Substudy 06D: Combination Therapies in Second Line (2L) Gastroesophageal Adenocarcinoma (MK-3475-06D/Keymaker-U06)

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

• Has histologically and/or cytologically confirmed diagnosis of previously treated,second line (2L) (received first line (1L) treatment) gastric adenocarcinoma,gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma

• Has metastatic disease or locally advanced, unresectable disease

• Has experienced documented objective radiographic or clinical disease progressionduring or after 1L therapy containing any platinum/fluoropyrimidine doublet with orwithout immunotherapy

• Tumor tissue must be confirmed as negative for HER2 expression (IHC 0/1+ or IHC2+/insitu hybridization negative) as classified by American Society of ClinicalOncology/College of American Pathologists (ASCO-CAP) guidelines

• Can provide a core/excisional biopsy of a tumor lesion not previously irradiated (collected from a biopsy performed after the most recent systemic anticancer therapyregimen)

• AEs due to previous anticancer therapies must be ≤Grade 1 or baseline (exceptalopecia and vitiligo). Endocrine-related AEs adequately treated with hormonereplacement are acceptable

• Has Eastern Cooperative Oncology Group performance status of 0 or 1

• Has a life expectancy of at least 3 months

• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible ifthey have received Hepatitis B Virus (HBV) antiviral therapy for at least 4 weeks,and have undetectable HBV viral load prior to allocation/randomization

• Participants with history of Hepatitis C Virus (HCV) infection are eligible if HCVviral load is undetectable at screening

• Human Immunodeficiency Virus (HIV)-infected participants must have well controlledHIV on antiretroviral therapy

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

• Has squamous cell or undifferentiated gastroesophageal cancer

• Has experienced weight loss >20% over 3 months before the first dose of studyintervention

• Has 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

• Has a serious or nonhealing wound or peptic ulcer or bone fracture within 28 daysprior to allocation/randomization

• Has a bowel obstruction, history or presence of inflammatory enteropathy orextensive intestinal resection (hemicolectomy or extensive small intestine resectionwith chronic diarrhea)

• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease

• Has experienced any arterial thrombotic event, including myocardial infarction,unstable angina, cerebrovascular accident, or transient ischemic attack, within 6months prior to allocation/randomization

• Has uncontrolled arterial hypertension ≥150/≥90 mm mercury (Hg)

• Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage ordiuretic drugs within 2 weeks prior to enrollment

• Has undergone major surgery within 28 days prior to allocation/randomization, orcentral venous access device placement within 7 days prior toallocation/randomization or planned major surgery following initiation of studytreatment

• Is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparinor similar agents

• Is receiving chronic therapy with nonsteroidal anti-inflammatory agents or otherantiplatelet agents

• Has a history of deep vein thrombosis, pulmonary embolism, or any other significantthromboembolism during the 3 months prior to allocation/randomization

• Has significant bleeding disorders, vasculitis, or had a significant bleedingepisode from the gastrointestinal (GI) tract within 3 months prior to study entry

• Has history of GI perforation and/or fistulae within 6 months prior toallocation/randomization

• HIV-infected participants with a history of Kaposi's sarcoma and/or MulticentricCastleman's Disease

• Has received prior treatment with a trophoblast cell-surface antigen 2 (TROP2)- orHER3-targeted agent, topoisomerase 1 inhibitor-based ADC and/or a topoisomerase 1inhibitor-based chemotherapy, or any previous systemic therapy targeting vascularendothelial growth factor (VEGF) or the vascular endothelial growth factor receptor (VEGFR) signaling pathways

• Has received prior systemic anticancer therapy within 4 weeks before the first doseof study intervention

• Has received prior radiotherapy within 2 weeks of start of study intervention, orhas radiation-related toxicities, requiring corticosteroids

• Has received a live or live-attenuated vaccine within 30 days before the first doseof study intervention. Administration of killed vaccines is allowed

• Has received an investigational agent or has used an investigational device within 4weeks prior to study intervention administration

• Has known additional malignancy that is progressing or has required active treatmentwithin the past 3 years. Basal cell carcinoma of the skin, squamous cell carcinomaof the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, thathave undergone potentially curative therapy are not excluded

• Has known active central nervous system metastases and/or carcinomatous meningitis

• Has an active infection requiring systemic therapy

• Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBVdeoxyribonucleic acid) and Hepatitis C virus (defined as anti-HCV antibody positiveand detectable HCV ribonucleic acid) infection

• History of (noninfectious) pneumonitis/interstitial lung disease that requiredsteroids or has current pneumonitis/interstitial lung disease, or where suspectedILD or pneumonitis cannot be ruled out by imaging at screening

• Has severe hypersensitivity (Grade ≥3) to MK-2870, or HER3-DXd, any of theirexcipients, and/or to another biologic therapy

• Has not adequately recovered from major surgery or have ongoing surgicalcomplications