Beamion LUNG-1: A Study to Test Different Doses of Zongertinib in People With Different Types of Advanced Cancer (Solid Tumours With Changes in the HER2 Gene)

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of an advanced, unresectableand/or metastatic non-haematologic malignancy. Patient must show presence of atleast one measurable lesion according to Response Evaluation Criteria In SolidTumors (RECIST) 1.1.

• Eastern Cooperative Oncology Group (ECOG) score of 0, 1 or 2 (ECOG=2 only forCohorts 6 and 7) .

• Availability and patient willingness to provide a sample of tumour for confirmationof the patient´s Human epidermal growth factor receptor 2 (HER2) status. This samplecan be archival material obtained at any time prior to study enrollment.

• Patient willing and able to comply with the protocol requirements for tumourbiopsies (biopsies from brain metastases are not allowed).

• Adequate organ function defined as all of the following:

• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (≥ 1.5 x 10^3/μL) (≥ 1500/mm^3);haemoglobin ≥ 9.0 g/dL (≥ 90 g/L) (≥ 5.6 mmol/L); platelets ≥ 100 x 10^9/L (100x 10^3/μL) (100 x 10^3/mm3) without the use of hematopoietic growth factorswithin 4 weeks of start of trial medication.

• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), except forpatients with Gilbert's syndrome: total bilirubin ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN.

• Estimated Glomerular Filtration Rate (eGFR) ≥ 50 mL/min - calculated usingChronic Kidney Disease Epidemiology (CKD-EPI) formula.

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN if nodemonstrable liver metastases, or otherwise ≤ 5 x ULN if transaminase elevationis attributable to liver metastases.

• Alkaline Phosphatase < 5 x ULN.

• Recovered from any previous therapy-related toxicity to ≤ Common TerminologyCriteria for Adverse Events (CTCAE) Grade 1 at start of treatment (except foralopecia, stable sensory neuropathy and hypothyroidism (patients on thyroidreplacement therapy) which must be ≤ CTCAE Grade 2)

• Life expectancy of at least 12 weeks at the start of treatment in the opinion of theinvestigator.

• At least 18 years of age at the time of consent or over the legal age of consent incountries where that is greater than 18 years.

• Signed and dated written informed consent in accordance with International Councilon Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior toadmission to the trial.

• Male or female patients. Women of childbearing potential (WOCBP) and men who areable to father a child must be ready and able to use highly effective methods ofbirth control per International Council on Harmonisation (ICH) M3 (R2) that resultin a low failure rate of less than 1% per year when used consistently and correctly.

Additional inclusion criteria for Phase Ia

• Patients with a documented diagnosis of HER2 aberration: overexpression OR geneamplification OR non-synonymous somatic mutation OR gene rearrangement involvingHER2 or Neuregulin 1 (NRG1)

• Patient who has failed conventional treatment or for whom no therapy of provenefficacy exists or who is not eligible for established treatment options. Patientmust have exhausted, or not be a suitable candidate for, available treatment optionsknown to prolong survival for their disease

Additional inclusion criteria for Phase Ib - Cohort 1 only

• Non-squamous non-small cell lung cancer (NSCLC) patients with documented humanepidermal growth factor receptor 2 (HER2) mutation in the tyrosine kinase domain (TKD) as per local lab results.

• Patient who had received, in the advanced/metastatic setting, at least one line ofsystemic therapy. Patients with non-squamous NSCLC harboring additionally genomicaberrations for which approved targeted therapy is available as standard of care.

Additional inclusion criteria for Phase Ib - Cohort 2 only

• Non-squamous NSCLC patient with a documented HER2 mutation in the tyrosine kinasedomain (TKD) as per local lab results.

• Treatment naïve for non-squamous NSCLC.

Additional inclusion criteria for Phase Ib - Cohort 3 only

• NSCLC Patient with a documented HER2 mutation outside of the tyrosine kinase domain (TKD) as per local lab results or squamous NSCLC patient with mutation in the TKD asper local lab results.

• Patient who had received, in the advanced/metastatic setting, at least one line ofsystemic therapy. Patients with NSCLC harboring additionally genomic aberrations forwhich approved targeted therapy is available as standard of care.

Additional inclusion criteria for Phase Ib - Cohort 4 only

• NSCLC patients with documented HER2 mutation in the TKD as per local lab results.

• NSCLC patients who are either treatment naïve or who had received any prior line oftreatment, in the advanced/metastatic setting. Patients with NSCLC harboringadditional genomic aberrations for which approved targeted therapy is available asstandard of care.

• Patient with active brain metastases who are not eligible for immediate localtherapy, as per investigator evaluation.

Additional inclusion criteria for Phase Ib - Cohort 5 only

• Non-squamous NSCLC patients with documented HER2 mutation in the TKD as per locallab results.

• Patient should have received, in the advanced/metastatic setting, at least one lineof systemic therapy that includes a platinum-based combination chemotherapy andshould have been treated with previous HER2 directed antibody-drug conjugates (ADC)in the same advanced/metastatic setting and developed disease progression recurrenceduring or after completing this therapy. Patients with NSCLC harboring additionalgenomic aberrations for which approved targeted therapy is available as standard ofcare.

Additional inclusion criteria for Phase Ib - Cohort 6 only

• Non-squamous NSCLC Patient with documented HER2 mutation in the TKD as per local labresults.

• Patient who had received, in the advanced/metastatic setting, at least one line ofsystemic therapy.

• Patient without active brain metastases or patient with active brain metastases whoare not eligible for immediate local therapy, as per investigator evaluation.

• Patient who is not eligible for any other recruiting cohort.

Additional inclusion criteria for Phase Ib - Cohort 7 only

• Non-squamous NSCLC patient with documented HER2 mutation in the TKD as per local labresults.

• Patient who had received, in the advanced/metastatic setting, at least one line ofsystemic therapy.

• Patient without active brain metastases or patient with active brain metastases whoare not eligible for immediate local therapy, as per investigator evaluation.

• Patient who is not eligible for any other recruiting cohort.

Additional inclusion criteria for Phase Ib - Cohort 8 only

• Treatment naïve for NSCLC

• NSCLC (adenocarcinoma or squamous) patient with documented HER2 mutation in thetyrosine kinase domain (TKD) or non-squamous NSCLC with a documented HER2 mutationin the non tyrosine kinase domain (non TKD) as per local lab results

Further inclusion criteria apply.

Exclusion Criteria:

• Major surgery (major according to the investigator's assessment) performed within 4weeks prior to first trial treatment or planned within 6 months after screening

• Previous or concomitant malignancies other than the one treated in this trial withinthe last 2 years, except:

• effectively treated non-melanoma skin cancers

• effectively treated carcinoma in situ of the cervix

• effectively treated ductal carcinoma in situ

• other effectively treated malignancy that is considered cured by localtreatment.

• Treatment with a systemic anti-cancer therapy or investigational drug within 21 daysor 5 half-lives (whichever is shorter) of the first treatment with the studymedication

• Patients who must or wish to continue the intake of restricted medication or anydrug considered likely to interfere with the safe conduct of the trial

• Previous treatment with zongertinib.

• Radiotherapy within 2 weeks prior to first study treatment, except palliativeradiotherapy to regions other than the chest, which is allowed up to 1 week prior tofirst study treatment.

Further exclusion criteria apply