

   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).

7. Summary of Plasma Concentration of Lenvatinib [Predose and 2 to 12 hours postdose at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), and Cycle 2 Day 1 (C2D1)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically confirmed diagnosis of melanoma.

2. Unresectable Stage III or Stage IV melanoma.

3. Evidence of disease progression according to RECIST 1.1 on prior regimen.

4. Participants with brain metastases will be eligible if they have undergone complete surgical excision and are more then 1 month post surgery with no radiographic evidence of disease recurrence in the brain or have undergone stereotactic radio surgery (gamma knife procedure) and are more then 1 month post procedure and with no radiographic evidence of disease progression in the brain; and are asymptomatic, and discontinued corticosteroid treatment at least 30 days prior starting treatment.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Adequately controlled blood pressure.

7. Adequate renal function, bone marrow function, blood coagulation function, and liver function, as defined in the study protocol.

Exclusion Criteria:

1. Melanoma of intraocular origin.

2. Leptomeningeal metastases or brain metastases except as for participants with brain metastases will be eligible if they have undergone complete surgical excision and are more then 1 month post surgery with no radiographic evidence of disease recurrence in the brain or have undergone stereotactic radio surgery (gamma knife procedure) and are more then 1 month post procedure and with no radiographic evidence of disease progression in the brain; and are asymptomatic, and discontinued corticosteroid treatment at least 30 days prior starting treatment.

3. More than 2 prior systemic anticancer regimen treatments including immunotherapies for unresectable Stage III or Stage IV disease (if BRAF V600E mutation negative) or not previously treated with BRAF V600E-targeted therapy or received in the past more than 2 prior systemic anticancer regimen treatments, including immunotherapies, in addition to a BRAF-V600E-targeted therapy (if BRAF V600E mutation positive).

4. Significant cardiovascular impairment.

5. Bleeding disorder or a thrombotic disorder requiring anticoagulant therapy.

6. Females who are pregnant or breastfeeding.

7. Prolongation of QTc interval to greater than 480 msec.

8. 24 hour urine protein greater than or equal to 1 gm.

9. Active hemoptysis within 3 wks prior to the first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Tucson	Arizona	United States
3		Los Angeles	California	United States
4		San Francisco	California	United States
5		Aurora	Colorado	United States
6		Boulder	Colorado	United States
7		Colorado Springs	Colorado	United States
8		Denver	Colorado	United States
9		Lakewood	Colorado	United States
10		Littleton	Colorado	United States
11		Lone Tree	Colorado	United States
12		Longmont	Colorado	United States
13		Parker	Colorado	United States
14		Thornton	Colorado	United States
15		Bonita Springs	Florida	United States
16		Bradenton	Florida	United States
17		Cape Coral	Florida	United States
18		Clearwater	Florida	United States
19		Englewood	Florida	United States
20		Fort Myers	Florida	United States
21		Gainesville	Florida	United States
22		Naples	Florida	United States
23		North Port	Florida	United States
24		Orlando	Florida	United States
25		Palm Harbor	Florida	United States
26		Port Charlotte	Florida	United States
27		Sarasota	Florida	United States
28		Sebring	Florida	United States
29		Tampa	Florida	United States
30		Venice	Florida	United States
31		Louisville	Kentucky	United States
32		Boston	Massachusetts	United States
33		Detroit	Michigan	United States
34		Burnsville	Minnesota	United States
35		Coon Rapids	Minnesota	United States
36		Edina	Minnesota	United States
37		Fridley	Minnesota	United States
38		Maplewood	Minnesota	United States
39		Minneapolis	Minnesota	United States
40		Saint Paul	Minnesota	United States
41		Woodbury	Minnesota	United States
42		Southaven	Mississippi	United States
43		Saint Louis	Missouri	United States
44		Henderson	Nevada	United States
45		Las Vegas	Nevada	United States
46		Lebanon	New Hampshire	United States
47		Morristown	New Jersey	United States
48		New York	New York	United States
49		Cincinnati	Ohio	United States
50		Cleveland	Ohio	United States
51		Columbus	Ohio	United States
52		Eugene	Oregon	United States
53		Portland	Oregon	United States
54		Springfield	Oregon	United States
55		Tualatin	Oregon	United States
56		Bethlehem	Pennsylvania	United States
57		Philadelphia	Pennsylvania	United States
58		Bartlett	Tennessee	United States
59		Franklin	Tennessee	United States
60		Gallatin	Tennessee	United States
61		Germantown	Tennessee	United States
62		Hermitage	Tennessee	United States
63		Lebanon	Tennessee	United States
64		Memphis	Tennessee	United States
65		Murfreesboro	Tennessee	United States
66		Nashville	Tennessee	United States
67		Smyrna	Tennessee	United States
68		Bedford	Texas	United States
69		Dallas	Texas	United States
70		Grapevine	Texas	United States
71		Houston	Texas	United States
72		Arlington	Virginia	United States
73		Fairfax	Virginia	United States
74		Gainesville	Virginia	United States
75		Leesburg	Virginia	United States
76		Winchester	Virginia	United States
77		Woodbridge	Virginia	United States
78		Vancouver	Washington	United States
79		Madison	Wisconsin	United States
80		Adelaide		Australia
81		Malvern		Australia
82		Newcastle		Australia
83		North Sydney		Australia
84		Perth		Australia
85		Westmead		Australia
86		Essen		Germany
87		Hannover		Germany
88		Heidelberg		Germany
89		Kiel		Germany
90		Mainz		Germany
91		Tubingen		Germany
92		Glasgow		United Kingdom
93		London		United Kingdom
94		Nottingham		United Kingdom
95		Surrey		United Kingdom

Sponsors and Collaborators

• Eisai Inc.

Investigators

• Study Director: Eisai US Medical Services, Eisai Limited

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT01136967
• Other Study ID Numbers: E7080-G000-206
• First Posted: Jun 4, 2010
• Last Update Posted: Nov 13, 2019
• Last Verified: Nov 1, 2016

• Additional relevant MeSH terms: Melanoma; Lenvatinib

Study Results

Participant Flow

Recruitment Details	A total of 298 participants were screened. Of these, 116 were screen failures and 182 received treatment (93 participants in Cohort 1 and 89 participants in Cohort 2).

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Period Title: Overall Study
STARTED	93	89
Disease Progression	55	56
Treatment Ongoing at Data Cutoff	14	6
COMPLETED	69	62
NOT COMPLETED	24	27

Baseline Characteristics

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)	Total
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Total of all reporting groups
Overall Participants	93	89	182
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.5 (11.71)	55.0 (14.18)	58.8 (13.47)
Sex/Gender, Customized (Number) [Number]
Female	29 31.2%	39 43.8%	68 37.4%
Male	64 68.8%	50 56.2%	114 62.6%
AJCC Melanoma Tumor, Node, Metastasis (TNM) Stage at Study Entry (Number) [Number]
Unresectable Stage III	5 5.4%	7 7.9%	12 6.6%
Unresectable Stage IV	88 94.6%	82 92.1%	170 93.4%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	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.
Time Frame	From date of treatment start until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to end of Cycle 6 (up to 24 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (Intent-to-Treat [ITT] Analysis Set) included all participants who received at least 1 dose study drug.

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Measure Participants	93	89
Number (95% Confidence Interval) [Percentage of participants]	8.6 9.2%	9.0 10.1%

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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.
Time Frame	From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Measure Participants	93	89
Determined by IRR	3.7	1.8
Determined by Investigator	3.7	2.3

3. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	From date of treatment start until date of death from any cause or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Measure Participants	93	89
Median (95% Confidence Interval) [Months]	8.9	6.3

4. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	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.
Time Frame	From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Measure Participants	93	89
Determined by IRR	52.7 56.7%	34.8 39.1%
Determined by Investigator	64.5 69.4%	48.3 54.3%

5. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	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.
Time Frame	From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Measure Participants	93	89
Determined by IRR	31.2 33.5%	14.6 16.4%
Determined by Investigator	33.3 35.8%	20.2 22.7%

6. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib
Description	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.
Time Frame	From date of treatment start up to 30 days after the last dose, or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 9 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included those participants who received at least 1 dose of study drug and had at least 1 post baseline safety evaluation.

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Measure Participants	93	89
AEs	93 100%	89 100%
SAEs	39 41.9%	36 40.4%

7. Secondary Outcome

Title	Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood
Description	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).
Time Frame	Cycle 1 Day 15 (C1 D15), Cycle 2 Day 1 (C2 D1), Cycle 3 Day 1 (C3 D1), Off-Treatment/Phase Visit 98 (V98)

Outcome Measure Data

Analysis Population Description

The Safety Analysis set was used and included all participants who received at least one dose of lenvatinib and had at least 1 postbaseline safety evaluation. Number analyzed (n) signifies participants who were evaluable at specific time points for this outcome measure.

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Measure Participants	93	89
Angiopoietin 2 76 C1D15	-1015.69 (946.596)
Angiopoietin 2 76 C2D1	-832.29 (1257.287)
Angiopoietin 2 76 C3D1	-923.82 (969.285)
Angiopoietin 2 76 V98	-947.00 (825.037)
Angiopoietin 2 90 C1D15	-1225.322 (1950.4525)
Angiopoietin 2 90 C2D1	-1100.235 (1378.4621)
Angiopoietin 1 C1D15	-3033.030 (8808.2059)	-2717.533 (16689.4536)
Angiopoietin 1 C2D1	-2802.306 (10202.7814)	-1743.569 (15546.4804)
Angiopoietin 1 C3D1	-859.021 (9994.6711)
Angiopoietin 1 V98	8107.400 (17740.0516)
Angiopoietin 2 C1D15	-1462.552 (1541.8074)	-2154.269 (3560.0029)
Angiopoietin 2 C2D1	-1225.462 (1872.5841)	-1884.439 (2357.1979)
Angiopoietin 2 C3D1	-1255.485 (1738.0891)
Angiopoietin 2 V98	-1374.183 (1158.2897)
CD40 Ligand C1D15	-24020.778 (62788.2464)	-4678.661 (41191.7303)
CD40 Ligand C2D1	-22957.613 (73677.4378)	-7254.754 (37794.5541)
CD40 Ligand C3D1	-16700.900 (48016.0710)
CD40 Ligand V98	2192.177 (86909.9688)
EGF 2 C1D15	-46.493 (101.0772)	-0.516 (219.9787)
EGF 2 C2D1	-39.636 (125.0664)	-29.803 (121.1705)
EGF 2 C3D1	-37.600 (113.8543)
EGF 2 V98	-2.230 (191.4129)
EGF 59 C1D15	-37.07 (81.051)
EGF 59 C2D1	-31.58 (96.200)
EGF 59 C3D1	-24.49 (93.102)
EGF 59 V98	10.17 (137.755)
EGF 80 C1D15	-31.519 (126.2579)
EGF 80 C2D1	-32.171 (121.7805)
Eotaxin-4 C1D15	51.456 (117.1266)	46.538 (128.398)
Eotaxin-4 C2D1	99.974 (207.0243)	60.919 (114.6134)
Eotaxin-4 C3D1	89.878 (108.6392)
Eotaxin-4 V98	104.613 (157.7527)
FGF 2 C1D15	-4.294 (51.3985)	8.325 (136.3433)
FGF 2 C2D1	-8.085 (48.8273)	-8.003 (144.9054)
FGF 2 C3D1	7.443 (45.7310)
FGF 2 V98	-3.917 (62.3623)
FGF 23 C1D15	6.549 (22.5297)
FGF 23 C2D1	6.496 (27.2305)
FGF 23 C3D1	6.691 (24.5203)
FGF 23 V98	13.430 (36.7130)
FGF 4 C1D15	-24.226 (100.6823)	50.369 (253.9626)
FGF 4 C2D1	-15.491 (104.9991)	55.785 (264.4585)
FGF 4 C3D1	5.283 (130.3452)
FGF 4 V98	33.860 (185.4616)
FGF Basic Form C1D15	-0.597 (18.6851)	43.457 (224.9856)
FGF Basic Form C2D1	-1.212 (38.4131)	64.237 (328.6676)
FGF Basic Form C3D1	2.060 (29.2405)
FGF Basic Form V98	18.384 (28.6214)
Flt3l C1D15	-0.037 (32.5371)	-8.877 (23.0368)
Flt3l C2D1	5.135 (28.0359)	-1.362 (39.2251)
Flt3l C3D1	5.439 (24.1985)
Flt3l V98	13.367 (17.7279)
Fractalkine C1D15	-11.700 (94.5115)	38.670 (237.5045)
Fractalkine C2D1	-1.175 (70.0858)	4.663 (58.1950)
Fractalkine C3D1	-5.588 (116.3955)
Fractalkine V98	15.838 (90.6004)
G-CSF C1D15	4.329 (20.8343)	6.368 (61.7181)
G-CSF C2D1	7.366 (32.5552)	12.601 (72.5113)
G-CSF C3D1	11.292 (24.1828)
G-CSF V98	34.653 (101.7055)
GM-CSF C1D15	0.767 (16.9314)	44.665 (220.9124)
GM-CSF C2D1	4.371 (38.3355)	139.491 (725.0903)
GM-CSF C3D1	10.036 (49.8538)
GM-CSF V98	-1.495 (5.1831)
Growth Regulated Oncogene C1D15	-141.838 (410.3579)
Growth Regulated Oncogene C2D1	-120.148 (456.3073)
Hepatocyte Growth Factor C1D15	102.527 (1309.4077)	-91.790 (781.2225)
Hepatocyte Growth Factor C2D1	-126.667 (693.2257)	-147.796 (411.1836)
Hepatocyte Growth Factor C3D1	61.257 (1062.3266)
Hepatocyte Growth Factor V98	404.700 (456.8130)
Interferon Gamma C1D15	4.072 (19.3994)	33.743 (100.3678)
Interferon Gamma C2D1	-0.392 (14.8083)	-10.164 (170.9869)
Interferon Gamma C3D1	2.986 (5.7591)
Interferon Gamma V98	2.455 (5.2255)
Interleukin 1 alpha C1D15	0.159 (7.9441)	67.203 (200.9806)
Interleukin 1 alpha C2D1	0.226 (8.2728)	-36.352 (198.1416)
Interleukin 1 alpha C3D1	-0.140 (13.7136)
Interleukin 1 Beta C1D15	0.279 (1.9668)	59.768 (137.6657)
Interleukin 1 Beta C2D1	1.198 (5.0044)	27.690 (61.2456)
Interleukin 1 Beta C3D1	1.882 (11.1737)
IL-1RA C1D15	14.490 (63.5869)	46.381 (132.3985)
IL-1RA C2D1	20.295 (61.9799)	38.131 (142.7521)
IL-1RA C3D1	7.048 (30.9383)
IL-1RA V98	84.614 (178.1590)
Interleukin 12 (p40) C1D15	14.514 (73.9806)	5.458 (28.8514)
Interleukin 12 (p40) C2D1	16.052 (40.3849)	918.03 (3917.8689)
Interleukin 12 (p40) C3D1	11.183 (36.3506)
Interleukin 12 (p40) V98	-8.130 (5.7276)
Interleukin 12 (p70) C1D15	1.241 (18.8429)	27.919 (62.8944)
Interleukin 12 (p70) C2D1	-5.622 (28.6381)	7.820 (71.1505)
Interleukin 12 (p70) C3D1	-6.099 (19.5015)
Interleukin 12 (p70) V98	11.275 (20.0182)
Interleukin 10 C1D15	-5.170 (38.0092)	-7.611 (22.1926)
Interleukin 10 C2D1	-1.901 (33.6203)	1.687 (72.7629)
Interleukin 10 C3D1	4.136 (10.8185)
Interleukin 10 V98	-28.065 (41.7547)
Interleukin 13 C1D15	0.961 (5.0066)	8.574 (13.4754)
Interleukin 13 C2D1	2.451 (7.6374)	8.536 (18.5220)
Interleukin 13 C3D1	5.404 (16.4719)
Interleukin 15 C1D15	0.128 (2.2957)	85.619 (234.7106)
Interleukin 15 C2D1	1.403 (4.1630)	574.776 (1709.9272)
Interleukin 15 C3D1	-0.178 (3.6993)
Interleukin 15 V98	3.930 (NA)
Interleukin 17 C1D15	3.434 (8.6463)	4.567 (12.1008)
Interleukin 17 C2D1	1.264 (8.0963)	3.035 (15.8736)
Interleukin 17 C3D1	0.011 (3.4100)
Interleukin 17 V98	8.440 (11.7663)
Interleukin 2 C1D15	-1.004 (7.1024)	173.878 (397.2754)
Interleukin 2 C2D1	5.853 (20.3294)	191.410 (461.1991)
Interleukin 2 C3D1	2.647 (19.5979)
Interleukin 4 C1D15	8.169 (30.0305)	12.815 (77.4310)
Interleukin 4 C2D1	20.167 (77.0619)	7.815 (54.5735)
Interleukin 4 C3D1	6.583 (20.3824)
Interleukin 5 C1D15	0.311 (1.1314)	6.088 (7.5239)
Interleukin 5 C2D1	0.205 (1.5931)	11.382 (9.8663)
Interleukin 5 C3D1	-0.327 (1.1102)
Interleukin 6 C1D15	0.166 (6.8774)	3.784 (30.0715)
Interleukin 6 C2D1	4.778 (34.0254)	5.524 (32.1205)
Interleukin 6 C3D1	2.027 (7.3121)
Interleukin 6 V98	3.160 (6.6276)
Interleukin 7 C1D15	1.267 (7.3732)	2.167 (8.8122)
Interleukin 7 C2D1	2.413 (8.8367)	5.744 (18.4339)
Interleukin 7 C3D1	0.616 (5.0590)
Interleukin 7 V98	20.760 (28.0439)
Interleukin 8 C1D15	-5.801 (46.1572)	-20.769 (52.1135)
Interleukin 8 C2D1	-5.431 (43.4197)	-14.303 (57.9561)
Interleukin 8 C3D1	-7.348 (43.0509)
Interleukin 8 V98	26.982 (32.7795)
IFN gamma Induced Protein 10 C1D15	453.684 (1446.5825)	184.891 (501.5782)
IFN gamma Induced Protein 10 C2D1	246.194 (246.194)	306.075 (792.5621)
IFN gamma Induced Protein 10 C3D1	201.923 (483.5088)
IFN gamma Induced Protein 10 V98	359.872 (501.1082)
Monocyte Chemotactic Protein 1 C1D15	0.733 (423.2721)	-101.580 (371.5381)
Monocyte Chemotactic Protein 1 C2D1	-19.036 (372.5242)	128.749 (541.1034)
Monocyte Chemotactic Protein 1 C3D1	13.542 (370.3700)
Monocyte Chemotactic Protein 1 V98	-128.627 (1234.5888)
MIP 1 alpha C1D15	-1.842 (11.9129)	-0.320 (38.5273)
MIP 1 alpha C2D1	-2.098 (12.0121)	-0.473 (35.4447)
MIP 1 alpha C3D1	-1.167 (15.9038)
MIP 1 alpha V98	7.563 (7.8802)
MIP 1 beta C1D15	0.032 (20.1490)	5.746 (64.1386)
MIP 1 beta C2D1	-1.198 (31.4522)	31.277 (261.3460)
MIP 1 beta C3D1	1.850 (15.208)
MIP 1 beta V98	7.518 (11.9566)
PDGF AA 31 P1 C1D15	-183.36 (2260.110)
PDGF AA 31 P1 C2D1	-268.83 (2054.666)
PDGF AB C1D15	-36.637 (353.6898)	-121.278 (325.1308)
PDGF AB C2D1	-99.852 (338.5816)	-80.778 (363.1249)
PDGF AB C3D1	-7.702 (311.6834)
PDGF AB V98	130.800 (382.6282)
PDGF BB C1D15	-120.317 (1758.7655)	-567.664 (1385.6740)
PDGF BB C2D1	-435.311 (1961.7449)	-371.888 (1186.1)
PDGF BB C3D1	333.637 (1516.1506)
PDGF BB V98	174.083 (3221.9009)
Placental Derived Growth Factor C1D15	55.444 (55.0671)	55.0671 (29.8457)
Placental Derived Growth Factor C2D1	50.439 (58.2571)	51.359 (76.6390)
Placental Derived Growth Factor C3D1	61.080 (58.2969)
Placental Derived Growth Factor V98	112.683 (110.3416)
Chemokine Ligand 5 C1D15	-2373.94 (46225.695)
Chemokine Ligand 5 C2D1	551.64 (49492.450)
SDF 1 alpha C1D15	441.305 (385.8988)	506.768 (487.7603)
SDF 1 alpha C2D1	520.051 (510.8558)	647.435 (470.0962)
SDF 1 alpha C3D1	509.483 (550.4383)
SDF 1 alpha V98	836.532 (686.4434)
Soluble IL2 Receptor alpha C1D15	-25.869 (86.0991)	-414.669 (765.1544)
Soluble IL2 Receptor alpha C2D1	-13.695 (65.5643)	-290.918 (1023.3392)
Soluble IL2 Receptor alpha C3D1	-12.233 (31.5415)
Soluble IL2 Receptor alpha V98	-19.238 (43.0942)
TGF alpha C1D15	-0.874 (4.6605)	21.148 (168.7766)
TGF alpha C2D1	-0.350 (6.5375)	-6.019 (24.3258)
TGF alpha C3D1	1.165 (11.8825)
TGF alpha V98	2.590 (3.4672)
Tie-2 C1D15	-2971.948 (2397.5234)	-3573.856 (2996.7139)
Tie-2 C2D1	-3447.692 (3577.1791)	-4088.214 (3191.9812)
Tie-2 C3D1	-2811.765 (3459.1934)
Tie-2 V98	-1924.000 (3215.5684)
TNF alpha C1D15	-0.233 (4.9747)	1.451 (24.8216)
TNF alpha C2D1	0.039 (3.9540)	1.741 (15.0677)
TNF alpha C3D1	0.614 (4.6336)
TNF alpha V98	3.027 (4.7343)
VEGF C1D15	-13.294 (112.6871)	10.709 (285.2533)
VEGF C2D1	-11.523 (122.6064)	-26.215 (239.4960)
VEGF C3D1	16.732 (160.3096)
VEGF V98	155.638 (352.8309)
VEGF A C1D15	78.868 (174.8011)	92.748 (273.6190)
VEGF A C2D1	76.041 (194.1394)	140.664 (336.9135)
VEGF A C3D1	116.800 (233.1657)
VEGF A V98	465.833 (515.7676)
VEGF D C1D15	0.953 (87.6513)	3.404 (42.7585)
VEGF D C2D1	-9.776 (98.0905)	11.043 (116.5445)
VEGF D C3D1	9.894 (57.1140)
VEGF D V98	-21.317 (88.6689)
VEGF Rec 1 C1D15	593.613 (3109.3343)	-221.867 (799.9202)
VEGF Rec 1 C2D1	-3.971 (739.7875)	-243.661 (1031.2376)
VEGF Rec 1 C3D1	-209.863 (809.7744)
VEGF Rec 1 V98	-15.567 (90.6274)
VEGF Rec 2 C1D15	-10110.096 (5626.0125)	-8842.040 (6078.7151)
VEGF Rec 2 C2D1	-9369.165 (17982.0625)	-10676.563 (7064.0825)
VEGF Rec 2 C3D1	-11389.576 (10955.1596)
VEGF Rec 2 V98	-9021.217 (5921.9619)
VEGF Rec 3 C1D15	-1174.650 (2226.7893)	-2251.867 (3231.1485)
VEGF Rec 3 C2D1	-1320.738 (3138.3810)	-2523.257 (3550.7291)
VEGF Rec 3 C3D1	-1488.140 (3687.8774)
VEGF Rec 3 V98	-1201.680 (2441.5741)

8. Secondary Outcome

Title	Summary of Plasma Concentration of Lenvatinib
Description	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.
Time Frame	Predose and 2 to 12 hours postdose at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), and Cycle 2 Day 1 (C2D1)

Outcome Measure Data

Analysis Population Description

The PK analysis set was used for analysis and included all participants who received at least one dose of lenvatinib and had at least one quantifiable lenvatinib concentration. Number analyzed (n) signifies participants who were evaluable at specific time points for this outcome measure.

Arm/Group Title	Cohort 1 (V600E BRAF Negative)	Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Measure Participants	93	89
C1D1 Pre-dose	0 (0)	0 (0)
C1D1 Post-dose	229.6 (148.98)	287.6 (168.97)
C1D15 Pre-dose	56.8 (82)	71.9 (104.09)
C1D15 Post-dose	284.0 (141.71)	332.1 (221.98)
C2D1 Pre-dose	38.7 (32.94)	52.0 (48.73)
C2D1 Post-dose	244.5 (182.67)	270.4 (143.64)

Adverse Events

Time Frame	From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Arm/Group Title	Cohort 1 (V600E BRAF Negative)		Cohort 2 (V600E BRAF Positive)
Arm/Group Description	Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.		Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
All Cause Mortality
	Cohort 1 (V600E BRAF Negative)		Cohort 2 (V600E BRAF Positive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1 (V600E BRAF Negative)		Cohort 2 (V600E BRAF Positive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/93 (41.9%)		36/89 (40.4%)
Blood and lymphatic system disorders
Anaemia	0/93 (0%)		1/89 (1.1%)
Cardiac disorders
Atrial thrombosis	1/93 (1.1%)		0/89 (0%)
Cardiac failure congestive	1/93 (1.1%)		0/89 (0%)
Supraventricular tachycardia	1/93 (1.1%)		0/89 (0%)
Atrioventricular block second degree	0/93 (0%)		1/89 (1.1%)
Myocardial infarction	0/93 (0%)		1/89 (1.1%)
Pericardial effusion	0/93 (0%)		1/89 (1.1%)
Endocrine disorders
Hypothyroidism	0/93 (0%)		1/89 (1.1%)
Gastrointestinal disorders
Nausea	3/93 (3.2%)		3/89 (3.4%)
Pancreatitis	2/93 (2.2%)		0/89 (0%)
Vomiting	2/93 (2.2%)		1/89 (1.1%)
Abdominal pain	1/93 (1.1%)		3/89 (3.4%)
Abdominal pain upper	1/93 (1.1%)		0/89 (0%)
Colitis	1/93 (1.1%)		0/89 (0%)
Oesophageal spasm	1/93 (1.1%)		0/89 (0%)
Rectal perforation	1/93 (1.1%)		0/89 (0%)
Constipation	0/93 (0%)		1/89 (1.1%)
Diarrhoea	0/93 (0%)		1/89 (1.1%)
Enterocolitis	0/93 (0%)		1/89 (1.1%)
Intestinal obstruction	0/93 (0%)		1/89 (1.1%)
Intestinal perforation	0/93 (0%)		1/89 (1.1%)
General disorders
Pyrexia	1/93 (1.1%)		0/89 (0%)
Fatigue	0/93 (0%)		2/89 (2.2%)
General physical health deterioration	0/93 (0%)		2/89 (2.2%)
Impaired healing	0/93 (0%)		1/89 (1.1%)
Pain	0/93 (0%)		1/89 (1.1%)
Hepatobiliary disorders
Cholelithiasis	1/93 (1.1%)		0/89 (0%)
Gallbladder perforation	1/93 (1.1%)		0/89 (0%)
Cholecystitis	0/93 (0%)		1/89 (1.1%)
Cholecystitis acute	0/93 (0%)		1/89 (1.1%)
Hepatic failure	0/93 (0%)		1/89 (1.1%)
Infections and infestations
Pneumonia	2/93 (2.2%)		2/89 (2.2%)
Appendicitis	1/93 (1.1%)		0/89 (0%)
Catheter site infection	1/93 (1.1%)		0/89 (0%)
Incision site infection	1/93 (1.1%)		0/89 (0%)
Oral herpes	1/93 (1.1%)		0/89 (0%)
Pelvic abscess	1/93 (1.1%)		0/89 (0%)
Urinary tract infection	1/93 (1.1%)		0/89 (0%)
Cellulitis	0/93 (0%)		1/89 (1.1%)
Infection	0/93 (0%)		1/89 (1.1%)
Peritonitis	0/93 (0%)		1/89 (1.1%)
Sepsis	0/93 (0%)		1/89 (1.1%)
Septic shock	0/93 (0%)		1/89 (1.1%)
Upper respiratory tract infection	0/93 (0%)		1/89 (1.1%)
Wound infection	0/93 (0%)		1/89 (1.1%)
Injury, poisoning and procedural complications
Chemical peritonitis	1/93 (1.1%)		0/89 (0%)
Spinal compression fracture	0/93 (0%)		1/89 (1.1%)
Investigations
Ejection fraction decreased	1/93 (1.1%)		0/89 (0%)
Lipase increased	1/93 (1.1%)		0/89 (0%)
Weight decreased	0/93 (0%)		1/89 (1.1%)
Metabolism and nutrition disorders
Hyponatraemia	2/93 (2.2%)		0/89 (0%)
Dehydration	1/93 (1.1%)		1/89 (1.1%)
Failure to thrive	0/93 (0%)		1/89 (1.1%)
Hyperuricaemia	0/93 (0%)		1/89 (1.1%)
Musculoskeletal and connective tissue disorders
Back pain	1/93 (1.1%)		0/89 (0%)
Myopathy	1/93 (1.1%)		0/89 (0%)
Pain in extremity	1/93 (1.1%)		0/89 (0%)
Groin pain	0/93 (0%)		2/89 (2.2%)
Musculoskeletal chest pain	0/93 (0%)		1/89 (1.1%)
Musculoskeletal pain	0/93 (0%)		1/89 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Infected neoplasm	1/93 (1.1%)		0/89 (0%)
Squamous cell carcinoma of skin	1/93 (1.1%)		0/89 (0%)
Tumour pain	1/93 (1.1%)		1/89 (1.1%)
Metastases to central nervous system	0/93 (0%)		1/89 (1.1%)
Metastatic pain	0/93 (0%)		1/89 (1.1%)
Nervous system disorders
Cerebrovascular accident	2/93 (2.2%)		0/89 (0%)
Hypoaesthesia	1/93 (1.1%)		0/89 (0%)
Somnolence	1/93 (1.1%)		0/89 (0%)
Syncope	1/93 (1.1%)		0/89 (0%)
Cranial nerve palsies multiple	0/93 (0%)		1/89 (1.1%)
Haemorrhage intracranial	0/93 (0%)		1/89 (1.1%)
Headache	0/93 (0%)		1/89 (1.1%)
Presyncope	0/93 (0%)		1/89 (1.1%)
Spinal cord compression	0/93 (0%)		1/89 (1.1%)
Psychiatric disorders
Mental status changes	2/93 (2.2%)		1/89 (1.1%)
Confusional state	1/93 (1.1%)		0/89 (0%)
Renal and urinary disorders
Renal failure	1/93 (1.1%)		0/89 (0%)
Renal failure acute	1/93 (1.1%)		0/89 (0%)
Urethral obstruction	1/93 (1.1%)		0/89 (0%)
Urinary retention	1/93 (1.1%)		0/89 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	3/93 (3.2%)		2/89 (2.2%)
Dyspnoea	0/93 (0%)		1/89 (1.1%)
Pleural effusion	0/93 (0%)		1/89 (1.1%)
Skin and subcutaneous tissue disorders
Angioedema	1/93 (1.1%)		0/89 (0%)
Dermatitis bullous	1/93 (1.1%)		0/89 (0%)
Vascular disorders
Hypertension	5/93 (5.4%)		1/89 (1.1%)
Deep vein thrombosis	3/93 (3.2%)		0/89 (0%)
Aortic aneurysm	1/93 (1.1%)		0/89 (0%)
Hypertensive crisis	1/93 (1.1%)		1/89 (1.1%)
Hypotension	1/93 (1.1%)		0/89 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1 (V600E BRAF Negative)		Cohort 2 (V600E BRAF Positive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/93 (100%)		88/89 (98.9%)
Blood and lymphatic system disorders
Anaemia	5/93 (5.4%)		6/89 (6.7%)
Thrombocytopenia	8/93 (8.6%)		9/89 (10.1%)
Endocrine disorders
Hypothyroidism	17/93 (18.3%)		24/89 (27%)
Gastrointestinal disorders
Abdominal pain	21/93 (22.6%)		19/89 (21.3%)
Abdominal pain upper	11/93 (11.8%)		6/89 (6.7%)
Constipation	25/93 (26.9%)		28/89 (31.5%)
Diarrhoea	44/93 (47.3%)		26/89 (29.2%)
Dry mouth	14/93 (15.1%)		10/89 (11.2%)
Dyspepsia	5/93 (5.4%)		9/89 (10.1%)
Flatulence	12/93 (12.9%)		2/89 (2.2%)
Gastrooesophageal reflux disease	10/93 (10.8%)		6/89 (6.7%)
Glossodynia	6/93 (6.5%)		2/89 (2.2%)
Nausea	48/93 (51.6%)		36/89 (40.4%)
Oral pain	10/93 (10.8%)		5/89 (5.6%)
Stomatitis	16/93 (17.2%)		12/89 (13.5%)
Vomiting	36/93 (38.7%)		32/89 (36%)
General disorders
Asthenia	6/93 (6.5%)		5/89 (5.6%)
Chills	6/93 (6.5%)		4/89 (4.5%)
Fatigue	62/93 (66.7%)		41/89 (46.1%)
Oedema peripheral	14/93 (15.1%)		10/89 (11.2%)
Pain	6/93 (6.5%)		5/89 (5.6%)
Pyrexia	7/93 (7.5%)		10/89 (11.2%)
Infections and infestations
Oral herpes	5/93 (5.4%)		0/89 (0%)
Upper respiratory tract infection	5/93 (5.4%)		4/89 (4.5%)
Urinary tract infection	10/93 (10.8%)		9/89 (10.1%)
Investigations
Aspartate aminotransferase increased	3/93 (3.2%)		5/89 (5.6%)
Blood alkaline phosphatase increased	7/93 (7.5%)		3/89 (3.4%)
Blood thyroid stimulating hormone increased	14/93 (15.1%)		7/89 (7.9%)
Gamma-glutamyltransferase increased	5/93 (5.4%)		1/89 (1.1%)
Lipase increased	7/93 (7.5%)		3/89 (3.4%)
Weight decreased	22/93 (23.7%)		12/89 (13.5%)
Metabolism and nutrition disorders
Decreased appetite	40/93 (43%)		30/89 (33.7%)
Dehydration	6/93 (6.5%)		12/89 (13.5%)
Hypokalaemia	6/93 (6.5%)		2/89 (2.2%)
Hyponatraemia	8/93 (8.6%)		4/89 (4.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	29/93 (31.2%)		20/89 (22.5%)
Back pain	17/93 (18.3%)		12/89 (13.5%)
Muscle spasms	7/93 (7.5%)		5/89 (5.6%)
Muscular weakness	8/93 (8.6%)		3/89 (3.4%)
Musculoskeletal chest pain	3/93 (3.2%)		6/89 (6.7%)
Musculoskeletal pain	6/93 (6.5%)		6/89 (6.7%)
Musculoskeletal stiffness	7/93 (7.5%)		4/89 (4.5%)
Myalgia	13/93 (14%)		9/89 (10.1%)
Pain in extremity	16/93 (17.2%)		9/89 (10.1%)
Nervous system disorders
Dizziness	10/93 (10.8%)		16/89 (18%)
Dysgeusia	12/93 (12.9%)		16/89 (18%)
Headache	29/93 (31.2%)		21/89 (23.6%)
Lethargy	1/93 (1.1%)		5/89 (5.6%)
Peripheral sensory neuropathy	10/93 (10.8%)		2/89 (2.2%)
Psychiatric disorders
Confusional state	2/93 (2.2%)		5/89 (5.6%)
Depression	4/93 (4.3%)		5/89 (5.6%)
Insomnia	7/93 (7.5%)		8/89 (9%)
Renal and urinary disorders
Haematuria	5/93 (5.4%)		3/89 (3.4%)
Proteinuria	23/93 (24.7%)		17/89 (19.1%)
Respiratory, thoracic and mediastinal disorders
Cough	18/93 (19.4%)		11/89 (12.4%)
Dysphonia	26/93 (28%)		33/89 (37.1%)
Dyspnoea	14/93 (15.1%)		13/89 (14.6%)
Epistaxis	8/93 (8.6%)		8/89 (9%)
Oropharyngeal pain	13/93 (14%)		5/89 (5.6%)
Skin and subcutaneous tissue disorders
Dry skin	16/93 (17.2%)		7/89 (7.9%)
Pruritus	7/93 (7.5%)		5/89 (5.6%)
Rash	16/93 (17.2%)		5/89 (5.6%)
Vascular disorders
Hot flush	5/93 (5.4%)		1/89 (1.1%)
Hypertension	53/93 (57%)		48/89 (53.9%)
Hypotension	4/93 (4.3%)		6/89 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.