Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of Stage IV (T any, N any, M1a, M1b, M1c - AJCC eighth Edition) squamous or nonsquamous NSCLC.
  • Note: Mixed tumors will be characterized by the predominant cell type; if small cell elements are present, the participant is ineligible.
• Has measurable disease based on RECIST 1.1, as determined by the local site assessment.
  • Note: Measurable disease is defined as having at least 1 measurable lesion by CT or MRI per RECIST 1.1. 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 growth since the completion of radiation.
• Has provided tumor tissue (post diagnosis of metastatic disease is preferred) for determination of PD-L1 status before randomization.
  • Note: Assessment of PD-L1 expression must be made from provided archival tumor tissue sample or newly obtained core or incisional or excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Details pertaining to tumor tissue submission can be found in the Laboratory Manual.
• Has confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy (documentation of the absence of tumor-activating EGFR mutations [e.g., DEL19 or L858R], AND absence of ALK and ROS1 gene rearrangements).
  • Note: If participant’s tumor is known to have a predominantly squamous histology, molecular testing for EGFR mutation and ALK and ROS1 translocations will not be required, as this is not part of current diagnostic guidelines.
• Has not received prior systemic treatment for metastatic NSCLC.
• Is male or female, from ≥ 18 years of age inclusive, at the time of signing the informed consent.
• Has an ECOG PS of 0 or 1 assessed within 7 days before randomization.
• Has a life expectancy of at least 3 months.
• If male, agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
  • Chemotherapy: at least 95 days from the last dose;
  • Refrain from donating sperm; PLUS either:
  • Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent; OR
  • Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview as detailed below:
  • Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
  • Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penilevaginal penetration.
• Contraceptive 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.
• A female participant is eligible to participate if she is not pregnant or breastfeeding and at least one of the following conditions applies:
  • Not a WOCBP; OR
  • Is a WOCBP and:
  • Uses a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
    • MK-7684A/pembrolizumab: 120 days;
    • Chemotherapy: 180 days.
• The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by women 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.
• Has a negative highly sensitive pregnancy test ( as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. 
• Abstains from breastfeeding during the study intervention period and for at least 120 days after the last dose of study intervention.
• Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
• The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR.  However, the participant may participate in the study without participating in FBR.
• Has adequate organ function. Specimens must be collected within 10 days before the start of study intervention.
• Absolute neutrophil count (ANC) ≥ 1500/μL.
• Platelets ≥ 100 000/μL.
• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/La.
• Estimated creatinine clearance using the Cockcroft-Gault equation.
• To initiate treatment with carboplatin or cisplatin, CrCl must be ≥ 60 mL/min
• Total bilirubin ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN.
• AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases).
• International normalized ratio (INR) OR prothrombin time (PT).
• Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); ANC=absolute neutrophil count; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
• Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
• Estimated creatinine clearance using Cockcroft-Gault:
  • (140-age [years] × weight (kg) (×F)*Serum creatinine (mg/dL) × 72 *where F = 0.85 for females and F = 1 for males
  • Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements are to be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

Exclusion Criteria:

• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
  • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
• Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (i.e., without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention.
• Participants with asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may participate.
• Severe hypersensitivity (≥ Grade 3) to MK-7684, MK-7684A, pembrolizumab, chemotherapy components, and/or any of its excipients.
• 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 medication.
• 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) is not considered a form of systemic treatment and is allowed.
• History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
  • Note: Lymphangitic spread of the NSCLC is not exclusionary.
• Active infection requiring systemic therapy.
• Known history of HIV infection. No HIV testing is required unless mandated by local health authority.
• Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• History or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
• Received prior therapy with an anti-TIGIT, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
• Received prior systemic anticancer therapy for metastatic disease.
  • Note: Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months before the development of metastatic disease.
• If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the operation before starting study intervention.
• Received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis. 
  • Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
• Received radiation therapy to the lung that is > 30 Gray within 6 months of the first dose of study intervention.
• Received a live or live attenuated vaccine within 30 days before the first dose of study
• intervention. Administration of killed vaccines are allowed. 
• Is unable to interrupt aspirin or other NSAIDs, other than an aspirin dose ≤ 1.3 g/day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
• Is unable or unwilling to take folic acid or vitamin B12 supplementation.
• Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
  • Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• History of allogenic tissue/solid organ transplant.

Eligibility last updated 2/18/22. Questions regarding updates should be directed to the study team contact.