The purpose of this study is to evaluate the efficacy and safety of zanidatamab for the treatment of participants with previously treated solid tumors that have Human Epidermal Growth Factor Receptor 2 (HER2) Immunohistochemistry (IHC) 3+ overexpression.

Inclusion Criteria:

1. Is at least 18 years of age inclusive at the time of signing the informed consent

2. Participants with locally advanced, unresectable, or metastatic solid tumors (except Biliary Tract Cancer (BTC), defined as gallbladder cancer or cholangiocarcinoma) who have progressed following at least 1 prior systemic treatment for metastatic or advanced disease and have no available treatment options that have confirmed benefit. Prior treatment with HER2-targeted therapy is not permitted (Cohort 1 only). For participants with breast cancer (Cohort 2) or GEA (Cohort 3), prior HER2-targeted therapy is permitted and prior therapy with trastuzumab deruxtecan (T-DXd) is required.

3. HER2 overexpression (IHC 3+) must be determined by a sponsor designated central laboratory.

4. All participants must have adequate tumor sample for submission to allow central HER2 testing.

5. Presence of at least 1 measurable lesion as assessed by Independent Central Review (ICR) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

6. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

7. Has a life expectancy of at least 3 months, in the opinion of the investigator.

8. Participants with history of treated and stable CNS metastases are eligible, provided the following criteria are met:

   1. Participants also have measurable metastatic disease with HER2 overexpression (IHC 3+) outside the CNS.
   2. Participants with treated CNS metastases that are no longer symptomatic may be included in the study if they recovered to < Grade 1 (CTCAE Version 5.0 or higher) or baseline from the acute toxic effect associated with the treatment > 7 days prior to Cycle 1 Day 1.
   3. Prior stereotactic radiosurgery or stereotactic radiotherapy should be completed at least 7 days (≥ 7 days) before the first dose of study intervention.

9. Adequate organ functions.

10. Females of childbearing potential must have a negative pregnancy test result.

11. Females of childbearing potential and males with a partner of childbearing potential must be willing to use 2 methods of birth control.

Exclusion Criteria:

1. Has known or suspected leptomeningeal disease and/or untreated brain metastasis.
2. Has uncontrolled or significant cardiovascular disease
3. Has ongoing toxicity related to prior cancer therapy
4. Has uncontrolled infection or requiring IV antibiotics, antivirals, or antifungals.
5. Has known Human Immunodeficiency Virus (HIV) infection.
6. Has active hepatitis B or C infection.
7. Has an active SARS-CoV-2 infection.
8. Has a history of life-threatening hypersensitivity to monoclonal antibody (mAbs) or to recombinant proteins or excipients in the drug formulation of zanidatamab.
9. Has any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site.
10. Has any issue or condition that, in the opinion of the investigator, would contraindicate the participant's participation in the study or confound the results of the study.
11. Prior treatment with HER2-targeted therapy (Cohort 1 only).
12. Has a history of trauma or major surgery
13. Was treated with systemic antineoplastic therapy, including hormonal therapies for breast cancer, or any investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1.
14. Received zanidatamab at any time prior to the current study.
15. Colorectal Cancer (CRC) participants with known KRAS/NRAS and BRAF mutations.
16. Non-Small Cell Lung Cancer (NSCLC) participants with known ALK, EGFR mutations and ROS1 fusion.
17. Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.
18. Prior or concurrent invasive malignancy other than the disease under study, whose natural history or treatment has, in the opinion of the investigator or medical monitor, the potential to interfere with the safety or efficacy assessment of the investigational regimen.

In accordance with ICMJE requirements, Jazz Pharmaceuticals may provide qualified external researchers access to individual participant data (IPD) and clinical trial data that underlie the results of this trial upon request. Qualified researchers can submit a request on https://www.jazzpharma.com/science/clinical-trial-data-sharing/ as outlined. Jazz Pharmaceuticals reserves the right not to consider a request. For inquiries about Jazz's data sharing policy contact clinicaldatasharing@jazzpharma.com.