A Study to Evaluate Sacituzumab Tirumotecan (MK-2870) in Advanced/Metastatic Gastroesophageal Adenocarcinoma (MK-2870-015)

Inclusion Criteria

• Has a histologically-or cytologically-confirmed diagnosis of advanced, unresectable or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma
• Has measurable disease per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by the local site investigator/radiology. Lesions situated in a previously-irradiated area are considered measurable if progression has been shown in such lesions.
• Has received, and progressed on, at least 2 prior chemotherapy and/or immunotherapy regimens for advanced, unresectable or metastatic gastroesophageal adenocarcinoma.
• Participants are eligible regardless of human epidermal growth factor receptor-2 (HER2) status. Participants who are HER2+ must have previously received trastuzumab where available/appropriate
• Has adequate organ function
• Has provided tumor tissue sample for determination of trophoblast cell-surface antigen 2 (TROP2) status by the central laboratory before randomization for stratification
• Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or baseline (except for alopecia and vitiligo). Participants with endocrine related AEs who are adequately treated with hormone replacement therapy are eligible
• Has measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 as assessed by the local site investigator/radiology
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days before randomization
• Has ability to swallow oral medication for those who may receive trifluridine-tipiracil
• Human immunodeficiency virus (HIV) infected participants must have well-controlled HIV on antiretroviral therapy (ART)
• Hepatitis B surface antigen (HBsAg) positive participants are eligible if they have received hepatitis B virus (HBV) antiviral therapy and have undetectable HBV viral load
• Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable

Exclusion Criteria

• Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing
• Has Grade ≥2 peripheral neuropathy
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or chronic diarrhea)
• 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 corrected QT interval (QTcF) to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within 6 months before the first dose of study intervention
• Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before the first dose of study intervention
• Has received prior treatment with a trophoblast antigen 2(TROP2) targeted antibody-drug conjugate (ADC), a topoisomerase 1 inhibitor based, and/or a topoisomerase 1 inhibitor-based chemotherapy.
• Has received prior systemic anticancer therapy within 2 weeks before the first dose of study intervention
• Has received prior radiotherapy within 2 weeks before the first dose of study intervention, has radiation-related toxicities, requiring corticosteroids, and/or has had radiation pneumonitis
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Is currently receiving a strong and/or moderate inducer/inhibitor of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of treatment with study intervention. The required washout period before starting study intervention is 2 weeks
• Has received an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active infection requiring systemic therapy
• HIV infected participants with a history of Kaposi's sarcoma and/or Multicentric Castlemans's Disease
• Has concurrent active hepatitis B (defined as hepatitis B surface antigen (HBsAg) positive and/or detectable HBV deoxyribonucleic acid (DNA)) and Hepatitis C virus (HCV) defined as anti-HCV antibody (Ab) positive and detectable HCV ribonucleic acid (RNA)) infection
• Has had major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention. Anticipation of the need for major surgery during the course of treatment with study intervention is also exclusionary
• Has severe hypersensitivity (Grades >=3) to the study interventions, any of their excipients, and/or to another biologic therapy
• Has a history of (noninfectious) pneumonitis/ interstitial lung disease (ILD) that required steroids or has current pneumonitis/ILD