Evaluation of Trastuzumab with Chemotherapy and Pembrolizumab in First-Line Treatment of HER2-Positive Esophageal Squamous Cell Carcinoma

The primary objective of the HERES trial is to evaluate the **efficacy** of adding **trastuzumab** to the standard treatment regimen, which includes a fluoropyrimidine/platinum doublet combined with **pembrolizumab**, in patients with HER2-positive esophageal squamous cell carcinoma (ESCC). This is assessed by measuring the progression-free survival (PFS) at 6 months, according to RECIST 1.1 criteria. The clinical relevance of this objective lies in determining whether the addition of trastuzumab can improve outcomes for patients with this specific type of esophageal cancer, potentially leading to enhanced treatment protocols and better patient prognoses.

The clinical trial focuses on patients diagnosed with **esophageal cancer**, specifically inoperable locally advanced or metastatic squamous cell carcinoma of the esophagus. The study population includes both male and female participants aged 18 years and older. Participants are required to have a HER2 positive status, as defined by specific immunohistochemistry (IHC) and in situ hybridization (ISH) criteria. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2 and a baseline left ventricular ejection fraction greater than 50%. Adequate bone marrow and organ function are also necessary, with specific thresholds for leucocytes, neutrocytes, thrombocytes, serum bilirubin, AST/ALT, and creatinine clearance. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection process for the trial population is not detailed in the available data.

The clinical trial is designed to evaluate the efficacy of **trastuzumab** in combination with standard chemotherapy and immunotherapy for patients with HER2-positive esophageal squamous cell carcinoma. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the progression-free survival over a period of six months, with the primary endpoint being the response in 12 out of 24 patients, which would support further evaluation of the drug. The trial is expected to conclude by February 2027, with recruitment having commenced in February 2022.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed through criteria such as age, HER2 status, and organ function. Follow-up visits will be scheduled to monitor treatment response and adverse events. The end-of-study visit will evaluate the overall outcomes and any long-term effects. The expected duration of participant involvement is up to 999 days, depending on individual response and tolerance to the treatment regimen. Conditions that may lead to early termination from the study include significant adverse reactions or disease progression that necessitates alternative therapeutic interventions.

The investigational products include **trastuzumab**, **fluorouracil**, **capecitabine**, **pembrolizumab**, and **oxaliplatin**, administered via intravenous or oral routes as appropriate. The trial will ensure rigorous monitoring of safety and efficacy, adhering to established protocols for dose administration and patient assessment. Participants will be closely monitored for compliance and any deviations from the protocol will be addressed promptly to maintain the integrity of the trial data.

The clinical trial involves the administration of **Trazimera**, a **trastuzumab**-based medication, which is provided as a 150 mg powder for concentrate for solution for infusion. This experimental medication is administered intravenously. The pharmaceutical form is a solution for infusion, and it is produced by Pfizer Europe MA EEIG. The maximum daily and total dose amounts are set at 9999 mg, with a maximum treatment period of 999 days. The administration schedule and participant compliance are monitored according to the study protocol.

**Fluorouracil** is used as a non-experimental treatment in this study. It is a chemotherapeutic agent provided in the form of a solution for infusion. The administration route is intravenous, with a maximum daily and total dose of 9999 mg. The treatment period is capped at 999 days. This medication is part of the standard-of-care therapy in combination with other treatments.

**Capecitabine** is another chemotherapeutic agent included in the study. It is administered orally in the form of a film-coated tablet. The maximum daily and total dose amounts are 9999 mg, with a treatment period of up to 999 days. Capecitabine is used in conjunction with other medications as part of the standard treatment regimen.

**Pembrolizumab** is an immunotherapeutic agent used in the trial. It is provided as a solution for infusion and administered intravenously. The maximum daily and total dose amounts are 9999 mg, with a treatment period of 999 days. Pembrolizumab is included in the standard treatment protocol to evaluate its efficacy in combination with other therapies.

**Oxaliplatin** is also part of the chemotherapeutic regimen in this study. It is administered intravenously as a solution for infusion. The maximum daily and total dose amounts are 9999 mg, with a treatment period limited to 99 days. Oxaliplatin is used alongside other chemotherapeutic agents to assess its role in the treatment protocol.

The efficacy of the clinical trial will be assessed by evaluating the addition of **trastuzumab** to the standard treatment regimen in patients with HER2 positive esophageal squamous cell carcinoma (ESCC). The primary endpoint for efficacy evaluation is the 6-month progression-free survival (PFS) rate, as determined by RECIST 1.1 criteria. This endpoint will be used to measure the effectiveness of the treatment in preventing disease progression over a specified period.

The trial will accept the alternative hypothesis if a response is observed in 12 out of 24 patients, indicating that the drug is appropriate for further evaluation. The assessment of efficacy will be conducted through a systematic collection and analysis of data at predetermined intervals, ensuring that the results are robust and reliable. The trial is designed to provide clear insights into the potential benefits of incorporating **trastuzumab** into the treatment protocol for this patient population.