Safety and Efficacy Study of Pembrolizumab (MK-3475) Combined With Lenvatinib (MK-7902/E7080) as First-line Intervention in Adults With Advance Melanoma (MK-7902-003/E7080-G000-312/LEAP-003)

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:

1. 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. Participants that do not have a BRAF V600 mutation but did receive BRAF or BRAF/mitogen-activated extracellular signal-regulated kinase 1/2 Inhibitor (MEKi) therapy are eligible to participate in this study after discussion with the medical monitor.

2. 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.

Have documentation of BRAF V600-activating mutation status or consent to BRAF V600 mutation testing during the Screening period (participants with BRAF mutation-positive melanoma as well as BRAF wild-type or unknown are eligible).

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 intervention.

Male participants must agree to use contraception during the treatment period and for at least 7 days after the last dose of study treatment and refrain from donating sperm during this period. Please note that 7 days after lenvatinib/placebo is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed. Contraception use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.

Female participants must not be pregnant, not breastfeeding, and ≥1 of the following conditions applies:

1. Not a woman of childbearing potential (WOCBP). OR

2. 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.

The participant (or legally acceptable representative) has provided documented informed consent for the study.

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 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). Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.

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 study treatment.

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

Has had an allogeneic tissue/solid organ transplant.

Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.

What this study is about