This is a randomized, 3-arm, open-label, active-comparator, global Phase 3 study to investigate the efficacy and safety of zanidatamab in combination with standard of care chemotherapy with or without tislelizumab in subjects with advanced or metastatic GEA, including gastric, gastroesophageal junction (GEJ), and esophageal

adenocarcinomas. Subjects must not have received prior systemic anticancer therapy in the advanced/metastatic setting, and must not have received prior human epidermal growth factor receptor 2 (HER2)- or programmed cell death-1 / programmed death-ligand 1 (PD-1/PD-L1)-targeted therapy in any setting. 

New or archival tumor tissue (most recent biopsy) for screening is required from all subjects for assessment of  HER2 gene amplification and HER2 protein expression. Enrollment will be based on central laboratory assessment  of HER2 status. Assessment of microsatellite instability (MSI) status and PD-L1 expression will not be required for enrollment but will be performed retrospectively. 

Gastroesophageal adenocarcinomas (GEAs) are medically defined as malignant tumors of the esophagus, stomach and/or gastroesophageal junction (GEJ), a poorly defined anatomic region where the distal esophagus joins the proximal stomach. The relatively recent term, GEA, acknowledges the evolving understanding of these cancers having similar histology and genetic profiles. Barrett’s esophagus, the replacement of the typical squamous epithelium of the upper esophagus with the columnar epithelium of the stomach, is recognized as a precursor to esophageal adenocarcinoma, highlighting the relationship of GEAs arising in the esophagus to those arising in the stomach. Principal Component Analysis of messenger ribonucleic acid (mRNA) and The Cancer Genome Atlas (TCGA) subtyping has also demonstrated that adenocarcinomas of the esophagus, stomach, and GEJ have similar mRNA expression patterns and are differentiated from adenocarcinomas of the colon and from esophageal squamous cell carcinomas (Barra, 2017). Based on these similarities, classifying these cancers together as GEA is appropriate. Additionally, the natural history, response to therapies, and overall prognosis is similar between GEAs. While most GEA studies have excluded adenocarcinomas arising in the esophagus, a study of capecitabine and oxaliplatin for patients with previously untreated advanced esophagogastric cancer did not show any difference in survival based on primary site or histology (Cunningham, 2008).  GEAs are a major cause of morbidity and mortality worldwide. According to GLOBOCAN 2020 data, GEA arising in the stomach (gastric cancer) is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide, while GEA arising in the esophagus is the eighth most commonly diagnosed cancer and the sixth leading cause of cancer death worldwide (Ferlay, 2020). The incidence of GEA arising in the esophagus has been increasing over time, particularly in the United States (US) and other Western countries, following the increased incidence of Barrett’s esophagus in these regions (Runge, 2015). This increased incidence is also associated with an increase in cancer deaths due to GEAs from the esophagus (Hur, 2013).  

Although the majority of early stage GEAs are resectable, more than half of all patients diagnosed with early-stage GEA relapse and ultimately die of their disease (Hur, 2013). Additionally, up to 80% of patients with GEAs arising in the stomach remain asymptomatic during the early stages of their disease; therefore, initial diagnosis is often delayed. Approximately 65% to 80% of patients in the US are found to have unresectable disease or distant metastases at initial diagnosis (DeVita, 2014; Kanat, 2015). Patients with GEA arising in the esophagus are more likely to be diagnosed at an earlier stage, likely due to the presence of symptoms and screening for Barrett’s esophagus; however, approximately half of these patients already have metastatic disease at the time of diagnosis (Hur, 2013). Patients with advanced GEA generally have a poor prognosis; in metastatic GEA, the 5-year survival rate is less than 10% (Orditura, 2014).