Substudy 06C: A Study of Sacituzumab Tirumotecan (MK-2870) With Pembrolizumab (MK-3475) and Chemotherapy in Participants With First-Line Locally Advanced Unresectable/Metastatic Gastroesophageal Adenocarcinoma (MK-3475-06C/KEYMAKER-U06)

Eligibility Criteria

• * Has histologically and/or cytologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic 1L gastroesophageal adenocarcinoma
• * Is not expected to require tumor resection during the treatment course- Has not had prior systemic therapy administered in the recurrent or metastatic setting
• * Has gastroesophageal adenocarcinoma that is not human epidermal growth factor receptor 2 (HER2)/neu positive
• * Has provided an archival tumor tissue sample or most recently obtained core, or incisional, or excisional biopsy for a tumor lesion
• * Participants who have adverse events (AEs) due to previous anticancer therapies must have recovered to \<Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible
• * Has adequate organ function
• * Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as determined by the local site investigator/radiology assessment and verified by blind independent review committee (BICR)
• * Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 3 days before allocation/randomization.
• * Has a life expectancy of at least 6 months
• * Who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.
• * Who has history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.
• * Human immunodeficiency virus (HIV)-infected participants must have well-controlled HIV on antiretroviral therapy (ART)
• * Has squamous cell or undifferentiated gastroesophageal cancer.
• * Has had previous therapy for locally advanced unresectable or metastatic gastric/GEJ/esophageal adenocarcinoma
• * 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
• * Has uncontrolled, significant cardiovascular disease or cerebrovascular disease within 6 months preceding study intervention
• * Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment
• * HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• * Has received prior treatment with a trophoblast antigen 2 (TROP2)-targeted antibody-drug conjugate (ADC)
• * Has received prior treatment with a topoisomerase I inhibitor-based ADC and/or a topoisomerase I inhibitor-based chemotherapy
• * Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention
• * Has received prior therapy with an anti-Programmed Cell Death Protein 1 (PD-1), anti-Programmed Cell Death-Ligand 1 (PD-L1), anti-Programmed Cell Death-Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR)
• * Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation related toxicities, requiring corticosteroids
• * Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• * Has received a strong inducer/inhibitor of CYP3A4 that cannot be discontinued
• * Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
• * Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
• * Has 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 Severe hypersensitivity (≥Grade 3) to pembrolizumab, sacituzumab tirumotecan, or other biologic therapy, chemotherapy (ie, oxaliplatin, fluorouracil, capecitabine), leucovorin, levoleucovorin, or any of their excipients
• * Has active autoimmune disease that has required systemic treatment in the past 2 years
• * Has history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• * Has an active infection requiring systemic therapy
• * Has concurrent active hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] positive and/or detectable HBV DNA) and hepatitis C virus (defined as anti-hepatitis C virus \[HCV\] Ab positive and detectable HCV ribonucleic acid \[RNA\] infection
• * Has GI obstruction, poor oral intake, or difficulty in taking oral medication
• * Has poorly controlled diarrhea
• * Has had a major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention
• * Has history of allogeneic tissue/solid organ transplant
• * Have not adequately recovered from major surgery or have ongoing surgical complications