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

All patients will receive tucatinib per-protocol at standard dose of 300 mg orally twice daily on days - 4, -3, -2, -1 and day 0 (in AM). The post-surgery treatment (systemic and/or local) will be decided according to treating physician discretion and is not a study intervention. Tissue samples of brain metastases along with blood/plasma and CSF samples will be analyzed to evaluate brain tumor penetration of tucatinib as well as biologic response to tucatinib in patients with brain metastases from HER2+/mutant breast cancer who are undergoing clinically indicated brain surgery. Patients may continue tucatinib post-operatively at the discretion of the treating oncologist with monitoring as per clinical routine; this is not a study intervention for Cohort A and Cohort B. Patients on Cohort C may receive tucatinib post-operatively through the study according to physician descretion.

Inclusion criteria

• Age ≥18 years with no impairment in decision making capacity
• Patients with HER2 overexpressed/amplified/mutant metastatic breast/lung/esophagogastric/colorectal cancer (IHC, fluorescent in situ hybridation or sequencing-confirmed primary, brain, or other metastatic site) and one or more brain tumor(s) planned for neurosurgical resection. Other untreated brain metastases, and prior radiation (whole brain radiation therapy and/or stereotactic radiosurgery) to the index site are allowed
• Patients with concomitant leptomeningeal disease are eligible provided they have parenchymal 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 tucatinib as most recent line of treatment (tucatinib-resistant) in patients with HER2 overexpressed/amplified breast cancer
• Clinical and or radiological CNS parenchymal progression with no prior tucatinib (tucatinib naïve) in patients with HER2 overexpressed/amplified breast cancer
• Clinical and or radiological CNS parenchymal progression in patients with HER2+/mutant lung/esophagogastric/colorectal cancer and HER2 mutant breast cancer

ALL PATIENTS:

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

• Absolute neutrophil count (ANC) ≥1.0 × 103μL, Platelet count ≥75 × 103 /μL, Hemoglobin ≥ 8.0 g/dL
• Total bilirubin ≤1.5 × upper limit of normal (ULN). Subjects with known history of 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)
• Calculated creatinine clearance ≥50 mL/min using the CKD-EPI (2021) (in Cohort A, in patients with elevated serum creatinine, eGFR can be calculated using cystatin C to confirm eligibility)
• 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 performed within 7 days prior to enrollment and must agree to use adequate contraception prior to 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 its excipients
• Significant medical co-morbidities as per investigator evaluation
• Inability to comply with protocol and /or not willing or not available for follow-up assessments or any condition which in the investigator's opinion makes the patient unsuitable for the study participation
• Have used a strong or moderate CYP2C8 inhibitor within 5 half-lives of the inhibitor or have used a strong or moderate CYP2C8 or CYP3A4 inducer within 2 weeks prior to first dose of study treatment (Appendix E)
• Receiving concomitant CYP3A or P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities
• Concurrent pregnancy