A Phase III Randomized Double-Blind Study of Pembrolizumab, Trastuzumab, and Chemotherapy in HER2-Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

The primary objective of this Phase III, randomized, double-blind trial is to compare **progression-free survival** (PFS) and **overall survival** (OS) between treatment groups in participants with HER2 positive advanced gastric or gastroesophageal junction adenocarcinoma. These endpoints are clinically relevant as they provide critical insights into the efficacy of the treatment regimens in delaying disease progression and extending patient survival.

Secondary objectives include:

• Comparing the **Objective Response Rate** (ORR) between treatment groups, which evaluates the proportion of patients with a significant reduction in tumor size.
• Estimating the **Duration of Response** (DOR) per RECIST 1.1 as assessed by BICR for each treatment group, which measures the length of time the tumor remains responsive to treatment.
• Assessing the safety and tolerability of pembrolizumab in combination with trastuzumab plus chemotherapy by the proportion of **adverse events** (AEs), which is crucial for understanding the treatment's risk profile.

The clinical trial involves a total of **578 participants** diagnosed with **gastric or gastroesophageal junction (GEJ) adenocarcinoma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) positive gastric or GEJ adenocarcinoma. The trial includes individuals with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have a life expectancy of greater than six months and adequate organ function. The trial population is diverse, including vulnerable populations, and encompasses individuals with measurable disease as defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of **pembrolizumab** in combination with **trastuzumab** and chemotherapy compared to trastuzumab and chemotherapy with a placebo in patients with HER2-positive advanced **gastric or gastroesophageal junction adenocarcinoma**. The trial aims to compare progression-free survival (PFS) and overall survival (OS) between the treatment groups. The study is expected to run from October 2018 to September 2025, with participants involved for a maximum treatment period of 156 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of HER2-positive gastric or gastroesophageal junction adenocarcinoma, measurable disease, and adequate organ function. Following the screening, eligible participants will be randomized to receive either the investigational treatment or the control treatment. The trial includes regular follow-up visits to monitor the participants' health, assess the efficacy of the treatment, and record any adverse events. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the primary and secondary endpoints, including PFS, OS, objective response rate, and duration of response.

Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. These conditions include significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **pembrolizumab**, marketed as KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is administered via **intravenous use**. The dosage is set at a maximum of 200 mg per day, with a total maximum dose of 7000 mg over a treatment period of 105 days. Pembrolizumab is a biological product, specifically a protein of other origin, and is provided by Merck Sharp & Dohme B.V.

**Oxaliplatin** is used as a non-experimental treatment in this study. It is a **concentrate for solution for infusion** and is administered through **intravenous infusion**. The maximum daily dose is 130 mg/m², with a total maximum dose of 6760 mg/m² over a treatment period of 156 days. Oxaliplatin is classified as a chemical medicinal product.

**Capecitabine** is another non-experimental treatment, provided in the form of a **film-coated tablet** for **oral** administration. The maximum daily dose is 2000 mg/m², with a total maximum dose of 1456000 mg/m² over 156 days. Capecitabine is also categorized as a chemical medicinal product.

**Cisplatin** is included in the trial as a **concentrate for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 80 mg/m², with a total maximum dose of 4160 mg/m² over a 156-day period. Cisplatin is classified as a chemical medicinal product.

A **placebo for pembrolizumab** is utilized in the study, serving as a comparator treatment. The placebo does not contain an active substance and is used to maintain the double-blind nature of the trial.

**Trastuzumab** is administered in two forms: as a **solution for injection** and as a **powder for concentrate for solution for infusion**, both via **intravenous infusion**. The maximum daily dose is 8 mg/kg, with a total maximum dose of 314 mg/kg over 156 days. Trastuzumab is a biological product.

**Fluorouracil** is used as a **solution for injection** and is administered through **intravenous infusion**. The maximum daily dose is 800 mg/m², with a total maximum dose of 208000 mg/m² over 156 days. Fluorouracil is classified as a chemical medicinal product.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. PFS will be evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and assessed by a Blinded Independent Central Review (BICR). OS will be measured as the time from randomization to death from any cause.

Secondary endpoints include the Objective Response Rate (ORR) and Duration of Response (DOR), both assessed per RECIST 1.1 by BICR. Additionally, the trial will monitor the number of participants who experience an adverse event (AE) and those who discontinue study treatment due to an AE. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, ensuring a comprehensive evaluation of the treatment's impact on participants with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma.