Sonesitatug Vedotin for Advanced Esophageal Cancer

Inclusion Criteria: * Capable of giving signed informed consent * Participant must be 18 years or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent. * Previously untreated histologically documented unresectable, locally advanced, or metastatic gastric, GEJ, or distal esophagus (distal third of the esophagus) adenocarcinoma * Positive CLDN18.2 expression, as determined prospectively by central IHC testing * Confirmed PD-L1 CPS status by central IHC testing and ICI eligibility per investigator judgement is required to determine cohort eligibility as described below: 1. Cohort 1: PD-L1 positive as determined by central IHC testing and the participant is deemed ICI eligible per investigator judgement. 2. Cohort 2: PD-L1 negative as determined by central IHC testing OR the participant is ICI ineligible * ECOG performance status of 0 or 1 with no deterioration to \> 1 over the previous 2 weeks prior to baseline at screening and prior to randomisation. * Minimum life expectancy of ≥ 12 weeks. * At least one lesion (measurable and/or non-measurable) that can be accurately assessed by the investigator based on RECIST 1.1. * Adequate organ and bone marrow function as specified in the protocol * Body weight ≥ 35 kg. * Sex and contraceptive requirements Exclusion Criteria: * Known HER2-positive status * Significant or unstable gastric bleeding and/or untreated gastric ulcers. * Active or history of autoimmune or inflammatory disorders requiring systemic treatment with steroids or other immunosuppressive treatment or assessed by investigator as not appropriate to participate due to undue risk are excluded. * CNS pathology * Clinically significant pleural effusions or ascites and/or pleural effusions or ascites that require drainage, peritoneal shunt, or indwelling catheter/drain. * Require parenteral nutrition support due to gastric or gastrointestinal obstruction. * Peripheral neuropathy, sensory or motor, ≥ CTCAE Grade 2 at screening. * Persistent toxicities caused by previous anticancer therapy excluding alopecia, not yet improved to Grade ≤ 1 or baseline. * Cardiac abnormalities as outlined in the protocol * Uncontrolled diabetes or diabetic neuropathy within 3 months prior to randomisation. * Infectious disease including active hepatitis A infection; uncontrolled hepatitis B and/or chronic or active hepatitis B with HBV DNA ≥ 100 IU/mL; Known chronic, active, or uncontrolled hepatitis C; HIV infection that is not well controlled * Known partial or total DPD enzyme deficiency