A Study of Tucatinib Given Before Surgery to People With HER2+ Cancers That Have Spread to the Brain

Inclusion Criteria:

• Age ≥18 years with no impairment in decision making capacity

• Patients with HER2 overexpressed/amplified/mutant metastaticbreast/lung/esophagogastric/colorectal cancer (IHC, fluorescent in situ hybridationor sequencing-confirmed primary, brain, or other metastatic site) and one or morebrain tumor(s) planned for neurosurgical resection. Other untreated brainmetastases, and prior radiation (whole brain radiation therapy and/or stereotacticradiosurgery) to the index site are allowed

• Patients with concomitant leptomeningeal disease are eligible provided they haveparenchymal brain metastases requiring resection.

• Life expectancy of >12 weeks.

• ECOG Performance Status (PS) of 0 to 2

• Prior treatments:

• Cohort A: Clinical and or radiological CNS parenchymal progression on tucatinibas most recent line of treatment (tucatinib-resistant) in patients with HER2overexpressed/amplified breast cancer

• Clinical and or radiological CNS parenchymal progression with no priortucatinib (tucatinib naïve) in patients with HER2 overexpressed/amplifiedbreast cancer

• Clinical and or radiological CNS parenchymal progression in patients withHER2+/mutant lung/esophagogastric/colorectal cancer and HER2 mutant breastcancer

ALL PATIENTS:

• Prior conventional dose lapatinib and neratinib are allowed in any cohort if > 6months prior

• No limit on prior lines of systemic therapy

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

1. Absolute neutrophil count (ANC) ≥1.0 × 103μL, Platelet count ≥75 × 103 /μL,Hemoglobin ≥ 8.0 g/dL

2. Total bilirubin ≤1.5 × upper limit of normal (ULN). Subjects with known historyof Gilbert's Syndrome and normal direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are eligible: AST and ALT ≤2.5 × ULN (≤5 × ULN if liver metastases are present)

3. Calculated creatinine clearance ≥50 mL/min using the CKD-EPI (2021) (in CohortA, in patients with elevated serum creatinine, eGFR can be calculated usingcystatin C to confirm eligibility)

4. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless on medication known to alter INR and/or aPTT

• Women of childbearing potential must have a negative serum pregnancy test performedwithin 7 days prior to enrollment and must agree to use adequate contraception priorto enrollment and for the duration of study participation

• Patients must be able to swallow and retain oral medication

Exclusion Criteria:

• Contraindications or history of allergic reaction to tucatinib or any of itsexcipients

• Significant medical co-morbidities as per investigator evaluation

• Inability to comply with protocol and /or not willing or not available for follow-upassessments or any condition which in the investigator's opinion makes the patientunsuitable for the study participation

• Have used a strong or moderate CYP2C8 inhibitor within 5 half-lives of the inhibitoror have used a strong or moderate CYP2C8 or CYP3A4 inducer within 2 weeks prior tofirst dose of study treatment (Appendix E)

• Receiving concomitant CYP3A or P-gp substrates where minimal concentration changesmay lead to serious or life-threatening toxicities

• Concurrent pregnancy