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, unresectableor metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, oresophageal 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 apreviously-irradiated area are considered measurable if progression has been shownin such lesions.

• Has received, and progressed on, at least 2 prior chemotherapy and/or immunotherapyregimens 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 trastuzumabwhere available/appropriate

• Has adequate organ function

• Has provided tumor tissue sample for determination of trophoblast cell-surfaceantigen 2 (TROP2) status by the central laboratory before randomization forstratification

• Participants who have AEs due to previous anticancer therapies must have recoveredto Grade ≤1 or baseline (except for alopecia and vitiligo). Participants withendocrine related AEs who are adequately treated with hormone replacement therapyare eligible

• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3days before randomization

• Has ability to swallow oral medication for those who may receivetrifluridine-tipiracil

• Human immunodeficiency virus (HIV)-infected participants must have well-controlledHIV on antiretroviral therapy (ART)

• Hepatitis B surface antigen (HBsAg)-positive participants are eligible if they havereceived hepatitis B virus (HBV) antiviral therapy and have undetectable HBV viralload

• Participants with a history of hepatitis C virus (HCV) infection are eligible if HCVviral load is undetectable

Exclusion Criteria:

• Has a history of documented severe dry eye syndrome, severe Meibomian gland diseaseand/or blepharitis, or severe corneal disease that prevents/delays corneal healing

• Has Grade ≥2 peripheral neuropathy

• Has active inflammatory bowel disease requiring immunosuppressive medication orprevious history of inflammatory bowel disease (e.g., Crohn's disease, ulcerativecolitis, 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 seriouscardiovascular and cerebrovascular diseases within 6 months before the first dose ofstudy intervention

• Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage ordiuretic drugs within 2 weeks before the first dose of study intervention

• Has received prior treatment with a trophoblast antigen 2(TROP2) targetedantibody-drug conjugate (ADC), a topoisomerase 1 inhibitor based, and/or atopoisomerase 1 inhibitor-based chemotherapy.

• Has received prior systemic anticancer therapy within 2 weeks before the first doseof study intervention

• Has received prior radiotherapy within 2 weeks before the first dose of studyintervention, has radiation-related toxicities, requiring corticosteroids, and/orhas had radiation pneumonitis

• Has received a live or live-attenuated vaccine within 30 days before the first doseof 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 studyintervention. The required washout period before starting study intervention is 2weeks

• Has received an investigational agent or has used an investigational device within 4weeks before the first dose of study intervention

• Has a known additional malignancy that is progressing or has required activetreatment within the past 3 years

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis

• Has an active infection requiring systemic therapy

• HIV-infected participants with a history of Kaposi's sarcoma and/or MulticentricCastlemans'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 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 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 thefirst dose of study intervention. Anticipation of the need for major surgery duringthe course of treatment with study intervention is also exclusionary

• Has severe hypersensitivity (Grades >=3) to the study interventions, any of theirexcipients, and/or to another biologic therapy

• Has a history of (noninfectious) pneumonitis/ interstitial lung disease (ILD) thatrequired steroids or has current pneumonitis/ILD