A signed and dated written consent form will be completed in accordance with international guidelines and local regulations prior to admission to the trial.

Eligibility will be confirmed, including age verification (18 years or older, or above the legal age of consent in the country).

A tumor tissue sample previously collected will be submitted to a central laboratory after inclusion to confirm the presence of HER2 mutations (specific changes in a gene called HER2 that can affect cancer growth).

Performance status will be evaluated using the ECOG score (a scale from 0 to 5 that measures how the disease affects daily living abilities). An ECOG score of 0 or 1 is required.

Laboratory tests will be performed to assess adequate organ function.

The cancer stage will be confirmed as not exceeding Stage IIIB (a classification indicating the extent of cancer spread).

The diagnosis of primary non-small cell lung cancer (a type of lung cancer) will be confirmed through tissue examination.

Random assignment will occur to one of the treatment groups: either zongertinib (the investigational medication) or standard of care treatment.

Standard of care may include one of the following medications administered through a vein: pembrolizumab, atezolizumab, nivolumab, or durvalumab, or observation without active treatment.

If assigned to the zongertinib group, the medication will be taken by mouth in the form of a film-coated tablet. Specific dosage, frequency, and duration will be determined by the study protocol.

If assigned to the standard of care group with active treatment, one of the following medications will be administered through a vein as an infusion: pembrolizumab (25 mg/mL concentrate), atezolizumab (1,200 mg concentrate), nivolumab (10 mg/mL concentrate), or durvalumab (50 mg/mL concentrate). The specific medication, dosage, and schedule will be determined according to standard treatment protocols.

If assigned to the observation arm of the standard of care group, no active medication will be administered during this phase.

Treatment will continue as specified in the study protocol.

Regular monitoring visits will occur throughout the treatment phase and follow-up period.

Safety will be assessed by monitoring for adverse events (unwanted or harmful reactions) of Grade 3 or higher according to CTCAE version 5.0 (a standardized system for classifying the severity of side effects).

Safety monitoring will continue from the start of treatment (or from randomization for those in the observation arm) until tumor recurrence or up to 3 years after treatment begins, whichever comes first.

Regular assessments will be conducted to monitor for disease-free survival (the length of time after treatment during which no cancer is found).

Monitoring will track the time from randomization until tumor recurrence or death from any cause, whichever occurs earlier.

Assessments will be performed by the investigator according to the study schedule.

Long-term follow-up will continue to assess overall survival (the length of time from randomization until death from any cause).

Follow-up visits will occur at specified intervals as outlined in the study protocol.

The trial is estimated to continue until September 2036.