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:

• 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 informed consent form (ICF)

• Cohorts A to K and Cohort O: Documented Human epidermal growth factor receptor 2overexpressing and/or amplified (HER2+), metastatic breast cancer (mBC) ormetastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, oresophageal adenocarcinoma (mGEAC).

• Cohorts L (L-ext), M, and N (metastatic colorectal cancer (mCRC)): Documented Humanepidermal growth factor receptor 2 (HER2) overexpression/amplification according toAmerican Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)gastric cancer guidelines and according to the result of local testing.

• For dose optimization and justification (Phase II): Patient must provide tumortissue from locations not radiated prior to biopsy, if possible, collected througharchival tissue

• History of prior treatment lines in palliative setting:

• For cohorts A, B, C, D, E, F, G, H, I, I-ext, J, J-ext, K and O documentedinvestigator assessed progression after HER2-directed treatment forunresectable locally advanced or metastatic disease (For Cohorts D, H, I (I-ext), J (J-ext) - patients must have been pretreated with trastuzumabderuxtecan (T-DXd) and have progressed or have been intolerant to previousT-DXd).

• For cohorts L, L-ext, M and N documented progression or recurrence of diseaseduring or following their latest line of therapy. Patients must have had atleast one prior line of therapy for locally advanced unresectable disease ormetastatic disease (adjuvant and neoadjuvant therapy excluded) and documenteddisease progression or recurrence of disease during or following their latestline of therapy. In the opinion of the Investigator, patients must be unlikelyto tolerate or derive clinically meaningful benefit from further standard ofcare therapy known to prolong survival.

• Presence of at least one measurable lesion according to RECIST 1.1

• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1

• Adequate organ function based on laboratory values Further inclusion criteria apply.

Exclusion criteria:

• Previous treatment with:

• Any small molecule HER2 inhibitor in the palliative setting in Cohorts D, E, F,H, L, L-ext, M, and N. In Cohort D allowed in up to 15 patients in each doselevel (DL).

• T-DXd in Cohorts E and F. In Cohort E allowed in up to 15 patients in each DL.

• trastuzumab emtansine (T-DM1) in the palliative setting in Cohort D and H. InCohort H allowed in up to 15 patients in each DL.

• Capecitabine in Cohort D and H. In Cohort D allowed in up to 15 patients ineach DL

• Presence of uncontrolled and/or symptomatic brain metastases, or leptomeningealdisease

• 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

• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis thatrequired steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitiscannot be ruled out by imaging at screening Further exclusion criteria apply.