Beamion LUNG-3 study evaluates whether zongertinib, an oral HER2-targeted treatment, can improve outcomes compared with standard adjuvant treatment in adults with completely resected Stage II-IIIB non-small cell lung cancer (NSCLC) whose tumors have activating HER2 tyrosine kinase domain (TKD) mutations. Eligible participants must have undergone curative-intent surgery and received guideline-appropriate perioperative systemic therapy, either neoadjuvant platinum-based chemotherapy with or without immunotherapy, or adjuvant platinum-based chemotherapy.

Participants are randomized 1:1 to receive zongertinib or standard of care, which may consist of approved adjuvant immunotherapy or active surveillance, based on local practice guidelines. The main purpose of the study is to determine whether zongertinib can prolong disease-free survival compared to standard treatment. Safety and patient-reported outcomes are also assessed.

Trial intervention: Zongertinib 120mgQD
Comparator: Standard of care (observation, Pembrolizumab/Atezolizumab every 3 weeks or nivolumab or durvalumab every 4 weeks)

• Disease-free survival (DFS) by investigator's assessment

Inclusion criteria:

1. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial

2. Patients must be ≥18 years old or over the legal age of consent in their country

3. Male or female patients. Women of childbearing potential (WOCBP) must be ready and able to use dual highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information and in the study protocol

4. HER2 mutation: Documented Tyrosine kinase domain (TKD) activating Human epidermal growth factor receptor 2 (HER2) mutations

5. Histology and tumor sample: Histologically confirmed diagnosis of primary NSCLC

6. An archival tumor tissue sample must be submitted to the central laboratory after inclusion of the patient to retrospectively confirm the HER2 status

7. Staging: Pretherapeutic classification not exceeding Stage IIIB

8. Performance status and organ function:

   • Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
   • Adequate organ function based on laboratory values Further inclusion criteria apply.

Exclusion criteria:

1. Diagnosis of NSCLC with mixed histology/positive neuroendocrine markers (synaptophysin/CD56)

2. Major surgery (major according to the investigator's assessment) performed within 4 weeks prior to randomization

3. Treatment with radiation therapy for primary NSCLC

4. Co-occurring actionable mutation with approved targeted therapy (e.g. Epidermal growth factor receptor (EGFR) or Anaplastic lymphoma kinase (ALK))

5. Any investigational drug within 5 half-lives of the compound or any of its related material, if known

6. History or presence of

   • Active or known pre-existing or history of non-infectious interstitial lung disease/pneumonitis
   • Active infectious disease requiring systemic therapy
   • Uncontrolled gastrointestinal disorders affecting drug intake/absorption
   • Previous or concomitant malignancies within the last 3 years, except certain effectively treated cancers
   • Significant and/or uncontrolled cardiovascular abnormalities, QT interval corrected for heart rate by Fridericia formula (QTcF) >470 msec, or ejection fraction <50% Further exclusion criteria apply.

• Diagnosis of NSCLC with mixed histology/positive
neuroendocrine markers (synaptophysin/CD56)
• Incomplete or aborted surgical resection (R1 or greater)
• Treatment with pre- or post-operative radiation therapy
for primary NSCLC
• Co-occurring actionable mutation with approved
targeted therapy (e.g. EGFR or ALK)
• Any prior anticancer therapy other than standard
neoadjuvant or adjuvant chemotherapy