用於罹患局部晚期無法切除或轉移性胃或胃食道交界腺癌，腫瘤為 HER2 陰性、Claudin (CLDN) 18.2 陽性且計畫性凋亡配體-1 (PD-L1) 陽性的參與者之第一線治療

主要： • 評估 zolbetuximab 加上 pembrolizumab 和化療（CAPOX 或 mFOLFOX6），相較於安慰劑加上 pembrolizumab 和化療（CAPOX 或 mFOLFOX6）（作為第一線治療）的療效 關鍵次要： • 評估 zolbetuximab 加上 pembrolizumab 和化療，相較於安慰劑加上 pembrolizumab 和化療的活性與療效 次要： • 評估 zolbetuximab 加上 pembrolizumab 和化療，相較於安慰劑加上 pembrolizumab 和化療的療效 • 評估 zolbetuximab 合併 pembrolizumab 和化療的安全性和耐受性 • 評估 zolbetuximab 合併 pembrolizumab 和化療的 PK • 評估 zolbetuximab 合併 pembrolizumab 和化療的免疫原性特性 探索性： • 評估可能與治療結果相關之探索性生物標記 • 評估 HRQoL • 評估後續抗癌療法後的 PFS (PFS2)

Zolbetuximab

Zolbetuximab

243

100 mg/vial, 300 mg/vial

OS，定義為從隨機分配日期起，到病歷記載的任何原因死亡日期之時間

Participant is eligible for participation in the study if all of the following apply:
Age
1. Participant is ≥ 18 years of age at the time of signing informed consent.
Type of Participant and Disease Characteristics
2. Participant has histologically confirmed gastric or GEJ adenocarcinoma.
3. Participant has radiographically confirmed, locally advanced, unresectable or metastatic disease within 28 days prior to randomization.
4. Participant has radiologically evaluable disease (measurable and/or nonmeasurable) according to RECIST V1.1, per investigator assessment, ≤ 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.
5. Participant has ECOG performance status 0 to 1.
6. Participant has predicted life expectancy ≥ 12 weeks in the opinion of the investigator.
7. Participant must be a candidate to receive mFOLFOX6 or CAPOX and pembrolizumab.
Sex and Contraceptive Requirements
8. Female participant:
● Is not pregnant (see [Section 10.2], Appendix 2) and at least 1 of the following conditions apply:
a. Not a WOCBP (see [Section 10.2], Appendix 2)
b. 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 (see [Section 10.2], Appendix 2) 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.
● 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).
● 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.
9. Male participant:
● Must agree to use contraception (see [Section 10.2], Appendix 2) with female partner(s) of childbearing potential (including breastfeeding partner) throughout the treatment period, and for 6 months after final investigational study intervention administration.
● 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.
● Must not donate sperm during the treatment period and for 6 months after final investigational study intervention administration.
Informed Consent
10. Participant or their LAR has provided informed consent which includes compliance with the requirements and restrictions listed in the ICF and protocol.
Laboratory Assessments
11. Participant has a HER2-negative tumor.
12. Participant’s tumor is positive for CLDN18.2 expression.
13. Participant’s tumor is positive for PD-L1 expression.
14. Participant must meet all of the following 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.
• Hgb ≥ 9 g/dL (transfusion is allowed, but posttransfusion Hgb [24 hours or later following transfusion] must be ≥ 9 g/dL)
• ANC ≥ 1.5 × 109/L
• Platelets ≥ 100 × 109/L
• Albumin ≥ 2.5 g/dL
• TBL ≤ 1.5 × ULN
• AST and ALT ≤ 2.5 × ULN in participants without liver metastases (≤ 5 × ULN if liver metastases are present)
• Estimated creatinine clearance ≥ 30 mL/min
• PT/INR and PTT ≤ 1.5 × ULN (except for participants receiving anticoagulation therapy)
Other Inclusion Criteria
15. Participant agrees not to participate in another interventional study while receiving study intervention in the present study.

Participant will be excluded from participation in the study if any of the following apply:
Medical Conditions
1. Participant has prior severe allergic reaction or intolerance to (zolbetuximab or other monoclonal antibodies, pembrolizumab, mFOLFOX6 or CAPOX).
2. Participant has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent recurrent vomiting.
3. Participant has significant gastric bleeding and/or untreated gastric ulcers that would preclude the participant from participation per investigator’s judgment.
4. Participant has unresolved pneumonitis or history of non-infectious pneumonitis such as immune-related pneumonitis, radiation induced pneumonitis.
5. Participant has history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer.
6. Participant has a known history of a positive test for HIV infection or known active hepatitis B (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 HCV serology, but negative HCV RNA test results are eligible.
• Participants treated for HCV with undetectable viral load results are eligible.
7. Participant has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization.
8. Participant has active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization.
9. Participant has a clinically significant disease or comorbidity that in the opinion of the investigator may adversely affect the safe delivery of treatment within this study or make the participant unsuitable for study participation.
10. Participant has another malignancy for which treatment is required, per investigator’s clinical judgment.
11. Participant has known DPD deficiency (screening for DPD deficiency should be conducted per local requirements).
12. Participant has known peripheral neuropathy > grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the participant ineligible).
13. Participant has sinusoidal obstruction syndrome, formerly known as veno-occlusive disease, if present, should be stable or improving per investigator’s judgment.
14. Participant has significant cardiovascular disease, including any of the following:
a. 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.
b. History of clinically significant ventricular arrhythmias (i.e., sustained; ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes).
c. QTc interval > 450 msec for male participants; QTc interval > 470 msec for female participants.
d. History or family history of congenital long QT syndrome.
e. Cardiac arrhythmias requiring anti-arrhythmic medications (participants with rate controlled atrial fibrillation for > 1 month prior to randomization are eligible).
15. 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.
16. 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.
17. Participant has known status for microsatellite instability-high or mismatch repair deficient tumors.
Prior/Concomitant Therapy
18. 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.
19. 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.
20. Participant has had major surgical procedure ≤ 28 days before randomization and has not completely recovered from the surgical procedure ≤ 14 days before randomization.
21. 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.
22. Participant has received prior CLDN18.2 agents.
23. Participant received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
Prior/Concurrent Clinical Study Experience
24. Participant has received other investigational agents or devices concurrently or within 28 days prior to randomization.
Other Exclusion Criteria
25. Participant has any condition, which, in the investigator’s opinion, makes the participant unsuitable for study participation.
26. 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 in the opinion of the investigator.