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 received, and progressed on, at least 2 prior chemotherapy and/or immunotherapy regimens.
Participants are eligible regardless of human epidermal growth factor receptor-2 (HER2) status. Participants who are HER2+ must have previously received trastuzumab.
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.

Exclusion Criteria:

Has experienced weight loss >20% over 3 months before the first dose of study intervention.
Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or 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 the study. The required washout period before starting sacituzumab tirumotecan 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 CNS metastases and/or carcinomatous meningitis.- Has an active infection requiring systemic therapy.
Has a history of human immunodeficiency virus (HIV) infection.- Has concurrent active hepatitis B (defined as hepatitis B surface antigen (HBsAg) reactive and/or detectable hepatitis B virus (HBV) deoxyribonucleic acid (DNA)) and/or hepatitis C (defined as anti-hepatitis C virus (HCV) antibody (Ab) positive and detectable HCV ribonucleic acid (RNA)) infection or a known history of hepatitis B and/or C infection.
Has had major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention.
Has severe hypersensitivity (Grades >=3) to sacituzumab tirumotecan, any of its excipients, and/or to another biologic therapy.