Amendment 01: The main reason for the protocol amendment is to align the safety data collection in the study with the Food and Drug Administration (FDA) guidance for long-term safety data collection for oncology studies. • Accordingly, the protocol has been updated to define that only treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) will be collected for all subjects. • It has been clarified that all safety related examinations (including vital signs, physical examination, electrocardiogram [ECG], echocardiogram [ECHO], multigated acquisition scan [MUGA], laboratory investigations should be performed as per local standard of care or as clinically indicated, and should be reported in the case report form (CRF) only if associated with an adverse event (AE/SAE) (ie, only the AE should be recorded in the CRF). Accordingly, all references to these procedures providing specific guidance on conduct of these procedures and statistical reporting in the study were deleted. • Routine reporting of concomitant medications in the study CRF has been deleted. Other global updates were made to the protocol as follows: • The terminology “study” has been used throughout to replace “trial.” • AE has been updated throughout the protocol to TEAE. Major revisions to individual sections are presented below: The abbreviation list was updated. The approximate number of sites and investigators initially planned for the study was updated from 100 sites and 100 investigators to 50 sites and 50 investigators (Synopsis). The primary objective was harmonized between the Synopsis and Section 8.1, and the term “Eisai-sponsored lenvatinib studies” was harmonized globally in the protocol. The definition of “Parent study” was added in Section 9.1 and the Synopsis.

Amendment 01 Continued: Figure 1 was updated in Section 9.1 to present all criteria for discontinuation. It was emphasized that the subject will not be without study drug during transition from the parent study to the roll-over study. Also, the timeline of 30 days from termination in the parent study to enrollment in the roll-over study was deleted (Synopsis and Section 9.1).” It was clarified in Section 9.1 and Synopsis that the SAE management and reporting requirements specific to study drugs will be as per the parent study protocol. It was also clarified that ongoing adverse events (AEs) in the parent study will remain ongoing at the time of discontinuation in the parent study, and that the roll-over study will only capture new or worsening TEAEs occurring after signing the ICF for the roll-over study. The number of subjects expected to initially roll over into the study was updated from 200 to 50 in Section 9.3 and Synopsis. Inclusion criterion 2 “Demonstrate compliance with study drug(s), treatment visit schedules, requirements and restrictions listed in the consent form” in Section 9.3.1 and Synopsis was deleted, and the following inclusion criterion was added “Must be able and willing to comply with the current roll-over protocol requirements.” All references to parent study protocols being included in the protocol appendices for E7080-G000-604 were deleted since the parent study protocols are not included in the protocol appendices for E7080-G000-604 (Sections 9.1.1, 9.5.9.1, 9.5.9.2, and Synopsis). Added statement that the study drug(s) administered and dispensed (kit number) will be recorded in the CRF (Section 9.4.1 and Section 9.4.4, respectively). Also, the following was added in Section 9.4.1: Subject must not be dispensed more than 2 months supply of study drug(s) at any particular time during participation in Study E7080-G000-604.

Amendment 01 Continued: Recording in the study of all prior medications administered 30 days before first dose of study drug, any concomitant therapy until 30 days after the final dose of study drug, and any other diagnostic, therapeutic, or surgical procedures relating to malignancy was deleted, and it was clarified that if concomitant medication/therapy is administered for an AE, investigators will record that AE on the Adverse Event CRF (Section 9.4.2.4 [Prior and Concomitant Therapy] and Synopsis). The prohibited concomitant therapies and drugs in Section 9.4.2.6 and Synopsis were harmonized. Also, it was clarified that palliative radiotherapy of painful pre-existing non-target bone metastases will be permitted without being considered progressive disease. This is in line with the current lenvatinib protocols. The requirement for a copy of the certification and a table of the normal laboratory ranges for the reference laboratory conducting the clinical laboratory tests required by this protocol was deleted since laboratory tests are not mandatory per protocol and will be performed as per local standards or only when clinically indicated [Section 9.4.4 (Drug Supplies and Accountability]). Clarified in Section 9.4.1 and Section 9.2 that subjects rolling over to the study will continue receiving (in addition to lenvatinib or Lenvatinib combination regimen) any other comparator therapy (except placebo). It was also added in Section 9.5.7.1 that, for this study, the study drugs include any other comparator therapy (except placebo) (in addition to lenvatinib or lenvatinib combination therapy). Study assessments: Deleted recording of baseline characteristics, since only demography information will be recorded (Section 9.5.1). Clarified that initial physical examination and any therapeutic area-specific assessments will be performed as per local standard of care or as clinicallyindicated (Section 9.5.2).

Amendment 01 Continued: Clarified that tumor assessments will be performed as per local standard of care (Section 9.5.3). Clarified that laboratory parameters, vital signs and physical examination should be performed as per local standard of care or as clinically indicated. Also, added that long term safety information will be collected at the time drug is dispensed to the subject (Section 9.5.7 and Synopsis). Clarified that only TEAEs will be collected in the study and definition of TEAE added (Section 9.5.7.1). Specific guidance and details on conduct of laboratory tests (including the names of the laboratory parameters [formerly Table 2]), procedure for vital signs and weight measurements, conduct of physical examination, and ECG recording was deleted (Sections 9.5.7.5, 9.5.7.6, 9.5.7.7, and 9.5.7.8, respectively, and Synopsis) and it has been mentioned that these procedures and assessments should be performed per local standard of care or as clinically indicated. It was also specified that for vital signs and ECG, only changes from screening vital signs or ECG findings that meet the definition of a TEAE will be recorded on the AE CRF (Section 9.5.7.6 and 9.5.7.8). Table 3 (Schedule of Procedures and Assessments; Section 9.5.8.1) was deleted and replaced with the following statement: All assessments for efficacy and safety will be performed as per local standard of care or as clinically indicated Reasons for discontinuation of the subjects from the study were harmonized between Section 9.1.1, Section 9.5.10, Figure 1 (Section 9.1) and Synopsis. Additional criterion of pregnancy mentioned in Section 9.5.10 was deleted (as it was added in error).

Amendment 01 Continued: Reporting for TEAEs and SAEs throughout the protocol was harmonized in Sections 9.1, 9.5.7.1, and Synopsis as follows: All TEAEs and SAEs, regardless of relationship to study drug or procedure, should be recorded beginning from the time the subject signs the roll-over study informed consent form (ICF) for up to 28 days after the last dose of study drug(s) (or 5 × half-life of the study drug[s], whichever is longer). Statistical analysis: The study analysis set was updated from the “all treated population” to the “Safety Analysis Set” in Section 9.7 and the Synopsis, and the set was defined as the group of subjects who received at least 1 dose of study drug(s). It was clarified that only demographic characteristics will be reported in the study and “other baseline characteristics” was deleted (Section 9.7.1.3). Former Section 9.7.1.3 (Prior and Concomitant Therapy) was deleted since this data will not be collected in the study. Section 9.7.1.6 (Safety Analyses) was modified to reflect that only TEAE and SAEs will be summarized. Laboratory test results, physical examination findings, vital signs, and echocardiogram results were deleted as these assessments will not be summarized in the study report (also deleted from Section 9.7). Accordingly Section 9.7.1.9 (Laboratory Values), Section 9.7.1.10 (Vital signs), Section 9.7.1.11 (Electrocardiogram), and Section 9.7.1.12 (Other Safety Analyses) were deleted. The definition of TEAE was updated in Section 9.7.1.8 as follows: An AE that emerges during treatment in the roll-over study, having been absent before the time the subject signs the roll-over study ICF or • Re-emerges during treatment in the roll-over study, having been present before signing the ICF but stopped before signing the ICF, or • Worsens in severity during treatment in the roll-over study relative to the pre-ICF state, when the AE is continuous.

Amendment 01 Continued: It was added that for the TEAEs, the incidence, severity, duration and timing in relation to the start of study medication will be summarized. Since the subjects are not required to adhere to a specific visit schedule, the following sentence was deleted from Section 9.5.10, “All subjects who discontinue the study are to complete the study’ s early discontinuation procedures indicated in the Schedule of Procedures/Assessments found in Table 3.” Also, reasons for discontinuation were added. Section 11.5 (Identification of Source Data): Recording of sampling date and time for drug concentration and sampling date and time for the clinical laboratory test in the CRF was deleted since these procedures will not be done in the study. Appendix 3 – Updated Sponsor’s Grading for Laboratory Values Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 for alkaline phosphatase and γ-glutamyl transpeptidase.

Amendment 02: Title page: The Investigational New Drug (IND) number was added. Synopsis (Study Design) and Section 9.1: Clarity was added regarding the study design, process of ICF signing, and intention of non-interruption of treatment during a subject’s transitioning from the parent study to Study E7080-G000-604. Section 9.1 (Figure 1): The figure was updated to clarify that the screening period for the study will overlap with the end of the parent study, and accordingly, subjects may remain on the parent study during the screening period. Also, the footnote was updated to state that the Screening Period is “Approximately from Day -30 to Day -1).” Section 9.4.1: It was clarified that subjects must not be dispensed more than a 3-months (formerly, 2 months) supply of study drug(s) at any particular time during participation in this study. Section 9.5.10: Study discontinuation criteria were harmonized with the synopsis. Synopsis (Inclusion Criteria): The statement “Subjects must be rolled overwithin 30 days of termination from their parent study” was deleted to harmonize with inclusion criteria in the protocol, since this was left in the previous amendment in error. The ICH definition was updated to match the current ICH definition on the title page, abbreviation list, Section 5.2, and investigator signature page.