A Study of Pembrolizumab With or Without Chemotherapy in Combination With Additional Treatments for Advanced Non-Small Cell Lung Cancer (NSCLC) (MK-3475-01G/KEYMAKER U01)

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

• Histologically or cytologically confirmed diagnosis of Stage IV squamous ornon-squamous non-small cell lung cancer (NSCLC) per American Joint Committee onCancer (AJCC) Staging Manual Version 8.

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1as assessed within 7 days before randomization.

• Has archival tumor tissue sample or newly obtained core, incisional, or excisionalbiopsy of a tumor lesion not previously irradiated has been provided.

• Human immunodeficiency virus (HIV)-infected participants must have well controlledHIV on ART.

• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible ifthey have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeksand have undetectable HBV viral load prior to treatment randomization.

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

• Has a diagnosis of small cell lung cancer or, for mixed tumors, presence of smallcell elements.

• Participants with squamous histology are excluded if there is a knowntumor-activating epidermal growth factor receptor (EGFR) mutation or anaplasticlymphoma kinase (ALK) or c ros oncogene 1 (ROS1) gene rearrangement.

• Is HIV-infected with a history of Kaposi's sarcoma and/or Multicentric Castleman'sDisease

• Clinically severe pulmonary compromise resulting from intercurrent pulmonaryillnesses including, but not limited to, any underlying pulmonary disorder, or anyautoimmune, connective tissue, or inflammatory disorders with pulmonary involvement.

• Has evidence of any leptomeningeal disease.

• Has known history of, or active, neurologic paraneoplastic syndrome.

• Has clinically significant corneal disease.

• Has myocardial infarction within 6 months.

• Has New York Heart Association (NYHA) Classes 3 or 4 congestive heart failure.

• Has uncontrolled angina pectoris within 6 months.

• Has cardiac arrhythmia requiring ongoing antiarrhythmic treatment.

• Has history of clinically relevant ventricular arrhythmias, such as ventriculartachycardia, ventricular fibrillation, or Torsade de Pointes.

• Has bradycardia of less than 50 beats per minute (bpm) unless the participant has apacemaker.

• Has history of second- or third-degree heart block. Candidates with a history ofheart block may be eligible if they currently have pacemakers and have no history offainting or clinically relevant arrhythmia with pacemakers.

• Has coronary/peripheral artery bypass graft within 6 months.

• Has complete left bundle branch block.

• Has inadequate washout period from prior concomitant therapy as specified inprotocol before randomization.

• Has received prior treatment with a topoisomerase I inhibitor or an anti-HER3antibody and/or ADC that consists of an exatecan derivative that is a topoisomeraseI inhibitor.

• Has received prior systemic anticancer therapy for their metastatic NSCLC.

• Has received prior therapy with an anti- programmed cell death 1 protein (anti-PD-1), anti- programmed cell death ligand 1 protein (anti-PD-L1), or anti-programmed cell death ligand 2 protein (anti-PD-L2) agent, or with an agent directedto another stimulatory or coinhibitory T-cell receptor.

• Has received prior radiotherapy within 2 weeks of start of study intervention or hasradiation related toxicity requiring corticosteroids.

• Has received radiation therapy to the lung that is >30 gray within 6 months of startof study intervention.

• Has received a live or live-attenuated vaccine within 30 days before the first doseof study intervention.

• Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapyor any other form of immunosuppressive therapy within 7 days prior to the first doseof study intervention.

• Has known additional malignancy that is progressing or has required active treatmentwithin the past 3 years.

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis.

• Has severe hypersensitivity to any of the study interventions and/or any of theirexcipients.

• Has active autoimmune disease that has required systemic treatment in the past 2years.

• Has active infection requiring systemic therapy.

• Has concurrent active Hepatitis B and Hepatitis C virus infection.

• Have not adequately recovered from major surgery or have ongoing surgicalcomplications.