TUGETHER: This study is evaluating the effectiveness of targeted therapy (tucatinib) in combination with other cancer therapies (immunotherapy, targeted therapy and chemotherapy) in people with HER2-positive, metastatic breast cancer who have progressed on previous treatmentA Phase II, Two-arm, Non-comparative, Multicentre Study of Tucatinib (ONT-380), Pembrolizumab and Trastuzumab in Patients With Pre-treated Advanced HER2-positive Breast Cancer

Exclusion

Exclusion Criteria (Pre-Registration):

Any one of the following is regarded as a criterion for exclusion from pre-registration to the study:

1. Previously treated with:

   1. Lapatinib within 12 months of registration OR
   2. Neratinib or afatinib within 12 months of registration, unless ceased due to toxicity and not progression.
2. Prior anti-PD-1, anti-PD-L1/L2 or anti-CTLA4 therapy, including, but not limited to: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab, tremelimumab.
3. Previous severe hypersensitivity reaction to treatment with TKI or monoclonal antibody that is biologically similar to the study treatments.
4. Known or suspected leptomeningeal disease as documented by the investigator.
5. Have poorly controlled (> 1/week) generalised or complex partial seizures, or manifest neurologic progression due to brain metastases despite CNS-directed therapy.
6. 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.

7. 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.

8. 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.
9. Pregnant, breastfeeding or planning a pregnancy; lactating participants must stop breast feeding before registration.
10. Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed).
11. Unable to swallow pills or has significant gastrointestinal disease which would preclude the adequate oral absorption of medications.
12. History of or active pneumonitis/interstitial lung disease requiring treatment with steroids.
13. History of current active tuberculosis.
14. Has had an allogenic tissue/solid organ transplant.
15. History of uncontrolled hypertension (≥ 180/110), dyspnoea at rest, or chronic therapy with oxygen.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

Exclusion Criteria (Registration):

In addition to the above listed pre-registration exclusion criteria, any one of the following is regarded as a criterion for exclusion from registration to the study:

1. Have received treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS radiation or experimental agent within 28 days of registration, except for participants with ER-positive breast cancer.

2. 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.
3. Any untreated brain lesions > 2.0 cm in size, unless discussed with BCT and Study Chair and approval for registration is given.
4. 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.
5. 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 Registration Inclusion Criteria 4.
6. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 450 ms from a single ECG.
7. Use of a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days before the first dose of study treatment. Use of sensitive CYP3A substrates should be avoided 2 weeks before registration and during study treatment.
8. 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.
9. Active infection requiring systemic therapy.
10. Administration of a live/live attenuated 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®) are live attenuated vaccines and are not allowed.