Beamion BCGC-1: A Study to Find a Suitable Dose of Zongertinib Used Alone and in Combination With Other Treatments to Test Whether it Helps People With Different Types of HER2+ Cancer That Has Spread

Inclusion Criteria:

• Signed and dated written Informed consent form (ICF) in accordance withInternational Council for Harmonisation-Good Clinical Practice (ICH-GCP) and locallegislation prior to admission to the trial.

• Patients ≥18 years of age or over the legal age of consent in countries where thatis greater than 18 years at the time of signature of the ICF.

• Documented Human epidermal growth factor receptor 2 overexpressing and/or amplified (HER2+), metastatic breast cancer (mBC) or metastatic gastric adenocarcinoma,gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma (mGEAC).

• For dose optimization (Phase II): Patient must provide tumor tissue from locationsnot radiated prior to biopsy, if possible, collected through archival tissue.

• Documented investigator assessed progression.

• 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).

• Presence of at least one measurable lesion according to Response evaluation criteriain solid tumors (RECIST) 1.1, as determined by the local site investigator/radiologyassessment.

• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. Further inclusioncriteria apply.

Exclusion Criteria:

• Previous or concomitant malignancies other than the one treated in this trial withinthe previous 2 years, which require current systemic therapy 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

• History or presence of cardiovascular abnormalities such as uncontrolledhypertension, congestive heart failure New York Heart Association (NYHA)classification of ≥ III or IV, unstable angina or poorly controlled arrhythmia whichare considered as clinically relevant by the investigator. Myocardial infarction (ortroponin levels consistent with myocardial infarction within 28 days ofrandomization), stroke, or pulmonary embolism within 6 months prior torandomization.

• Any clinically important abnormalities (as assessed by the investigator) in rhythm,conduction, or morphology of resting electrocardiograms, e.g. complete left bundlebranch block, third degree heart block.

• Mean resting corrected QT interval (QT interval corrected for heart rate byFridericia´s formula (QTcF)) >470 msec.

• Any factors that increase the risk of QT interval corrected for heart rate (QTc)prolongation or risk of arrhythmic events such as heart failure, hypokalemia,congenital long QT syndrome, personal or family history of long QT syndrome orunexplained sudden death under 40 years-of-age.

• Ejection fraction <50% or the lower limit of normal of the institutional standardwithin 28 days prior to randomization.

• Women who are pregnant or nursing or who plan to become pregnant or nurse during thetrial or within 7 months after the last dose of trial treatment with T-DXd, T-DM1,trastuzumab or capecitabine and trastuzumab.

Further exclusion criteria apply.