Safety and Efficacy Study of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) With or Without Lenvatinib (MK-7902/E7080) as First-line Intervention in Adults With Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-7902-006/E7080-G000-315/LEAP-006)

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of Stage IV (American JointCommittee on Cancer [AJCC], version 8 or current version), nonsquamous NSCLC.

• Confirmation that Epidermal Growth Factor Receptor (EGFR), ALK Receptor TyrosineKinase (ALK), or ROS1 Receptor Tyrosine Kinase (ROS1)-directed therapy is notindicated as primary treatment (documentation of absence of tumor-activating EGFRmutations AND absence of ALK and ROS1 gene rearrangements OR presence of a KirstenRat Sarcoma (KRAS) gene mutation).

• Have measurable disease based on RECIST 1.1. Note: Lesions that appear measurable,but are situated in a previously irradiated area, can be considered measurable (eligible for selection as target lesions) if they have shown documented growthsince the completion of radiation.

• Provided an archival tumor tissue sample or newly obtained core or excisional biopsyof a tumor lesion (not previously irradiated).

• Life expectancy of at least 3 months.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 daysprior to the first dose of study intervention but before randomization.

• Contraceptive use by men should be consistent with local regulations regarding themethods of contraception for those participating in clinical studies. If thecontraception requirements in the local label for any of the study interventions ismore stringent than the requirements above, the local label requirements are to befollowed.

• Male participants must agree for at least 7 days after the last dose oflenvatinib/matching placebo and up to 180 days after the last dose ofchemotherapeutic agents to:

1. Refrain from donating sperm PLUS either:

2. Be abstinence from heterosexual intercourse as their preferred and usuallifestyle (abstinent on a long term and persistent basis) and agree to remainabstinent OR

3. Must agree to use contraception unless confirmed to be azoopsermic (vasectomized or secondary to medical cause) as detailed below:

4. Agree to use a male condom plus partner use of an additional contraceptivemethod when having penile-vaginal intercourse with a woman of childbearingpotential (WOCBP) who is not currently pregnant Note: Men with a pregnantor breastfeeding partner must agree to remain abstinent frompenile-vaginal intercourse or use a male condom during each episode ofpenile-vaginal penetration.

Note: 7 days after lenvatinib/matching placebo is stopped, if the participant is on pembrolizumab only and is greater than 180 days post chemotherapy, no male contraception measures are needed.

• Contraceptive use by women should be consistent with local regulations regarding themethods of contraception for those participating in clinical studies.

• Female participant is eligible to participate if she is not pregnant orbreastfeeding, and at least one of the following conditions applies:

1. Is not a WOCBP OR

2. Is a WOCBP and using a contraceptive method that is highly effective (with afailure rate of <1% per year), with low user dependency, or be abstinent fromheterosexual intercourse as their preferred and usual lifestyle (abstinent on along term and persistent basis), during the intervention period and for atleast 120 days post pembrolizumab and/or 30 days post-lenvatinib/matchingplacebo, and up to 180 days post last dose of chemotherapeutic agents,whichever occurs last.

• Adequate organ function.

• Adequately controlled blood pressure (BP) with or without antihypertensivemedications, defined as BP ≤150/90 mm Hg and no change in antihypertensivemedications within 1 week prior to randomization. Note: Participants must not have ahistory of uncontrolled or poorly-controlled hypertension, defined as >150/90 mm Hgfor >4 weeks despite standard medical management.

Exclusion Criteria:

• Known untreated central nervous system (CNS) metastases and/or carcinomatousmeningitis. Participants with previously treated brain metastases may participateprovided they are radiologically stable, clinically stable, and have not requiredsteroids for at least 14 days prior to the first dose of study intervention.

• History of (noninfectious) pneumonitis that required systemic steroids or currentpneumonitis/interstitial lung disease.

• Radiographic evidence of intratumoral caviations, encasement, or invasion of a majorblood vessel. Additionally, the degree of proximity to major blood vessels should beconsidered for exclusion because of the potential risk of severe hemorrhageassociated with tumor shrinkage/necrosis after lenvatinib-therapy. (In the chest,major blood vessels include the main pulmonary artery, the left and right pulmonaryarteries, the 4 major pulmonary veins, the superior or inferior vena cava, and theaorta).

• Known history of an additional malignancy, except if the participant has undergonepotentially curative therapy with no evidence of that disease recurrence for atleast 3 years since initiation of that therapy. Note: The time requirement also doesnot apply to participants who underwent successful definitive resection of basalcell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma ofthe skin, in situ cervical cancer, or other in situ cancers.

• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.

• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (doses exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior the first dose of study intervention.

• Has had allogeneic tissue/solid organ transplant.

• Known history of human immunodeficiency virus (HIV) infection. HIV testing is notrequired unless mandated by the local health authority.

• Known history of Hepatitis B or active Hepatitis C. No testing for Hepatitis B orHepatitis C is required unless mandated by the local health authority.

• History of a gastrointestinal condition or procedure that in the opinion of theinvestigator may affect oral drug absorption.

• Active hemoptysis (at least 0.5 teaspoon of bright red blood) within 2 weeks priorto the first dose of study intervention.

• Significant cardiovascular impairment within 12 months prior to the first dose ofstudy intervention, including history of congestive heart failure greater than NewYork Heart Association (NYHA) Class II, unstable angina, myocardial infarction,cerebrovascular accident (CVA)/stroke, or cardiac arrhythmia associated withhemodynamic instability.

• Known history of active tuberculosis.

• Active infection requiring systemic therapy.

• Has not recovered adequately from any toxicity and/or complication from majorsurgery prior to the first dose of study intervention.

• Previously had a severe hypersensitivity reaction to treatment with a monoclonalantibody or has a known sensitivity to any component of lenvatinib or pembrolizumab,or as applicable, carboplatin, cisplatin, or pemetrexed.

• A WOCBP who has a positive urine pregnancy test within 24 hours prior torandomization or treatment allocation. If the urine test is positive or cannot beconfirmed as negative, a serum pregnancy test will be required.

• Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.

• Received prior systemic chemotherapy or other targeted or biological antineoplastictherapy for their metastatic NSCLC. Note: Prior treatment with chemotherapy and/orradiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy wascompleted at least 6 months prior to the diagnosis of metastatic NSCLC.

• Received prior treatment with pembrolizumab or any other anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2 agent, with lenvatinib or any other receptor tyrosinekinase inhibitor (RTKi), or with an agent directed to another stimulatory orco-inhibitory T cell receptor.

• Received radiotherapy within 14 days prior to the first dose of study interventionor received lung radiation therapy of >30 Gy within 6 months prior to the first doseof study intervention. Note: Participants must have recovered from allradiation-related toxicities to Grade ≤1, not required corticosteroids, and not havehad radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

• Received systemic steroid therapy (in doses exceeding 10 mg daily of prednisoneequivalent) within 7 days prior to the first dose of study intervention.

• Received a live or live attenuated vaccine within 30 days prior to the first dose ofstudy intervention. Note: killed vaccines are allowed.

• Currently participating and receiving study therapy or has participated in a studyof an investigational agent and received study therapy or used an investigationaldevice within 4 weeks prior to the first dose of study intervention.

• Has a prolongation of QTc interval (calculated using Fridericia's formula) of >480msecl.

• Left ventricular ejection fraction (LVEF) below the institutional (or locallaboratory) normal range as determined by multigated acquisition scan (MUGA) orechocardiogram (ECHO).

• Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula