- Has histologically or cytologically confirmed melanoma
- Has unresectable Stage III or Stage IV melanoma, as per American Joint Committee on
Cancer guidelines, not amenable to local therapy
- Has been untreated for advanced or metastatic disease except as follows: a.
proto-oncogene B-Raf (BRAF) V600 mutation-positive melanoma may have received standard
of care targeted therapy as first-line therapy for advanced or metastatic disease. b.
Prior adjuvant or neoadjuvant therapy, with targeted therapy or immunotherapy (such as
anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], anti-programmed cell death
1 [anti-PD-1] therapy or Interferon) will only be permitted if relapse did not occur
during active treatment or within 6 months of treatment discontinuation.
- Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
- Has the presence of ≥1 measurable lesion by computed tomography (CT) or magnetic
resonance imaging (MRI) per RECIST 1.1
- Provides a tumor biopsy. Participants must submit tumor sample during Screening for
confirmation of adequacy of tumor tissue at a central pathology laboratory.
Participants who do not submit a tumor tissue sample will not be randomized. The tumor
biopsy may not be obtained from a lone target lesion. Confirmation of presence of
tumor tissue is not required prior to randomization.
- Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less
(except alopecia). If participant received major surgery or radiation therapy of >30
Gray (Gy), they must have recovered from the toxicity and/or complications from the
- Male participants must agree to use contraception during the treatment period and for
at least 120 days after the last dose of study treatment and refrain from donating
sperm during this period
- Female participants must not be pregnant, not breastfeeding, and ≥1 of the following
conditions applies: a. Not a woman of childbearing potential (WOCBP) OR b. A WOCBP who
agrees to use study-approved contraception during the treatment period and for at
least 120 days after the last dose of study treatment
- Has adequately controlled blood pressure (BP) with or without antihypertensive
medications, defined as BP ≤150/90 mmHg at screening and no change in antihypertensive
medications within 1 week before Cycle 1 Day 1
- Has adequate organ function
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days before the first dose of study treatment.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include early stage cancers (carcinoma in situ or Stage 1, non-ulcerated
primary melanoma <1 mm in depth with no nodal involvement) treated with curative
intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ
cervical cancer, or in situ breast cancer that has undergone potentially curative
- Has known active central nervous system metastases and/or carcinomatous meningitis
- Has ocular melanoma
- Has known hypersensitivity to active substances or any of their excipients including
previous clinically significant hypersensitivity reaction to treatment with another
- Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease-modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
- Has an active infection requiring systemic therapy
- Has known history of human immunodeficiency virus (HIV) infection
- Has known history of or is positive for hepatitis B virus or hepatitis C virus
- Has a history of (non-infectious) pneumonitis that required steroids or current
- Has a history of active tuberculosis (Bacillus tuberculosis)
- Has presence of gastrointestinal condition including malabsorption, gastrointestinal
anastomosis, or any other condition that might affect the absorption of lenvatinib
- Has had a major surgery within 4 weeks prior to Cycle 1 Day 1. Adequate wound healing
after major surgery must be assessed clinically and have resolved completely prior to
Cycle 1 Day 1.
- Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula
- Has radiographic evidence of major blood vessel invasion/infiltration
- Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the
first dose of study treatment
- Has clinically significant cardiovascular disease within 12 months of the first dose
of study treatment including New York Heart Association Class III or IV congestive
heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or
cardiac arrhythmia associated with hemodynamic instability
- Has received prior systemic treatment for unresectable or metastatic melanoma other
than targeted therapy as noted in Inclusion Criteria above
- Has received prior therapy with a monoclonal antibody, chemotherapy, or an
investigational agent or device within 4 weeks or 5 half-lives (whichever is longer)
before administration of study treatment or not recovered (≤Grade 1 or at Baseline)
from adverse events due to previously administered agents.
Exception to this rule would be use of denosumab, which is not excluded. Note: Participants
with alopecia and ≤Grade 2 neuropathy are an exception and may enroll.
- Has received prior radiotherapy within 2 weeks of first dose of study treatment (Cycle
1 Day 1) with the exception of palliative radiotherapy to bone lesions, which is
allowed if completed 2 weeks prior to Cycle 1 Day 1. Participants must have recovered
from all radiation-related toxicities, not require corticosteroids, and not have had
- Has received live vaccine within 30 days before the first dose of study treatment
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
- Has had an allogeneic tissue/solid organ transplant