KEYMAKER-U01 Substudy 01A: Efficacy and Safety Study of Pembrolizumab (MK-3475) With or Without Chemotherapy When Used With Investigational Agents in Treatment-naïve Participants With Stage IV Non-small Cell Lung Cancer (NSCLC) (MK-3475-01A/KEYMAKER-U01A)

Inclusion Criteria:

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

• Has histologically- or cytologically-confirmed diagnosis of Stage IV squamous ornonsquamous NSCLC

• Participants with nonsquamous NSCLC who are not eligible for an approved targetedtherapy

• Is able to provide archival tumor tissue sample collected either within 5 years orwithin the interval from completion of last treatment but before entering thescreening period or newly obtained core or excisional biopsy of a tumor lesion notpreviously irradiated obtained within 90 days of treatment initiation

• Has not received prior systemic treatment for their metastatic NSCLC

• Is able to complete all screening procedures within the 35-day screening window forPart A and 28-day screening window for Part B

Exclusion Criteria:

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

• Has a diagnosis of small cell lung cancer

• 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 ofimmunosuppressive therapy within 7 days before the first dose of study treatment

• Has a known additional malignancy that is progressing or has required activetreatment within the past 2 years

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

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

• Has a history of (noninfectious) pneumonitis that required steroids or has currentpneumonitis

• Has an active infection requiring systemic therapy

• Has clinically significant cardiac disease, including unstable angina, acutemyocardial infarction within 6 months from Day 1 of study treatment administration,or New York Heart Association Class III or IV congestive heart failure

• Has a known history of human immunodeficiency virus (HIV) infection. Well-controlledHIV with anti-retroviral therapy (ART) is not excluded

• Has a known history of Hepatitis B (HPV) or known active Hepatitis C virusinfection. Hepatitis B surface antigen (HBsAg) positive is eligible if on HBVantiviral therapy for at least 4 weeks and HBV viral load is undetectable prior torandomization

• Has had major surgery <3 weeks before the first dose of study treatment

• Is expected to require any other form of antineoplastic therapy while on study

• Has a history or current evidence of a gastrointestinal (GI) condition (e.g.inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liverfunction or diseases that in the opinion of the investigator may significantly alterthe absorption or metabolism of oral medications

• Is getting chemotherapy and has clinically active diverticulitis, intra-abdominalabscess, GI obstruction, or peritoneal carcinomatosis

• Has preexisting neuropathy that is moderate in intensity

• Has received prior systemic cytotoxic chemotherapy or other targeted or biologicalantineoplastic therapy for metastatic disease

• Is unable or unwilling to take folic acid or vitamin B12 supplementation, forparticipants who will receive pemetrexed

• Has a known sensitivity to any component of carboplatin, paclitaxel, pemetrexed orany of their excipients

• Has received prior radiation therapy to the lung that is >30 Gray (Gy) within 6months of the first dose of study treatment

• Has received a live vaccine within 30 days before the first dose of study treatment.Any licensed COVID-19 vaccine (including for Emergency Use) in a particular countryis allowed as long as they are messenger ribonucleic acid (mRNA) vaccines,adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, thosenot licensed or approved for Emergency Use) are not allowed

• Has received any prior immunotherapy and was discontinued from that treatment due toa severe or worse immune-related adverse event (irAE)

• Has had chemotherapy or biological cancer therapy within 4 weeks before the firstdose of study treatment or has not recovered to Common Terminology Criteria forAdverse Events (CTCAE) Grade 1 or better from the AEs due to cancer therapeuticsadministered more than 4 weeks before the first dose of study treatment (includingparticipants who had previous immunomodulatory therapy with residual irAEs)

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks before the first dose ofstudy treatment

• Previously had a severe hypersensitivity reaction to treatment with monoclonalantibodies (including pembrolizumab) and/or any of their excipients

• Has had an allogenic tissue/solid organ transplant