The primary objective of the study is to compare sacituzumab tirumotecan combined with pembrolizumab to pembrolizumab alone with respect to overall survival (OS). The primary hypothesis is that the combination of sacituzumab tirumotecan and pembrolizumab is superior to pembrolizumab alone with respect to OS.

All participants who have completed the first course of pembrolizumab may be eligible for up to an additional 9 cycles of pembrolizumab monotherapy if there is blinded independent central review (BICR)-verified progressive disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) after initial treatment.

BIOLOGICAL: Sacituzumab tirumotecan

IV infusion

BIOLOGICAL: Pembrolizumab

IV infusion

DRUG: Supportive care measures

Participants are allowed to take supportive care measures at the discretion of the investigator. Prophylactic supportive care measures may include but are not limited to antiemetic agents, antidiarrheal agents, granulocyte and erythroid growth factors, and blood transfusions

• Overall Survival (OS)

• Histologically or cytologically confirmed diagnosis of squamous or nonsquamous NSCLC

  • Confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), or proto-oncogene tyrosine-protein kinase ROS (ROS1-) directed therapy is not indicated as primary therapy
  • Provided tumor tissue that demonstrates programmed cell death ligand 1 (PD-L1) expression in ≥50% of tumor cells as assessed by an immunohistochemistry (IHC) central laboratory
  • An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 7 days before randomization.
  • A life expectancy of at least 3 months.
  • Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)

• Diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements.
• Has Grade ≥2 peripheral neuropathy.
• History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea).
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease within the 6 months preceding study intervention.
• Received prior systemic anticancer therapy for their metastatic NSCLC.
• Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor Note: Prior treatment with an anti-PD-1, anti-PD- L1, or anti-PD-L2 agent in the neoadjuvant or adjuvant setting for nonmetastatic resectable NSCLC is allowed as long as therapy was completed at least 12 months before diagnosis of metastatic NSCLC.
• Received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization.
• Received radiation therapy to the lung that is >30 Gy within 6 months of start of study intervention.
• Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids.
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Known intolerance to sacituzumab tirumotecan or pembrolizumab and/or any of their excipients; for pembrolizumab, severe hypersensitivity (≥Grade 3) is exclusionary.
• Known hypersensitivity to sacituzumab tirumotecan or other biologic therapy.
• Active autoimmune disease that has required systemic treatment in the past 2 years.
• History of (noninfectious) pneumonitis/interstitial lung disease (ILD) that required steroids or has current pneumonitis/ILD.
• Active infection requiring systemic therapy
• Concurrent active Hepatitis B and Hepatitis C virus infection.
• Human immunodeficiency virus (HIV)-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
• History of allogeneic tissue/solid organ transplant.
• Requires treatment with a strong inhibitor or inducer of Cytochrome P450 3A4 (CYP3A4) at least 14 days before the first dose of study intervention and throughout the study.