Beamion LUNG-3: A randomized, controlled, multi-center trial evaluating zongertinib as an adjuvant monotherapy compared with standard of care in patients with early-stage, resectable non-small cell lung cancer (Stage II-IIIB) harboring tyrosine kinase domain activating HER2 mutations

The primary objective of this trial is to demonstrate the superiority of zongertinib over standard of care based on the log-rank test on disease-free survival (DFS). This endpoint is clinically relevant for assessing the efficacy of adjuvant therapy in patients with early-stage, resectable non-small cell lung cancer (Stage II-IIIB) harboring tyrosine kinase domain activating HER2 mutations, as prolongation of disease-free survival may translate into improved long-term outcomes following surgical resection.

The secondary objectives include:

• The key secondary objective is to demonstrate superiority of zongertinib over standard of care based on the log-rank test on overall survival (OS), which provides critical data on the impact of treatment on long-term mortality.

• Additional secondary objectives are to evaluate supplementary efficacy parameters and the safety and tolerability profile of zongertinib compared with standard of care.

The clinical trial enrolled a total of **307 participants** diagnosed with **non-small cell lung cancer** harboring documented **HER2 mutations** in the tyrosine kinase domain. The study population included both **male and female** patients aged **18 years and older**, with participants classified as adults and elderly individuals. Eligible patients were required to have **histologically confirmed primary non-small cell lung cancer** with disease staging not exceeding **Stage IIIB**. Participants were selected based on documented **HER2 tyrosine kinase domain activating mutations** confirmed through tumor tissue analysis, with archival tumor samples submitted to a central laboratory for retrospective verification. Key health status requirements included an **Eastern Cooperative Oncology Group performance status** of 0 or 1 and adequate organ function as determined by laboratory assessments. Female participants of childbearing potential were required to use dual highly effective contraceptive methods throughout the trial period. The trial population did not include vulnerable populations.

This is a randomized, controlled, multi-center clinical trial designed to evaluate the efficacy and safety of **zongertinib** as adjuvant monotherapy compared with standard of care in patients with early-stage, resectable **non-small cell lung cancer** (Stage II-IIIB) harboring tyrosine kinase domain activating **HER2 mutations**. The trial is classified as a **Phase III** study. The primary objective is to demonstrate superiority of zongertinib over standard of care based on the log-rank test on **disease-free survival**. The trial involves the investigational medicinal product zongertinib (BI 1810631) administered as a **film-coated tablet** via **oral** route, with a maximum treatment period of 36 months. The comparator arm includes standard of care options comprising **pembrolizumab**, **atezolizumab**, **nivolumab**, and **durvalumab**, all administered as **solution for infusion** via **intravenous** route, with maximum treatment periods of 12 months. The estimated recruitment start date is January 2026, and the estimated trial completion date is September 2036.

Eligible participants must be at least 18 years of age or over the legal age of consent in their country and must have documented tyrosine kinase domain activating HER2 mutations. Additional key inclusion criteria include histologically confirmed diagnosis of primary non-small cell lung cancer, pretherapeutic classification not exceeding Stage IIIB, **Eastern Cooperative Oncology Group** performance status of 0 or 1, and adequate organ function based on laboratory values. An archival tumor tissue sample must be submitted to the central laboratory after inclusion to retrospectively confirm the HER2 status. Women of childbearing potential must be ready and able to use dual highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly.

The primary endpoint is disease-free survival by investigator's assessment, defined as the time from randomization until recurrence of tumor or death from any cause, whichever occurs earlier. Secondary endpoints include **overall survival**, defined as the time from randomization until death from any cause, and the occurrence of trial-related **adverse events** of Grade 3 or higher, graded according to **Common Terminology Criteria for Adverse Events** version 5.0, from first treatment administration (or from randomization for patients in the observation arm) until the earliest of tumor recurrence or 3 years since treatment start.

The trial involves a screening visit during which eligibility is assessed and informed consent is obtained in accordance with **ICH-GCP** and local legislation. Following randomization, participants will undergo regular follow-up visits throughout the treatment period and post-treatment observation phase. The expected duration of participant involvement extends up to 36 months for those receiving zongertinib, with follow-up continuing until the end of the study. Conditions that may lead to early termination from the study include tumor recurrence, unacceptable toxicity, withdrawal of consent, or other protocol-specified criteria. The overall trial duration is estimated to span approximately 10 years from recruitment initiation to study completion.

The experimental medication in this clinical trial is zongertinib, also known by the sponsor product code BI 1810631. This investigational agent is supplied as a **film-coated tablet** for **oral use**. Zongertinib is a chemical compound that will be administered for a maximum treatment period of 36 months. The product is not a marketed medicinal product and has been specifically developed for this trial.

The comparator treatments in this study consist of standard-of-care therapies that include several approved **immune checkpoint inhibitors**. **Pembrolizumab** (KEYTRUDA 25 mg/mL) is provided as a concentrate for **solution for infusion** and is administered via the **intravenous route**. The maximum daily dose is 200 mg, with a maximum total dose of 3600 mg over a treatment period of up to 12 months. This product is supplied with trial-specific labeling and packaging.

**Atezolizumab** (Tecentriq 1200 mg) is supplied as a concentrate for solution for infusion for intravenous administration. The maximum daily dose is 1200 mg, and the maximum total dose is 21600 mg over a treatment period of up to 12 months. This comparator product is also provided with trial-specific labeling and packaging.

**Nivolumab** (OPDIVO 10 mg/mL) is available as a concentrate for solution for infusion administered intravenously. The maximum daily dose is 480 mg, with a maximum total dose of 6240 mg over a maximum treatment period of 12 months. This product is supplied with trial-specific labeling and packaging for use in this clinical trial.

**Durvalumab** (IMFINZI 50 mg/mL) is provided as a concentrate for solution for infusion for intravenous administration. The maximum daily dose is 1500 mg, and the maximum total dose is 19500 mg over a treatment period of up to 12 months. This comparator treatment is also supplied with trial-specific labeling and packaging.

Efficacy will be assessed through the evaluation of disease-free survival and overall survival as the primary and secondary endpoints. The primary endpoint is **disease-free survival** as determined by investigator's assessment, defined as the time from randomization until recurrence of tumor or death from any cause, whichever occurs earlier. Superiority of zongertinib over standard of care will be demonstrated based on the log-rank test on disease-free survival. **Overall survival** will be evaluated as a secondary endpoint, defined as the time from randomization until death from any cause. Additionally, the occurrence of trial-related adverse events of Grade 3 or higher will be assessed as a secondary endpoint, graded according to CTCAE version 5.0, from first treatment administration or from randomization for patients in the observation arm until the earliest of tumor recurrence or 3 years since treatment start.