Phase Ib/II Study of Zongertinib with Trastuzumab Deruxtecan or Trastuzumab Emtansine in HER2+ Metastatic Breast and Gastroesophageal Adenocarcinomas

The primary objective of this clinical trial is to characterize the **safety**, tolerability, and dose-toxicity curve of **zongertinib** in combination with **trastuzumab deruxtecan** (T-DXd) or **trastuzumab emtansine** (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC) or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC). This is achieved by assessing escalating dose levels with overdose control to determine the maximum tolerated doses (MTDs) and/or doses for further development. The clinical relevance of this objective lies in identifying safe and effective dosing regimens that can be advanced in clinical development, potentially improving therapeutic outcomes for patients with these advanced cancers.

Secondary objectives include:

• Characterizing the pharmacokinetic properties of zongertinib and T-DXd or T-DM1 when administered in combination.
• Further evaluating the preliminary efficacy, safety, and risk-benefit profile of zongertinib in combination with T-DXd or T-DM1.
• Evaluating patient-reported outcomes (PROs) to optimize dosing.

The clinical trial involves a total of **122 participants** diagnosed with **metastatic gastric adenocarcinoma**, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, or metastatic breast cancer. The study population includes both male and female subjects, aged 18 years and older, with no vulnerable populations selected. Participants were chosen based on specific criteria, including a documented HER2-positive status for metastatic breast cancer or gastroesophageal adenocarcinoma, progression assessed by an investigator, and the presence of at least one measurable lesion according to RECIST 1.1. All participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ function is also a prerequisite for inclusion. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures a representative sample of the target population, focusing on individuals who meet the outlined health and diagnostic criteria.

The clinical trial is designed as a **randomized**, open-label, multicenter study with a focus on dose escalation and dose optimization. The trial aims to evaluate the safety, tolerability, and anti-tumor activity of **zongertinib** in combination with either **trastuzumab deruxtecan** or **trastuzumab emtansine** in patients with advanced HER2-positive metastatic breast cancer and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma. The trial is divided into two phases: Phase Ib for dose escalation and Phase II for dose optimization. The estimated duration of the trial is from June 2024 to August 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, documented HER2-positive status, and adequate organ function. The screening will also involve the collection of tumor tissue for Phase II participants. Following the screening, eligible participants will enter the treatment phase, where they will receive the investigational products according to the assigned regimen. The primary endpoint for Phase Ib is the occurrence of dose-limiting toxicities within the first 21 days of the first treatment cycle, while Phase II focuses on the objective response rate as per RECIST version 1.1.

Participants are expected to be involved in the trial for the duration of their treatment cycles, with regular follow-up visits to monitor safety, efficacy, and pharmacokinetics. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination. Conditions that may lead to early termination include the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent. The trial will employ a Bayesian Logistic Regression Model with overdose control to determine the maximum tolerated dose during Phase Ib, ensuring patient safety and optimal dosing for further development.

The clinical trial involves the administration of **zongertinib**, an experimental medication, under the product name BI 1810631. This medication is provided in the form of a **film-coated tablet** and is administered **orally**. The specific dosage and frequency of administration are determined based on the phase of the trial and the individual patient's response. Zongertinib is of chemical origin and is developed by Boehringer Ingelheim International. The trial aims to evaluate the safety, tolerability, and optimal dosing of zongertinib in combination with other treatments for patients with advanced HER2+ metastatic breast cancer and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma.

In addition to zongertinib, the trial includes the administration of **trastuzumab deruxtecan**, marketed as Enhertu. This medication is provided as a **powder for concentrate for solution for infusion** and is administered **intravenously**. Trastuzumab deruxtecan is a monoclonal antibody developed by Daiichi Sankyo Europe GmbH. It is used as an auxiliary treatment in the trial to assess its efficacy in combination with zongertinib. The dosing schedule and administration are conducted according to the trial protocol, ensuring participant safety and compliance.

Another auxiliary treatment used in the trial is **trastuzumab emtansine**, marketed as Kadcyla. Similar to trastuzumab deruxtecan, it is provided as a **powder for concentrate for solution for infusion** and administered **intravenously**. Trastuzumab emtansine is also a monoclonal antibody, developed by Roche Registration GmbH. The trial evaluates its use in combination with zongertinib to determine the optimal therapeutic regimen for the target patient population. The administration and dosing of trastuzumab emtansine are carefully monitored to ensure adherence to the trial's objectives and safety standards.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for the dose escalation phase (Phase Ib) is the occurrence of dose-limiting toxicities (DLTs) within the maximum tolerated dose (MTD) evaluation period, defined as the first 21 days of the first treatment cycle. For the dose optimization phase (Phase II), the primary endpoint is the proportion of patients with an objective response (OR), which includes confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.1, as assessed by investigator review.

Secondary endpoints include the occurrence of DLTs during the entire treatment period, progression-free survival (PFS), and disease control (DC). PFS is defined as the time from treatment start until the earliest date of tumor progression or death from any cause. DC is defined as the best overall response of CR, PR, or stable disease (SD) according to RECIST 1.1. Additionally, the trial will evaluate treatment-emergent adverse events (TEAEs) leading to dose reduction of **zongertinib** (BI 1810631) during the on-treatment period.

Pharmacokinetic (PK) parameters of **zongertinib** and the combination therapies will be assessed through both intensive and sparse PK sampling, measuring maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t2). Patient-reported outcomes (PROs) will also be collected using the PRO-CTCAE and EORTC questionnaires, covering symptoms such as mouth/throat sores, taste changes, and fatigue, from the first administration until the end of treatment for each patient.