Tucatinib Together With Pembrolizumab and Trastuzumab
Tucatinib Together With Pembrolizumab and Trastuzumab
Women or men with HER2-positive, metastatic breast cancer, who have progressed on previous
 treatment, will receive tucatinib in combination with:

 -  Pembrolizumab and trastuzumab (PD-L1 positive); or

 -  Pembrolizumab, trastuzumab and capecitabine (PD-L1 negative)
Despite significant advances in systemic treatment options, advanced HER2-positive breast
 cancer post treatment with trastuzumab, pertuzumab and T-DM1 still remains incurable, with
 brain metastases remaining a major cause of patient morbidity and mortality.

 HER2-positive breast cancers have relatively high tumour infiltrating lymphocytes (TILs) that
 may be targeted with immune checkpoint blockade. Studies in metastatic breast cancer with PD1
 or PD-L1 inhibition have shown an overall survival (OS) benefit for those that are enriched
 for pre-existing immunity, such as positive expression of PD-L1 protein or TILs present.

 One of the main areas of disease progression in HER2 positive disease is in the central
 nervous system (CNS), supporting the need to find an effective combination for patients with
 brain metastases.

 Tucatinib (ONT-380) is a potent, highly selective, oral HER2 small molecule tyrosine kinase
 inhibitor (TKI) with demonstrated clinical benefit notable for its minimal inducement of
 EGFR-type toxicities when administered in combination-type studies including proven
 intra-cranial efficacy in studies of patients with brain metastases.

 The investigators hypothesise that the combination of tucatinib with trastuzumab and PD-1
 inhibition will result in a similar ORR as that seen in HER2CLIMB, along with comparable PFS
 and duration of response, particularly through prevention and treatment of CNS metastases.
 The advantage of adding PD-1 inhibition and omitting capecitabine in the PD-L1 positive group
 is to increase the durability of the response, with hopefully less added toxicity for
 patients. The investigators believe this regimen will result in comparable outcomes as those
 seen in HER2CLIMB, with fewer adverse events. In the PD-L1 negative cohort, the HER2CLIMB
 regimen (tucatinib + capecitabine) will be used with the addition of pembrolizumab with the
 hypothesis that its anti-tumour activity may overcome the lower immunogenicity of this
 subgroup. Importantly, the side effect profiles of all agents in the proposed combination are
 non-overlapping and this combination provides a unique opportunity for excellent tolerability
 and durable disease control in this patient group.
Inclusion Criteria:

 1. Female or male, age >= 18 years.

 2. 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 immunohistochemistry (IHC).

 3. Have sufficient tumour material available for assessment of PD-L1 and TIL status, as
 well as for correlative research

 4. Confirmed PD-L1 positive or PD-L1 negative status evaluated by immunohistochemistry
 (IHC) to determine treatment cohort

 5. Must have previously received trastuzumab, pertuzumab and T-DM1 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 after
 last systemic therapy (as confirmed by investigator), or be intolerant of last
 systemic therapy.

 7. Have measurable disease assessable by RECIST v1.1.

 8. Have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

 9. Have a life expectancy of at least 6 months, in the opinion of the investigator.

 10. 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.

 Females:

 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).

 11. Have a left ventricular ejection fraction (LVEF) of >= 50% as assessed by
 echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4
 weeks before registration.

 12. Evidence of post-menopausal status or negative urine or serum pregnancy test for
 female pre-menopausal participants. 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 if they have been
 amenorrhoeic for 12 months or more following cessation of exogenous hormonal
 treatments or chemotherapy (whichever is most recent) and if they have
 luteinizing hormone and follicle-stimulating hormone levels in the
 post-menopausal range for the institution or underwent surgical sterilization
 (bilateral oophorectomy or hysterectomy).

 2. 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, had
 chemotherapy-induced menopause with last menses > 1 year ago, or underwent
 surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy or
 hysterectomy).

 13. Women of childbearing potential (WOCBP) and men with partners of childbearing
 potential must agree to use a highly effective barrier contraception from the signing
 of informed consent until 7 months after the last dose of protocol treatment

 14. 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.

 15. Must have one of the following (based on screening brain MRI):

 1. No evidence of brain metastases OR

 2. Untreated brain metastases not needing immediate local therapy. Participants with
 CNS measurable disease criteria by RECIST 1.1, 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

 3. 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 CNS 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 therapy (WBRT) is >= 21 days before registration, or

 2. Time since surgical resection is >= 7 days before registration, or time since surgical
 resection is >= 28 days

 3. Other sites of disease assessable by RECIST 1.1. are present. iii) Relevant records of
 any CNS treatment must be available to allow for classification of target and
 non-target lesions.

 Exclusion Criteria:

 1. Previously treated with:

 1. Lapatinib within 12 months of registration OR

 2. Neratinib, afatinib, or other investigational HER2/epidermal growth factor
 receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) within 12 months of
 registration, unless ceased due to toxicity and not progression.

 2. Prior therapy with anti-PD-1, anti- PD-L1/, L2 or anti-CTLA4 therapy.

 3. Previous severe hypersensitivity reaction to treatment with a biologically similar TKI
 or monoclonal antibody.

 4. Have received treatment with any systemic anti-cancer therapy (including hormonal
 therapy), non-CNS radiation or experimental agent within 28 days of registration.

 a) GnRH therapy can continue in pre-menopausal women with ER-positive breast cancer
 who were receiving it before study entry.

 5. Have any toxicity related to prior cancer therapies that has not resolved to <= Grade
 1, with the following exceptions:

 1. Alopecia

 2. Neuropathy, which must have resolved to <= Grade 2

 3. Menopausal symptoms.

 6. Any untreated brain lesions > 2.0 cm in size, unless discussed with BCT and Study
 Chair and approval for registration is given.

 7. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at
 a total daily dose of > 2 mg of dexamethasone (or equivalent). However, patients on a
 chronic stable dose of <= 2 mg total daily of dexamethasone (or equivalent) may be
 eligible with discussion and approval by BCT and the Study Chair.

 8. Any brain lesion thought to require immediate local therapy, including (but not
 limited to) a lesion in an anatomic site where increase in size or possible
 treatment-related oedema may pose risk to patient (e.g. brain stem lesions).
 Participants who undergo local treatment for such lesions identified by screening
 contrast brain MRI may still be eligible for the study based on criteria described
 under Inclusion Criteria 15.

 9. Known or suspected leptomeningeal disease as documented by the investigator.

 10. Have poorly controlled (> 1/week) generalised or complex partial seizures, or manifest
 neurologic progression due to brain metastases notwithstanding CNS-directed therapy.

 11. History of clinically significant or uncontrolled cardiac disease, including
 congestive heart failure (New York Heart Association functional classification ≥ 3),
 angina, myocardial infarction or ventricular arrhythmia. Have known myocardial
 infarction or unstable angina within 6 months before registration.

 12. Active infection requiring systemic therapy.

 13. Active or history of autoimmune disease or immune deficiency, including but not
 limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
 erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
 antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré
 syndrome, or multiple sclerosis, with the following exceptions:

 1. History of autoimmune-related hypothyroidism who are on thyroid-replacement
 hormone are eligible

 2. Stable diabetes mellitus are eligible

 3. Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic
 manifestations only (e.g. patients with psoriatic arthritis are excluded) are
 eligible provided ALL the following conditions are met:

 i) Rash must cover < 10% of body surface area ii) Disease is well controlled at
 baseline and requires only low-potency topical corticosteroids iii) No occurrence of
 acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A
 radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or
 high-potency or oral corticosteroids within the previous 12 months.

 14. Chronic systemic therapy with either corticosteroids (> 10 mg daily prednisone or
 equivalent) or other immunosuppressive medications within 7 days before registration.
 Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone
 equivalent, are permitted in the absence of active autoimmune disease. Replacement
 therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy
 for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
 treatment. Participants requiring steroids as a once-off, short term anti-emetics
 (such as that prescribed with chemotherapy) are allowed.

 15. Administration of a live vaccine within 30 days before registration. Note: Seasonal
 influenza vaccines for injection are generally inactivated flu vaccines and are
 allowed, however intranasal influenza vaccines (e.g. FluMist(R)) are live attenuated
 vaccines and are not allowed.

 16. Known human immunodeficiency virus (HIV) (HIV1/2antibodies) or active Hepatitis B
 (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).

 1. Participants with past hepatitis B virus (HBV) infection or resolved HBV
 infection (defined as having a negative HBsAg test and a positive antibody to
 hepatitis B core antigen antibody test) are eligible

 2. Participants positive for HCV antibody are eligible only if polymerase change
 reaction is negative for HCV RNA.

 17. Pregnant, breastfeeding or planning a pregnancy; lactating participants must stop
 breast feeding before registration. Use of oral, injectable or implant hormonal
 contraceptives or medicated IUD must stop before registration.

 18. Require therapy with warfarin or other coumarin derivatives (non-coumarin
 anticoagulants are allowed).

 19. Unable to swallow pills or has significant gastrointestinal disease which would
 preclude the adequate oral absorption of medications.

 20. Use of a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or a strong
 CYP3A4 or CYP2C8 inducer within 5 days before registration. Use of sensitive CYP3A
 substrates should be avoided 2 weeks before registration and during study treatment.

 21. Treatment with botanical preparations (e.g. herbal supplements) and traditional
 Chinese medicines, intended for general health support or to treat the disease under
 study, within 7 days before registration.

 22. Interstitial lung disease.

 23. History of or active pneumonitis requiring treatment with steroids.

 24. History of active tuberculosis.

 25. Has had an allogenic tissue/solid organ transplant.

 26. Known history of uncontrolled hypertension (>= 180/110), unstable diabetes mellitus,
 dyspnoea at rest, or chronic therapy with oxygen.

 27. Considered a poor medical risk due to a serious, uncontrolled medical disorder,
 non-malignant systemic disease or active, uncontrolled infection. Examples include,
 but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months)
 myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord
 compression, superior vena cava syndrome, or any psychiatric disorder or psychosocial
 situation that prohibits obtaining informed consent.