• Histologically confirmed HER2-positive metastatic solid tumor. HER2 positivity defined as HER2 overexpression by immunohistochemistry (IHC) 3+ or 2+ and fluorescence in situ hybridization (FISH) positive and/or HER2 amplification by in situ hybridization (ISH) or next generation sequencing (NGS) and/or activating ERBB2 mutation(s) (verified by MDACC Precision Oncology Decision Support).

• Patients must have one of the following on the screening brain MRI:

‣ Untreated brain metastases not requiring immediate local CNS therapy

⁃ Previously treated brain metastases with progression of previous lesions or new lesions, but not requiring immediate local CNS therapy

⁃ At least one measurable untreated brain lesion ≥0.5 cm and \<3.0 cm in the longest axis

⁃ Prior SRS radiosurgery (must be completed within 7 days of study treatment initiation) is allowed as long as the previous treatment volume does not overlap with the current targets.

• Measurable (per the RECIST v1.1) or evaluable extracranial disease.

• Prior treatment with HER2-targeted treatments such as trastuzumab, pertuzumab, T-DM1, neratinib, lapatinib, or tucatinib is allowed, but not required. Patients with breast and gastric cancer must have received at least 1 line of HER2 targeted treatment.

• Age ≥18 years at the time of consent.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix B).

• Life expectancy ≥3 months, in the opinion of the investigator.

• Adequate hematological and end-organ function, defined by the following laboratory test results, obtained within 28 days prior to study treatment initiation:

‣ Absolute neutrophil count ≥1,200/μL

⁃ Platelet count ≥100,000/μL

⁃ Hemoglobin ≥9g/dL

⁃ Total bilirubin ≤1.5 × upper limit of normal (ULN), except for patients with known Gilbert's disease, who may enroll if conjugated bilirubin is ≤1.5 × ULN

⁃ Transaminases (AST/ALT) ≤1.5 × ULN (≤5 × ULN if liver metastases are present)

⁃ Creatinine level \<1.5 x ULN or estimated glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) study equation as applicable.

• International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤1.5 × ULN, unless on medication known to alter INR and PTT/aPTT. Proprietary Information of MD Anderson Protocol 2021-0899 v.5.0,04/24/2023 28

⁃ LVEF ≥50% as assessed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan documented within 3weeks prior to study treatment initiation.

⁃ For patients of childbearing potential, as defined in Section 4.3, the following stipulations apply:

∙ Must have a negative serum or urine pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta-human chorionic gonadotropin \[β-hCG\]) result within 3 days prior to study treatment initiation. A patient with a false positive result and documented verification that the patient is not pregnant will be eligible.

‣ Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of study treatment

‣ Must agree not to breastfeed or donate ova starting at the time of informed consent and continuing through the study and for 7 months after the final dose of study treatment

‣ If sexually active in a way that could lead to pregnancy, must consistently use highly effective methods of birth control (i.e., methods that achieve a failure rate of \<1% per year when used consistently and correctly) starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment.

⁃ Highly effective methods of birth control include:

⁃ i. Intrauterine device ii. Bilateral tubal occlusion/ligation iii. Vasectomized partner iv. Sexual abstinence when it is the preferred and usual lifestyle choice of the patient.

⁃ For patients who can father children, the following stipulations apply:

∙ Must agree not to donate sperm starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment

‣ If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use a barrier method of birth control starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment

‣ If sexually active with a person who is pregnant or breastfeeding, must consistently use a barrier method of birth control starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment.

⁃ The patient must provide written informed consent.

⁃ Must be willing to undergo biopsy as required by the study, if clinically considered safe and feasible by the investigator.