Zolbetuximab (Vyloy), has received marketing approval in Japan. The study is considered a post marketing study in Japan.
Inclusion Criteria:
* Participant has histologically confirmed gastric or Gastroesophageal Junction (GEJ) adenocarcinoma.
* Participant has radiographically confirmed, locally advanced, unresectable or metastatic disease within 28 days prior to randomization.
* Participant has radiologically evaluable disease (measurable and/or nonmeasurable) according to Response Evaluation Criteria in Solid Tumors (RECIST) V1.1, ≤ 28 days prior to randomization. For participants with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before randomization, the lesion must either be outside the field of prior radiotherapy or have documented progression following radiation therapy.
* Participant has Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0 to 1.
* Participant has predicted life expectancy ≥ 12 weeks.
* Participant must be a candidate to receive mFOLFOX6 or CAPOX and pembrolizumab.
* Female participant is not pregnant and at least 1 of the following conditions apply:
* Not a woman of child bearing potential (WOCBP)
* WOCBP who has a negative urine or serum pregnancy test at screening (Specific to Japan: with a medical interview), and agrees to follow the contraceptive guidance from the time of informed consent through at least 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention.
* Female participant must not be breastfeeding or lactating starting at screening and throughout the investigational period and for 5 half-lives (at least 9 months after the final oxaliplatin administration and 6 months after final study intervention administration).
* Female participant must not donate ova starting at first administration of study intervention and throughout the investigational period, and for 9 months after the final administration of oxaliplatin and for 6 months after final administration of all other study interventions.
* Male participant must agree to use contraception with female partner(s) of childbearing potential (including breastfeeding partner) throughout the treatment period, and for 6 months after final investigational study intervention administration.
* Male participant must agree to remain abstinent or use a condom with pregnant partner(s) for the duration of the pregnancy throughout the investigational period and for 6 months after final investigational study intervention administration.
* Male participant must not donate sperm during the treatment period and for 6 months after final investigational study intervention administration
* Participant has a Human Epidermal Growth Factor Receptor 2 (HER2) -negative tumor.
* Participant's tumor is positive for Claudin18.2 (CLDN18.2) expression.
* Participant's tumor is positive for Programmed death ligand (PD-L1) expression.
* Participant must meet all of the criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to randomization. In case of multiple central laboratory data within this period, the most recent data should be used.
* Participant agrees not to participate in another interventional study while receiving study intervention in the present study.
Exclusion Criteria:
* Participant has prior severe allergic reaction or intolerance to zolbetuximab or other monoclonal antibodies, pembrolizumab, mFOLFOX6 or CAPOX.
* Participant has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent recurrent vomiting.
* Participant has significant gastric bleeding and/or untreated gastric ulcers that would preclude the participant from participation.
* Participant has unresolved pneumonitis or history of non-infectious pneumonitis such as immune-related pneumonitis, radiation induced pneumonitis.
* Participant has history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer.
* Participant has a known history of a positive test for Human Immunodeficiency Virus (HIV) infection or known active Hepatitis B Surface Antigen (positive HBsAg) or hepatitis C infection. NOTE: Screening for these infections should be conducted per local requirements.
* For participants who are negative for HBsAg, but hepatitis B core antibody (HBcAb) positive, a hepatitis B DNA test will be performed and if positive the participant will be excluded.
* Participants with positive Hepatitis C virus (HCV) serology, but negative HCV RNA test results are eligible.
* Participants treated for HCV with undetectable viral load results are eligible.
* Participant has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization.
* Participant has active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization.
* Participant has a clinically significant disease or comorbidity that may adversely affect the safe delivery of treatment within this study or make the participant unsuitable for study participation.
* Participant has another malignancy for which treatment is required.
* Participant has known Dihydropyrimidine Dehydrogenase (DPD) deficiency (screening for DPD deficiency should be conducted per local requirements).
* Participant has known peripheral neuropathy \> grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the participant ineligible).
* Participant has sinusoidal obstruction syndrome, formerly known as veno-occlusive disease, if present, should be stable or improving.
* Participant has significant cardiovascular disease, including any of the following:
* Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to randomization.
* History of clinically significant ventricular arrhythmias (i.e., sustained; ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes).
* QTc interval \> 450 msec for male participants; QTc interval \> 470 msec for female participants.
* History or family history of congenital long QT syndrome.
* Cardiac arrhythmias requiring anti-arrhythmic medications (participants with rate controlled atrial fibrillation for \> 1 month prior to randomization are eligible).
* Participant has ongoing or previous autoimmune disease or interstitial lung disease, active diverticulitis or peptic ulcerative disease, or solid organ or stem cell transplant or other uncontrolled or clinically significant medical disorders.
* Participant has type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy or skin disorders (e.g., vitiligo, psoriasis or alopecia) not requiring systemic treatment are allowed.
* Participant has known status for microsatellite instability-high or mismatch repair deficient tumors.
* Participant has received prior systemic chemotherapy and/or immunotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, except for a maximum of 1 dose of mFOLFOX6 or CAPOX with or without pembrolizumab. However, participants may have received either neo-adjuvant or adjuvant chemotherapy, immunotherapy or other systemic anticancer therapies as long as it was completed at least 6 months prior to randomization. Participant may have received treatment with herbal medications that have known antitumor activity \> 28 days prior to randomization.
* Participant has received systemic immunosuppressive therapy, including systemic corticosteroids 14 days prior to randomization. Participants using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single-dose of systemic corticosteroids or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.
* Participant has had major surgical procedure ≤ 28 days before randomization and has not completely recovered from the surgical procedure ≤ 14 days before randomization.
* Participant has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days prior to randomization and has NOT recovered from any related toxicity. Palliative radiotherapy is allowed and must be completed \> 14 days prior to randomization.
* Participant has received prior CLDN18.2 agents.
* Participant received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
* Participant has received other investigational agents or devices concurrently or within 28 days prior to randomization.
* Participant has any condition which makes the participant unsuitable for study participation.
* Participant has any concurrent disease, infection, or co-morbid condition that interferes with the ability of the participant to participate in the study, which places the participant at undue risk or complicates the interpretation of data.
