Tucatinib Together with Pembrolizumab and Trastuzumab (TUGETHER)

• Drug: Tucatinib
• Drug: Pembrolizumab
• Drug: Trastuzumab
• Drug: Capecitabine

Inclusion Criteria (Pre-Registration):

1. Has provided written, informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment. to participate in the study.
2. Female or male, age ≥ 18 years.
3. Local histologically confirmed HER2-positive unresectable loco-regional or metastatic breast cancer. HER2-positive according to ASCO CAP 2018 guidelines defined as:
   1. ISH testing with ERBB2-amplification as demonstrated by ratio ERBB2/centromeres ≥ 2.0 or mean gene copy number ≥ 6 OR
   2. 3+ staining by IHC.
4. FFPE tumoura tissue mass that forms from groups of unhealthy cells samples (preferably two blocks) available from newly obtained biopsies of advancedat a late stage, far along disease for assessment of PD-L1, TILs status and correlative research. If new biopsies are not obtainable then primary/metastatic archival biopsies (preferably two samples) from within 12 months of registration may be provided.For those participants whose tissuea group of cells that work together to perform a function is unavailable despite best efforts (e.g. inadequate sample or primary tumour lost/discarded), please discuss with BCT and the Study Chairs.
5. Must have previously received taxane, trastuzumab, pertuzumab and an antibody-drug conjugate (ADC) in either the (neo) adjuvant or advanced disease setting. Any number of prior lines of anti-HER2 therapy is acceptable.
6. Have progression of unresectable locally advanced or metastatic breast cancer during or after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy.
7. Have a life expectancy of at least 6 months, in the opinion of the investigator.
8. Women of childbearing potential (WOCBP) and men with partners of childbearing potential must agree to use a highly effective contraception from the signing of informed consent until 7 months after the last dosethe amount of medication taken of protocol treatment.Note: Use of oral, injectable or implant hormonal contraceptives or medicated IUD must stop before registration.
9. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations during both the treatment and follow-up phases.

Inclusion Criteria (Registration):

In addition to the above listed pre-registration inclusion criteria, participants must fulfill all the following criteria before registration:

1. Confirmed submission to the central laboratory of tumour tissue for PD-L1 status to determine cohort . For those participants whose tissue is unavailable for testing, individual cases must be discussed with BCT and the Study Chairs. Note: the first 10 participants will be reviewed for PD-L1 positivity rates
2. Have Eastern Cooperative Oncologythe study, diagnosis and treatment of cancer Group (ECOG) Performance Status of 0 or 1.
3. Have measurable disease assessable by RECIST v1.1.
4. Must have one of the following (based on screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening brain MRI):a) No evidence of brain metastases OR b) Untreated brain metastases not needing immediate local therapy. Participants with CNS measurable disease by RECIST 1.1 criteria, with or without measurable extracranial disease by RECIST are eligible. For participants with untreated CNS lesions > 2.0 cm on screening MRI, discussion with and approval from BCT and the Study Chair is required before registration OR c) Previously treated brain metastases: i) Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local brain metastasiswhen the cancer has spread to other parts of the body, also known as mets therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator.ii) Participants treated with CNS local therapy for newly identified lesions found on initial MRI performed during screening for this study may be eligible if the following criteria are met: (1) Time since whole brain radiation therapya treatment that uses controlled doses of radiation to damage or kill cancer cells (WBRT) is ≥ 14 days before registration, or (2) Time since stereotactic radiosurgery is ≥ 7 days before registration, or time since surgical resectionsurgical removal of tissue or part/all of an organ is ≥ 28 days (3) Other sites of disease assessable by RECIST 1.1. are present.
5. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions.
6. Have a left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by echocardiograma type of ultrasound that uses sound waves to create detailed images of the heart to assess heart structure, function and blood flow (ECHO) or multiple-gated acquisition scan (MUGA) documented within 8 weeks before registration.
7. Have adequate haematological, coagulation, hepatic and renal functions within 7 days before registration as defined as:
   1. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
   2. Platelet count ≥ 100 x 10^9/L
   3. Haemoglobin ≥ 90 g/L
   4. Creatinine ≤ 1.5 x ULN or serum creatinine clearance > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance:
   5. Serum total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). In the case of known Gilbert’s disease, serum total bilirubin < 2 x ULN is allowed
   6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤ 5 x ULN
   7. International normalised ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless on medication known to alter INR and aPTT (Note: Warfarin and other coumarin derivatives are prohibited).
8. Evidence of post-menopausal status, or negative urine or serum pregnancy test for female pre-menopausal participants. Women who have undergone surgical sterilisation (bilateralaffecting both sides oophorectomy, bilateral salpingectomyremoval of one (unilateral) or both (bilateral) fallopian tubes/tubal ligation, or hysterectomycomplete or partial removal of the uterus) do not require pregnancy testing. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
   1. Women < 50 years of age would be considered post-menopausal/non-fertile if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments or chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells (whichever is most recent) and if they have luteinizing hormonea chemical substance produced by glands in the endocrine system that regulates various functions in the body and follicle-stimulating hormone levels in the post-menopausal range for the institution.
   2. b) Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, or had chemotherapy-induced menopause with last menses > 1 year ago.