Phase 3 Evaluation of Trastuzumab Deruxtecan and Rilvegostomig Versus Standard Chemotherapy in HER2-Expressing Advanced Biliary Tract Cancer

The primary objective of this study is to evaluate the **efficacy** of Trastuzumab Deruxtecan (T-DXd) combined with Rilvegostomig compared to Standard of Care (SoC) in terms of overall survival (OS) in the full analysis set (FAS) of patients with HER2 immunohistochemistry (IHC) 3+ **Advanced HER2-expressing Biliary Tract Cancer**. This is clinically relevant as it aims to determine the potential of T-DXd and Rilvegostomig to improve survival outcomes in this patient population, which could lead to advancements in first-line treatment options.

Key secondary efficacy objectives include:

• Assessing the efficacy of T-DXd with Rilvegostomig versus SoC in terms of OS in the FAS (HER2 IHC 3+/2+) population.
• Evaluating the efficacy of T-DXd monotherapy versus SoC in terms of OS in the FAS (HER2 IHC 3+) population.
• Determining the efficacy of T-DXd monotherapy versus SoC in terms of OS in the overall FAS population.

The clinical trial involves a total of **194 participants** diagnosed with **Advanced HER2-expressing Biliary Tract Cancer**. The study population includes both male and female subjects who are **18 years of age or older**. Participants were selected based on specific criteria, including having unresectable, previously untreated, locally advanced or metastatic biliary tract cancer (BTC), with a histologically confirmed HER2-expressing status. The trial includes individuals with a **WHO/ECOG performance status** of 0 or 1, indicating a relatively good general health status. Participants must have adequate organ and bone marrow function and provide a tumor sample no older than three years. The study population is diverse, encompassing both genders and including vulnerable populations. Lifestyle considerations such as diet and physical activity are not specified in the available data. Key inclusion criteria include the provision of a negative serum pregnancy test for females of childbearing potential and evidence of post-menopausal status. The trial aims to assess the efficacy of T-DXd with rilvegostomig compared to the standard of care in terms of overall survival in the HER2 IHC 3+ population.

The clinical trial is designed to evaluate the efficacy and safety of **trastuzumab deruxtecan** combined with **rilvegostomig** compared to the standard-of-care regimen, which includes **gemcitabine**, **cisplatin**, and **durvalumab**, in patients with advanced HER2-expressing biliary tract cancer. This is a Phase 3, randomized, double-blind, controlled trial. The primary objective is to assess overall survival in the full analysis set (FAS) of patients with HER2 IHC 3+ expression. Secondary objectives include evaluating progression-free survival, overall response rate, duration of response, and safety profiles in both HER2 IHC 3+ and HER2 IHC 2+ populations.

The trial is expected to commence recruitment on May 30, 2025, and conclude by May 16, 2029. Participants will be involved in the study for the duration of the treatment period, which is determined by the progression of the disease or the occurrence of unacceptable toxicity. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The screening visit will involve assessments such as histological confirmation of HER2 expression, performance status evaluation, and organ function tests. Follow-up visits will occur at regular intervals to evaluate treatment efficacy and monitor adverse events. The end-of-study visit will include a comprehensive evaluation of the participant's health status and final data collection.

Participants are expected to remain in the study unless they experience disease progression, unacceptable adverse effects, or choose to withdraw consent. Additionally, any significant protocol deviations or non-compliance may result in early termination from the study. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several experimental and non-experimental treatments for the evaluation of efficacy in patients with HER2-expressing biliary tract cancer. **Durvalumab**, marketed as IMFINZI, is a **concentrate for solution for infusion** with a concentration of 50 mg/mL. It is administered via **intravenous use**. The dosing schedule and frequency are determined by the study protocol, and participant compliance is monitored throughout the trial.

**Trastuzumab deruxtecan**, also known as DS-8201a, is another experimental treatment used in this study. It is provided as a **solution for infusion** and administered intravenously. The specific dosage and administration schedule are outlined in the study protocol, ensuring adherence to the trial's objectives.

**Rilvegostomig**, referred to by its sponsor product code AZD2936, is a **solution for infusion** administered intravenously. This bispecific IgG1 monoclonal antibody targets PDCD1 and TIGIT, and its administration is carefully monitored to ensure compliance with the trial's requirements.

In addition to the experimental treatments, the study includes non-experimental treatments such as **Mycophenolate mofetil**, which is provided in the form of a **hard capsule** for **oral use**. The dosage and administration are consistent with standard practices, and compliance is tracked as part of the study's monitoring procedures.

**Cisplatin** is used as a comparator treatment in the trial. It is a **concentrate for solution for infusion** administered intravenously. The dosing regimen follows established protocols for its use in cancer treatment, and participant adherence is monitored.

**Gemcitabine** is another comparator treatment, provided as a **powder for solution for infusion**. It is administered intravenously, with dosing schedules aligned with standard-of-care practices. Compliance with the administration schedule is an integral part of the trial's monitoring process.

Lastly, **Infliximab** is included as an auxiliary treatment. It is a **powder for concentrate for solution for infusion** administered intravenously. The administration and dosing are conducted according to the study's protocol, with compliance monitoring to ensure adherence to the trial's objectives.

The efficacy of the investigational treatments in this clinical trial will be assessed primarily through the evaluation of **Overall Survival (OS)** in patients with HER2-expressing biliary tract cancer. The primary endpoint focuses on comparing the efficacy of Trastuzumab Deruxtecan (T-DXd) with Rilvegostomig against the Standard of Care (SoC) in the Full Analysis Set (FAS) population characterized by HER2 IHC 3+ expression. Secondary endpoints include the evaluation of OS in the broader FAS population (HER2 IHC 3+/2+), as well as the assessment of Progression-Free Survival (PFS), Objective Response Rate (ORR), and Duration of Response (DoR) in both HER2 IHC 3+ and HER2 IHC 3+/2+ populations.

Data collection will involve the use of validated scales and criteria, such as RECIST v1.1, to assess target lesions. The trial will also monitor patient-reported outcomes to evaluate tolerability and side-effect profiles. The schedule for measuring these parameters will be aligned with the trial's protocol, ensuring systematic data collection at predefined intervals. The analysis will be conducted to compare the investigational treatments with the SoC, providing insights into the relative efficacy and safety of the therapeutic options under investigation.