• Overall Survival [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from randomization to death due to any cause.
• PFS per RECIST v1.1 by blinded independent committee review (BICR) [ Time Frame: Up to approximately 5 years ]
  PFS per BICR is defined as the time from the date of randomization to the centrally-reviewed documented disease progression according to RECIST v1.1 or death from any cause, whichever occurs first.
• PFS per RECIST v1.1 by investigator assessment in participants with brain metastases at baseline [ Time Frame: Up to approximately 5 years ]
• PFS per RECIST v1.1 by BICR in patients with brain metastases at baseline [ Time Frame: Up to approximately 5 years ]
• Objective response rate (ORR) per RECIST v1.1 by investigator assessment [ Time Frame: Up to approximately 3 years ]
  ORR is defined as the proportion of subjects with complete response (CR) or partial response (PR) according to RECIST v1.1.
• ORR per RECIST v1.1 by BICR [ Time Frame: Up to approximately 3 years ]
• Duration of response (DOR) per RECIST v1.1 by investigator assessment [ Time Frame: Up to approximately 5 years ]
  DOR is defined as the time from first documentation of objective response to the first documentation of disease progression or death from any cause, whichever occurs earlier.
• DOR per RECIST v1.1 by BICR [ Time Frame: Up to approximately 5 years ]
• Clinical benefit rate (CBR) per RECIST v1.1 by investigator assessment [ Time Frame: Up to approximately 3 years ]
  CBR is defined as the proportion of subjects with stable disease (SD) or non-CR or non-PD for ≥6 months or best response of CR or PR according to RECIST v1.1.
• CBR per RECIST v1.1 by BICR [ Time Frame: Up to approximately 3 years ]
• Number of participants with adverse events (AEs) [ Time Frame: Through 1 month following last dose; up to approximately 9 months overall per participant ]
  An AE is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

This study is being done to see if tucatinib with ado-trastuzumab emtansine (T-DM1) works better than T-DM1 alone to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery.

Patients in this study will be randomly assigned to get either tucatinib or placebo (a pill with no medicine). This is a blinded study, so neither patients nor their doctors will know whether a patient gets tucatinib or placebo. All patients in the study will get T-DM1, a drug that is often used to treat this cancer.

Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills or placebo pills two times every day. Patients will get T-DM1 injections from the study site staff on the first day of every cycle.

This study is designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in subjects with unresectable locally-advanced or metastatic HER2+ breast cancer who have had prior treatment with a taxane and trastuzumab in any setting. Prior pertuzumab treatment is permitted, but not required. Subjects will be randomized in a 1:1 manner to receive 21-day cycles of either tucatinib or placebo in combination with T-DM1.

While on study treatment, subjects will be assessed for progression every 6 weeks for the first 24 weeks, and every 9 weeks thereafter, irrespective of dose holds or interruptions. Study treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. After completion of study treatment and after occurrence of disease progression, subjects in both arms of the study will continue to be followed for survival until study closure or withdrawal of consent.

• Drug: tucatinib
  300mg given twice per day by mouth (orally)
  Other Name: ONT-380
• Drug: placebo
  Given twice per day orally
• Drug: T-DM1
  3.6 mg/kg given into the vein (IV; intravenously) every 21 days
  Other Name: Kadcyla

• Experimental: Tucatinib + T-DM1
  Tucatinib + T-DM1
  Interventions:

  • Drug: tucatinib
  • Drug: T-DM1
• Active Comparator: Placebo + T-DM1
  Placebo + T-DM1
  Interventions:

  • Drug: placebo
  • Drug: T-DM1

• Inclusion Criteria:

  • Histologically confirmed HER2+ breast carcinoma as determined by a sponsor-designated central laboratory
  • History of prior treatment with a taxane and trastuzumab in any setting, separately or in combination
  • Have progression of unresectable locally advanced/metastatic breast cancer after last systemic therapy, or be intolerant of last systemic therapy
  • Measurable or non-measurable disease assessable by RECIST v1.1
  • ECOG performance status score of 0 or 1

  • CNS Inclusion - Based on screening contrast brain magnetic resonance imaging (MRI), subjects must have at least one of the following:

    (a) No evidence of brain metastases

    (b) Untreated brain metastases not needing immediate local therapy

    (c) Previously treated brain metastases

    1. 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

    2. Subjects treated with CNS local therapy for newly identified lesions or previously treated and progressing lesions may be eligible to enroll if all of the following criteria are met:

       (i) Time since SRS is at least 7 days prior to first dose of study treatment, time since WBRT is at least 21 days prior to first dose, or time since surgical resection is at least 28 days.

       (ii) Other sites of evaluable disease are present

    3. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions

• Exclusion Criteria:

  • Prior treatment with tucatinib, afatinib, trastuzumab deruxtecan (DS-8201a), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with lapatinib or neratinib within 12 months of starting study treatment (except in cases where they were given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity). Prior treatment with pyrotinib for recurrent of mBC (except in cases where pyrotinib was given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity).

  • CNS Exclusion - Based on screening contrast brain magnetic resonance imaging (MRI), subjects must not have any of the following:

    1. Any untreated brain lesions >2 cm in size
    2. Ongoing use of corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent).
    3. Any brain lesion thought to require immediate local therapy
    4. Known or concurrent leptomeningeal disease as documented by the investigator
    5. Poorly controlled generalized or complex partial seizures