This clinical trial is designed for men and women with HER2 positive gastric cancer.
   
The purpose of this study is to assess the efficacy and safety of rilvegostomig in combination with fluoropyrimidine and T-DXd (Arm A) compared to trastuzumab, chemotherapy, and pembrolizumab (Arm B) in HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma participants whose tumors express PD L1 CPS ≥ 1. Rilvegostomig in combination with trastuzumab and chemotherapy will be evaluated in a separate arm (Arm C) to assess the contribution of each component in the experimental arm.

Rilvegostomig is considered investigational, which means it has not been approved by the U.S. Food and Drug Administration (FDA). The other drugs in this study are FDA-approved. 

Participants will be randomized into one of 3 treatment arms. 
   
Participants in arm A will receive the following drugs every 3 weeks: an infusion into the vein (IV) of T-DXd and rilvegostomig on Day 1 of each cycle, and either IV of 5-FU as a continuous infusion over 24 hours for the first 5 days of each cycle or capecitabine orally twice a day for 14 days during each cycle.
   
Participants in arm B will receive the following drugs every 3 weeks: IV of pembrolizumab and trastuzumab on Day 1 of each cycle, and either IV of cisplatin on Day 1 and IV of 5-FU as a continuous infusion over 24 hours for the first 5 days during each cycle, or IV of oxaliplatin on Day 1 and capecitabine orally twice a day for 14 days during each cycle.
   
Participants in arm C will receive the following drugs every 3 weeks: IV of rilvegostomig and trastuzumab on Day1 of each cycle, and either IV of cisplatin on Day 1 and IV of 5-FU as a continuous infusion over 24 hours for the first 5 days during each cycle, or IV of oxaliplatin on Day 1 and capecitabine orally twice a day for 14 days during each cycle.
   
Total study participation is expected to last about 2 years.