The purpose of this study is to evaluate the efficacy and safety of sonesitatug vedotin in combination with capecitabine with or without rilvegostomig in first-line (1L) Claudin18.2 (CLDN18.2)-positive, human epidermal growth factor receptor 2 (HER2)-negative, gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.

The purpose of this Phase III study is to evaluate the efficacy and safety of sonesitatug vedotin in combination with capecitabine with or without rilvegostomig in 1L CLDN18.2-positive, HER2-negative gastric, GEJ, and esophageal adenocarcinoma, and the clinical performance of the investigation in vitro diagnostics (IVDs). The study will include 2 cohorts to provide a treatment option for all participants that are HER2-negative and CLDN18.2-positive. Cohort 1 will evaluate sonesitatug vedotin in combination with rilvegostomig with capecitabine in participants who are CLDN18.2-positive and programmed death-ligand 1 (PD-L1) positive. Cohort 2 will evaluate sonesitatug vedotin in combination with capecitabine in participants who are CLDN18.2-positive and PD-L1 negative or immune checkpoint inhibitor (ICI) ineligible.

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

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. 'Yes' indicates that AstraZeneca is accepting requests for IPD, but this does not mean that all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved, AstraZeneca will provide access to the anonymized individual patient-level data via the secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing the requested information.

This is an open-label study; however, it will be conducted 'sponsor blind' and the specific treatment to be taken by a participant will be assigned using an IRT/RTSM.

To maintain the integrity of the study, sponsor access to treatment records will be restricted, unless a positive result is observed at an interim analysis and access is required as per protocol-defined procedures