Clinical Research Directory

Inclusion Criteria: 1. Age ≥ 18 years at the time of consent. 2. Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or metastatic non-small cell lung cancer (NSCLC). 3. Baseline archival tumor tissue available, either from primary or metastatic sites. If archival material is not available, a fresh tumor biopsy should be performed if feasible and if the procedure poses no significant risk for the participant. 4. Next generation sequencing (NGS) test documenting activating HER2 mutation in the tyrosine kinase domain assessed by a Clinical Laboratory Improvement Amendments (CLIA)-certified (United States \[US\] sites) or an equally accredited (outside of the US) local laboratory. 5. Patients may be treatment-naïve in the advanced/metastatic setting (limited to a maximum of 12 patients) or may have received prior systemic therapy for advanced/metastatic disease. Prior treatment with HER2-targeted agents (including sevabertinib, zongertinib, and trastuzumab deruxtecan), cytotoxic chemotherapy, and immunotherapy is allowed. 6. Must have at least one measurable cancer lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) 7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. 8. Ability to take pills or capsules by mouth. 9. Life expectancy of at least 12 weeks at the start of treatment in the opinion of the investigator. 10. Patients must have adequate bone marrow and organ functions as defined: * Hemoglobin ≥9 g/dL * ANC ≥1.0 x 109 /L * Platelets ≥75 x 10 ⁹ /L * AST and ALT ≤3 x ULN if no demonstrable liver metastases, or otherwise ≤ 5 x ULN if transaminase elevation is attributable to liver metastases. * Total bilirubin ≤1.5 x ULN; subjects with Gilbert's syndrome can enroll if conjugated bilirubin is within normal limits * Serum creatinine \<1.5 x ULN or calculated or estimated glomerular filtration rate \>50 mL/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology (CKD-EPI) formula 11. Recovered from any previous therapy-related toxicity to CTCAE Grade 1 or lower at start of treatment (except for alopecia, stable sensory neuropathy and hypothyroidism). 12. The effects of zanidatamab in combination with zongertinib on the developing human fetus are unknown. For this reason and because these agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to treatment initiation and for the duration of study treatment and for at least 4 months after the last dose of study intervention. (Refer to Pregnancy Assessment Policy UT MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: * Postmenopausal (no menses in greater than or equal to 12 consecutive months). * History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy). * History of bilateral tubal ligation or another surgical sterilization procedure * Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. * Men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study treatment and for at least 4 months after the last dose of study intervention. 13. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. 14. Ability to understand and the willingness to sign a written informed consent document. 15. CNS metastasis are allowed as long as asymptomatic and stable - defined as patients who are either off steroids or on a low dose (prednisone \<10 mg/day), with no neurological symptoms and no evidence of radiographic progression for at least 2 weeks prior to the study screening. Exclusion Criteria: 1. Prior or concurrent malignancy 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. 2. Patients who have not recovered from adverse events due to prior anti-cancer therapy (have residual toxicities \> Grade 1) except for alopecia, stable neuropathy, hypothyroidism and parameters superseded by other eligibility criteria \[e.g., laboratory parameters\]). 3. Any of the following cardiac criteria: * Baseline left ventricular ejection fraction (LVEF) \< 50% or history of symptomatic congestive heart failure (New York Heart Association Class II to IV). * Any Grade 2 or higher CHF related to a prior anti-cancer therapy. If grade 1 CHF occurred with prior treatment, it needs to be completely resolved prior to enrollment * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \>250msec • Prolonged QTc interval (\>470 milliseconds for women and \>450 milliseconds for men), or medical history of congenital Long QT Syndrome. * The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy. 4. Any evidence of severe or uncontrolled systemic diseases. Screening for chronic conditions is not required. 5. Presence or history of uncontrolled or symptomatic brain metastases, unless considered stable by the investigator - defined as patients who are either off steroids or on a low dose (prednisone \<10 mg/day), with no neurological symptoms. 6. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of zongertinib. 7. Pregnant women are excluded from this study because zanidatamab in combination with zongertinib is HER2-inhibiting antineoplastic class of agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with zanidatamab and zongertinib, breastfeeding should be discontinued if the mother is treated with either agent. These potential risks may also apply to other agents used in this study.. 8. Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator's opinion, makes the patient an unreliable trial participant) 9. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation. 10. Active or history of \>Grade 2 interstitial lung disease/pneumonitis. 11. Patients who are receiving any other investigational agents 12. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. 13. Patients with psychiatric illness/social situations that would limit compliance with study requirements.