Inclusion Criteria:

• Has histological or cytological confirmation of squamous or nonsquamous non-small cell lung cancer (NSCLC), resectable clinical Stage II, IIIA or IIIB (with nodal involvement [N2]) per AJCC eighth edition guidelines.
• Has confirmation that epidermal growth factor receptor (EGFR)-directed therapy is not indicated as primary therapy.
• Is able to undergo surgery based on opinion of investigator after consultation with surgeon.
• Is able to receive neoadjuvant pembrolizumab and platinum-based doublet chemotherapy.
• Applies to screening for the adjuvant period only, before randomization: Has not achieved pathological complete response (pCR) at surgery by local review of pathology.
• Applies to screening for the adjuvant period only, before randomization: Tumor tissue sample from surgical resection has been provided for determination of programmed cell death ligand 1 (PD-L1) and trophoblast cell surface antigen 2 (TROP2) status by central vendor before randomization into the adjuvant period.
• Applies to screening for the adjuvant period only, before randomization: Confirmed to be disease-free based on re-baseline radiological assessment as documented by contrast enhanced chest/abdomen/pelvis computed tomography (CT) (or magnetic resonance imaging (MRI)) within 28 days before randomization.
• Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement are eligible.
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART).
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load at screening.
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at least 4 weeks before the start of study intervention.

Exclusion Criteria:

• Has one of the following tumor locations/types:
  • NSCLC involving the superior sulcus
  • Large cell neuro-endocrine cancer (LCNEC)
  • Sarcomatoid tumor
  • Diagnosis of SCLC or, for mixed tumors, presence of small cell elements
  • Documentation by local test report indicating presence of anaplastic lymphoma kinase (ALK) gene rearrangements
• Has Grade ≥2 peripheral neuropathy.
• Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease.
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QT corrected for heart rate by Fridericia's cube root formula (QTcF) interval to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention.
• Has received prior neoadjuvant therapy for their current NSCLC diagnosis.
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention.
• Has received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids.
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• 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 of immunosuppressive therapy within 7 days prior the first dose of study medication.
• Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years.
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Is an HIV-infected participant with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
• Has a concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV deoxyribonucleic acid (DNA)) and Hepatitis C virus (defined as anti-HCV antibody (Ab) positive and detectable HCV ribonucleic acid (RNA)) infection.
• Has a severe hypersensitivity (Grade ≥3) to sacituzumab tirumotecan, any of its excipients and/or to another biologic therapy.
• Has a history of allogeneic tissue/solid organ transplant.
• Has not adequately recovered from major surgery or have ongoing surgical complications.