A Study of Zanidatamab in Combination With Chemotherapy Plus or Minus Tislelizumab in Patients With HER2-positive Advanced or Metastatic Gastric and Esophageal Cancers

Inclusion Criteria:

• Histologically confirmed unresectable locally advanced, recurrent or metastaticHER2-positive gastroesophageal adenocarcinoma (adenocarcinomas of the stomach oresophagus, including the gastroesophageal junction), defined as 3+ HER2 expressionby IHC or 2+ HER2 expression by IHC with ISH positivity per central assessment.Subjects with esophageal adenocarcinoma must not be eligible for combinedchemoradiotherapy at the time of enrollment

• Assessable (measurable or non-measurable) disease as defined by RECIST 1.1

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1,assessed within 3 days prior to randomization

• Adequate organ function

• Left ventricular ejection fraction (LVEF) ≥ 50% as determined by eitherechocardiogram or multiple gated acquisition scan (MUGA)

Exclusion Criteria:

• Prior treatment with a HER2-targeted agent, with the exception of subjects whoreceived HER2-targeted treatment for breast cancer > 5 years prior to initialdiagnosis of GEA

• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody ordrug specifically targeting T-cell co-stimulation or checkpoint pathways

• Prior treatment with systemic antineoplastic therapy or intraperitoneal chemotherapyfor unresectable locally advanced, recurrent or metastatic GEA

• Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, orradiation treatment for CNS metastases within 4 weeks prior to randomization.Stable, treated brain metastases are allowed (defined as subjects who are completelyoff steroids and anticonvulsants and are neurologically stable with no evidence ofradiographic progression for at least 4 weeks prior to randomization)

• Known history of or ongoing leptomeningeal disease (LMD)

• Known additional malignancy that is not considered cured or that has requiredtreatment within the past 3 years

• Known active hepatitis

• Any history of human immunodeficiency virus (HIV) infection

• Known SARS-CoV-2 infection; subjects with prior infection that has resolved perlocal institutions' requirements and screening guidance are eligible

• QTc Fridericia (QTcF) > 470 ms

• Clinically significant cardiac disease, such as ventricular arrhythmia requiringtherapy, uncontrolled hypertension or any history of symptomatic congestive heartfailure (CHF)