Sacituzumab Tirumotecan (MK-2870) Versus Chemotherapy in Previously Treated Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With EGFR Mutations or Other Genomic Alterations (MK-2870-004)

Inclusion Criteria

• Histologically- or cytologically-documented advanced (Stage III not eligible for resection or curative radiation) or metastatic non-squamous NSCLC with specific mutations.
• Documentation of locally assessed radiological disease progression while on or after last treatment based on Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1.
• Participants with genome mutations must have received 1 or 2 prior lines of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), including a third generation TKI for participants with a T790M mutation; and 1 platinum-based therapy after progression on or after EGFR TKI.
• Measurable disease per RECIST 1.1 as assessed by the local site investigator.
• Archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated has been provided
• Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or baseline.
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy.
• Have an ECOG performance status of 0 or 1 within 3 days before randomization.

Exclusion Criteria

• Has predominantly squamous cell histology NSCLC.
• Has mixed tumor(s) with small cell elements.
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease.
• 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 uncontrolled, significant cardiovascular disease or cerebrovascular disease.
• Has an EGFR T790M mutation and has not received a third generation EGFR TKI (eg, osimertinib).
• Received prior systemic anticancer therapy including investigational agents within 4 weeks or 5 half-lives (whichever is shorter) before randomization.
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
• Completed palliative radiotherapy within 7 days of the first dose. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
• Received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study intervention.
• Received prior treatment with a trophoblast cell-surface antigen 2 (TROP2)-targeted antibody-drug conjugate (ADC).
• Received prior treatment with a topoisomerase I-containing ADC.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Active infection requiring systemic therapy.
• History of noninfectious pneumonitis/ILD that required steroids or has current pneumonitis/ILD.
• Has known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are clinically stable, radiologically stable for at least 4 weeks and do not require glucocorticoids for at least 14 days prior to randomization.
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
• Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.