• Adult patients ≥ 18 years of age with one or more brain tumors planned for neurosurgical resection/biopsy

• Pathologically-documented glioblastoma; or

• Metastatic cancer that:

• o Has a history of Her2 expression or activating Her2-mutation

• Her2+ defined as 3+ on IHC

• Her2-low defined as IHC1+ or 2+ and ISH- according to ASCO-CAP 2018 Her2 testing guidelines52

• Her2 mutations must be described to be activating, occur at a known hotspot (e.g. exon 20 insertions, S310, G660, R678, L755, D769, L777), or involve the transmembrane, juxtamembrane or tyrosine kinase domains

• Other untreated brain tumors (and prior radiation, including whole-brain and/or stereotactic radiation) are allowed

• Patients with concomitant leptomeningeal metastasis are eligible provided they have parenchymal brain neoplastic disease requiring resection/biopsy

• Prior treatments:

‣ Cohort A: Brain parenchymal metastases in patients with Her2-expressing/ERBB2- activating-mutant cancer with no prior T-DXd exposure (T-DXd naïve)

⁃ Cohort B: Brain parenchymal metastases in patients with Her2-expressing/ERBB2- activating-mutant cancer with prior T-DXd exposure

⁃ Cohort C: Recurrent glioblastoma

⁃ For all cohorts: no limit on prior CNS radiation or systemic therapy, including Her2- targeting antibody therapy (including trastuzumab, pertuzumab, trastuzumab emtansine)

• KPS ≥ 60 Or ECOG \< 2

• Life expectancy \>12 weeks

• Left ventricular ejection fraction ≥50%

• Adequate bone marrow, renal, hepatic, and coagulation parameters (obtained ≤7 days prior to the first day of study treatment):

‣ Absolute neutrophil count (ANC) ≥1.5 × 103/μL (granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1)

⁃ Platelet count ≥10.0x104/μL. Note: Participants requiring ongoing transfusions or growth factor support to maintain platelet count ≥10.0x104/μL are not eligible. (Platelet transfusion is not allowed within 1 week prior to C1D1)

⁃ Hemoglobin ≥ 8.0 g/dL. Note: Participants requiring ongoing transfusions or growth factor support to maintain hemoglobin ≥8.0 g/dL are not eligible (\> 8 g/dL in gastric cancer / gastroesophageal cancer indications). (Red blood cell transfusion is not allowed within 1 week prior to C1D1)

⁃ Serum albumin ≥ 2.5 g/dL

⁃ Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation

⁃ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN) (\<5x ULN in participants with liver metastases)

⁃ Total bilirubin ≤1.5 × ULN) if no liver metastases or \<3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline

⁃ International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.0xULN unless on medication known to reversibly alter INR and/or aPTT

• Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available within 7 days of the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of T-DXd.

• Women of childbearing potential are defined as those who are not surgically sterile (i.e.

∙ underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy). Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.

• Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 1 from the time of screening and must agree to continue using such precautions for 7 months after the last dose of T-DXd. Note: estrogen/progesterone is contraindicated in ER+ breast cancer, and in other cancers could increase the risk of DVT. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of T-DXd.

• Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose ofT-DXd. Complete heterosexual abstinence for the drug washout period is an acceptable contraceptive method if it is in line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use ≥1 highly effective method of contraception throughout this period, as described in Table 1. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of enrollment until 4 months after the last dose of T-DXd; sperm preservation should be considered prior to enrollment in this study.

• Female subjects must not donate, or retrieve for their own use, ova from the time of enrollment through at least 7 months after the final study drug administration. Preservation of ova may be considered prior to enrollment in this study.

• Adequate treatment washout period from prior therapies to allow recovery from any prior treatment-related toxicities before enrollment in the judgment of the Investigator.

∙ Table 1: Highly effective methods of contraception (\<1% failure rate) Non-Hormonal Methods

• Total heterosexual abstinence (evaluate in relation to the duration of the clinical study and the preferred and usual lifestyle choice of the participant)

• Vasectomised sexual partner (if partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success)

• Bilateral tubal occlusion

• Intrauterine device (provided coils are copper banded)

∙ Hormonal Methods

• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (noting relevant contraindications in ER+ breast cancer, and risk of DVT in other cancers)

• oral

• intravaginal

• transdermal

• Progestogen-only hormonal contraception associated with inhibition of ovulation

• oral

• injectable

• implantable

• Intrauterine hormone-releasing system (IUS)