Phase 3 Trial of Domvanalimab, Zimberelimab, and Chemotherapy vs. Nivolumab and Chemotherapy in Advanced Gastric and Esophageal Adenocarcinoma

The primary objective of this study is to compare the **overall survival (OS)** of domvanalimab + zimberelimab + chemotherapy versus nivolumab + chemotherapy in participants with high programmed death ligand 1 (PD-L1) expression, positive PD-L1 expression, and in all randomized participants. This is clinically relevant as it aims to determine the efficacy of the new combination treatment in improving survival outcomes for patients with previously untreated locally advanced unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma.

Secondary objectives include:

• Comparing progression-free survival (PFS) of domvanalimab + zimberelimab + chemotherapy versus nivolumab + chemotherapy in participants with high PD-L1 expression, positive PD-L1 expression, and in all randomized participants.
• Assessing disease-related symptoms and impact using the Functional Assessment of Cancer Therapy – Gastric (FACT-Ga) in participants with high PD-L1 expression, positive PD-L1 expression, and in all randomized participants.
• Evaluating additional measures of clinical activity in participants with high PD-L1 expression, positive PD-L1 expression, and in all randomized participants.
• Assessing the safety and tolerability of domvanalimab + zimberelimab + chemotherapy in all randomized participants.

The clinical trial involves a total of **563 participants** diagnosed with **esophageal or gastric cancer**, including those with metastatic forms of the disease. The study population comprises both male and female subjects, aged 18 years and older, who have a histologically confirmed diagnosis of locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes individuals with at least one measurable target lesion as per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The selection process ensures that participants are capable of providing informed consent in compliance with the study's requirements. The trial population includes vulnerable groups, reflecting a diverse cohort in terms of health status and demographic characteristics. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, open-label, multicenter Phase 3 study designed to evaluate the efficacy of a combination treatment involving **domvanalimab**, **zimberelimab**, and chemotherapy compared to **nivolumab** and chemotherapy in participants with previously untreated locally advanced unresectable or metastatic **gastric**, **gastroesophageal junction**, and **esophageal adenocarcinoma**. The trial aims to compare overall survival (OS) in participants with high programmed death ligand 1 (PD-L1) expression, positive PD-L1 expression, and all randomized participants. The study is expected to run from October 28, 2022, to January 1, 2027, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance score, and histologically confirmed diagnosis. Following randomization, participants will receive the assigned treatment regimen. Regular follow-up visits will be conducted to monitor treatment response, assess progression-free survival (PFS), and evaluate the incidence and severity of adverse events (AEs) and serious adverse events (SAEs). The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is up to 24 months, contingent upon disease progression or the occurrence of unacceptable toxicity. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or investigator decision based on clinical judgment. The primary endpoint is overall survival, while secondary endpoints include progression-free survival, time to first symptom deterioration, objective response rate, duration of response, and safety assessments.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Nivolumab** is utilized as a comparator treatment in this study. It is provided in the form of a **concentrate for solution for infusion**. The active substance, nivolumab, is of chemical origin. The administration route is intravenous infusion, and the treatment period is up to 24 months. The dosage is expressed in milligrams per milliliter, although specific dosing details are not provided.

**Zimberelimab** is another experimental medication used in the trial. It is also a **concentrate for solution for infusion** and is administered intravenously. Zimberelimab is a protein-based substance, specifically a human IgG4 lambda monoclonal antibody against programmed death cell 1. The treatment duration is up to 24 months, with dosing details similarly expressed in milligrams per milliliter.

**Domvanalimab** is included as an experimental treatment. It is provided as a **concentrate for solution for infusion** and administered intravenously. Domvanalimab is a protein-based substance, specifically an anti-TIGIT humanized IgG1 monoclonal antibody. The treatment period is up to 24 months, with dosing details expressed in milligrams per milliliter.

**Calcium Folinate** is used as an auxiliary treatment. It is available in the form of a **solution for injection** and is administered intravenously. The active substance is of chemical origin, and the treatment period is up to 24 months. Dosing details are expressed in milligrams per milliliter.

**Oxaliplatin** is another auxiliary treatment in the study. It is provided as a **concentrate for solution for infusion** and administered intravenously. The active substance is of chemical origin, with a treatment period of up to 24 months. Dosing details are expressed in milligrams per milliliter.

**Capecitabine** is used as an auxiliary treatment and is available in **tablet** form for oral administration. The active substance is of chemical origin, and the treatment period is up to 24 months. Dosing details are expressed in milligrams.

**Fluorouracil** is included as an auxiliary treatment in two forms: **solution for injection** and **concentrate for solution for injection/infusion**. It is administered intravenously, with the active substance being of chemical origin. The treatment period is up to 24 months, with dosing details expressed in milligrams per milliliter.

Participant compliance with the treatment regimen is monitored throughout the study, although specific compliance measures are not detailed in the provided data. The trial aims to compare overall survival rates between the experimental and comparator treatment groups in participants with various levels of PD-L1 expression.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, defined as the length of time from the date of randomization until the date of death from any cause. Secondary endpoints include **Progression-Free Survival (PFS)**, which measures the time from randomization until disease progression or death, as assessed by the investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Additionally, the **Objective Response Rate (ORR)** will be evaluated, defined as the proportion of participants achieving a confirmed complete response (CR) or partial response (PR) according to RECIST 1.1.

Other secondary endpoints include the **Duration of Response (DOR)**, measured from the time of first confirmed response until disease progression or death, and the **Time to First Symptom Deterioration** in the FACT-Ga gastric cancer subscale. The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) will also be monitored to identify any clinically meaningful trends in safety parameters. These efficacy parameters will be collected and analyzed at various timepoints throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on participants with locally advanced unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma.