Phase III Randomized Trial of AZD0901 with Capecitabine ± Rilvegostomig in First‑Line Claudin‑18.2‑Positive HER2‑Negative Advanced Gastric, GEJ or Esophageal Adenocarcinoma

Primary objective: In cohort 1, superiority of sonesitatug vedotin + rilvegostomig + capecitabine versus standard of care (SoC) will be evaluated by progression‑free survival and overall survival; in cohort 2, superiority of sonesitatug vedotin + capecitabine versus SoC will be evaluated by progression‑free survival. This objective addresses potential improvements in disease control and survival for patients with advanced or metastatic gastric, gastro‑esophageal junction, or esophageal adenocarcinoma expressing Claudin‑18.2.

Secondary objectives include:

• Demonstration of superiority of sonesitatug vedotin + capecitabine versus SoC for overall survival in cohort 2.
• Evaluation of sonesitatug vedotin + nivolumab + capecitabine versus SoC for PFS and overall survival in cohort 1.
• Assessment of objective response rate for sonesitatug vedotin + rilvegostomig + capecitabine (cohort 1) and for sonesitatug vedotin + capecitabine (cohort 2).
• Assessment of duration of response for the regimens in the respective cohorts.
• Evaluation of both objective response rate and duration of response for sonesitatug vedotin + nivolumab + capecitabine in cohort 1.
• Pharmacokinetic and immunogenicity profiling of sonesitatug vedotin (cohorts 1 and 2) and of rilvegostomig (cohort 1).
• Safety and tolerability comparisons of each investigational regimen—sonesitatug vedotin + rilvegostomig + capecitabine, sonesitatug vedotin + nivolumab + capecitabine, and sonesitatug vedotin + capecitabine—versus SoC in the respective cohorts.

The trial enrolled 1,614 adult patients (both male and female) with histologically confirmed unresectable, locally advanced, or metastatic gastric, gastroesophageal junction, or distal esophageal adenocarcinoma expressing Claudin18.2, who were at least 18 years of age and weighed ≥35 kg. Participants were required to have an ECOG performance status of 0 or 1, a minimum life expectancy of 12 weeks, and adequate organ and bone‑marrow function. Inclusion required measurable disease per RECIST 1.1, positive PD‑L1 CPS status (≥1 for Cohort 1 or <1/ICI ineligible for Cohort 2), and the ability to provide informed consent. Both sexes and vulnerable individuals were represented, and selection was based on the specified histologic, molecular, and clinical criteria; no additional lifestyle information such as diet or physical activity was stipulated.

The study is a phase III, multicentre, randomized, controlled trial evaluating sonesitatug vedotin in combination with capecitabine, with or without rilvegostomig, versus standard of care in adults with unresectable, locally advanced or metastatic gastric, gastro‑oesophageal junction, or distal oesophageal adenocarcinoma that are Claudin18.2‑positive. Eligible participants undergo an initial screening visit to confirm histology, CLDN18.2 expression, PD‑L1 CPS status, ECOG performance status (0‑1), organ function, and informed consent. After successful screening, a baseline/randomisation visit initiates treatment according to cohort allocation; participants receive the investigational regimen or comparator therapy in 21‑day cycles. Subsequent study visits are scheduled every 3 weeks for safety assessments, laboratory tests, ECGs, and drug administration, with tumour imaging performed every 8 weeks to evaluate progression per RECIST 1.1. Follow‑up visits continue after treatment discontinuation to capture overall survival, lasting until death, loss to follow‑up, or the planned study termination date (approximately 5 years from the first patient enrolment). Participants remain in the trial for the duration of active therapy and subsequent follow‑up, typically ranging from several months up to a few years. Early termination of individual participation may occur due to disease progression, unacceptable adverse events, withdrawal of consent, major protocol deviations, or investigator‑determined clinical necessity.

AZD0901 is provided as a solution for infusion and administered intravenously. The protocol specifies a dose expressed in milligrams per kilogram body weight, with dosing frequency defined by the study schedule.

Nivolumab (OPDIVO 600 mg) is supplied as a solution for injection and given by intravenous infusion. The assigned dose is expressed in milligrams per administration, with intervals determined by the trial regimen.

Rilvegostomig is formulated as a solution for infusion for intravenous use. Dosing is expressed in milligrams per millilitre, administered according to the investigational schedule.

Capecitabine (Capecitabine Accord 150 mg) is presented as film‑coated tablets. Although the route is listed as intravenous, the product is taken according to the dosing plan defined in the protocol, with the amount expressed in milligrams per square metre.

Zolbetuximab (Vyloy 100 mg powder for concentrate) is a solution for infusion administered intravenously. The dose is expressed in milligrams per square metre and is given per the study’s treatment cycle.

Oxaliplatin (Oxaliplatin Bendalis 5 mg/ml concentrate) is supplied as a solution for infusion for intravenous administration. The dosage is reported in milligrams per square metre, with administration timing defined by the protocol.

Folinic acid (BENDAFOLIN 10 mg/ml injection) is provided as a solution for injection and given intravenously. Dosing is expressed in milligrams per square metre and follows the schedule outlined in the trial design.

Fluorouracil (50 mg/ml solution for injection or infusion) is administered intravenously as a solution for injection/infusion. The dose is recorded in milligrams per square metre according to the study regimen.

Mycophenolate mofetil (Mycofit 250 mg hard capsules) is taken orally. The dosage is expressed in grams per administration, with compliance monitored through capsule count and patient diary entries.

Infliximab (Inflectra 100 mg powder for concentrate) is supplied as a solution for infusion for intravenous use. Dosing is indicated in milligrams per administration and is administered per the protocol schedule.

All investigational and comparator agents are administered in accordance with the predefined treatment cycles. Dosing compliance is documented in the case report forms, and infusion records are reviewed regularly to ensure adherence to the protocol.

The trial evaluates efficacy primarily through Progression Free Survival (PFS) and Overall Survival (OS) as defined by RECIST 1.1. Secondary efficacy measures include Objective Response Rate (ORR) and Duration of Response (DoR). Baseline and follow‑up imaging (CT or MRI) are performed at protocol‑specified intervals to assess tumor size and determine response status according to RECIST criteria. Serum concentrations of sonesitatug vedotin and rilvegostomig are quantified using validated immunoassays for pharmacokinetic evaluation, and anti‑drug antibodies are detected with standardized immunogenicity assays.

Time‑to‑event endpoints (PFS, OS) are analyzed with Kaplan‑Meier survival estimates and compared between arms using log‑rank tests; hazard ratios and 95 % confidence intervals are derived from Cox proportional hazards models. ORR and DoR are summarized descriptively and compared with chi‑square or Fisher’s exact tests as appropriate. Pharmacokinetic parameters are calculated by non‑compartmental methods. All efficacy analyses are performed on the intention‑to‑treat population.