Tucatinib and trastuzumab in HER3-mutant and HER2-not amplified metastatic breast cancer

Prior treatment

• Having received any prior treatment targeting HER2. Prior treatment with trastuzumab deruxtecan is allowed, per label, in patients with HER2-low metastatic breast cancer (IHC 1+ or 2+, ISH non-amplified)
• Major surgery (including surgery of brain metastases) < 21 days prior to first dose of treatment
• Have known myocardial infarction or unstable angina within 24 weeks prior to first dose of study treatment
• Patients who are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of study drug
• Having used a strong CYP2C8 inhibitor within a duration of 5 half-lives prior to the first dose of study treatment, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment (see Appendix B and Appendix C)
• Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-central nervous system (CNS) radiation, or experimental agent ≤ 3 weeks prior to the first dose of study treatment, except gonadotropin releasing hormone (GnRH) agonists
• Symptomatic and untreated brain metastases or brain metastases requiring urgent treatment, or brain metastases requiring a dose > 2 mg of dexamethasone (or equivalent)
• Whole brain radiotherapy < 21 days prior to first dose of treatment, stereotactic radiotherapy < 7 days prior to first dose of treatment

Other illness

• Evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment
• Are known carriers of active Hepatitis B or Hepatitis C or have other known chronic liver disease
• Are known to be positive for human immunodeficiency virus (HIV)
• Altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
• History of allergic reactions to trastuzumab or tucatinib or chemically similar drugs
• Inability to swallow pills or having a significant gastro-intestinal disease or a history of surgery which would preclude the adequate oral absorption of medications

Lab values

• Have clinically significant cardiopulmonary disease such as: • Ventricular arrhythmia requiring therapy, • Uncontrolled hypertension (defined as persistent systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mm Hg on antihy) due to complications of advanced malignancy, • Hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for obstructive sleep apnea, • Presence of ≥ Grade 2 QTc prolongation on screening ECG, • Conditions potentially resulting in drug-induced prolongation of the QT interval or torsade de pointes: o Congenital or acquired long QT syndrome, o Family history of sudden death, o History of previous drug-induced QT prolongation, o Current use of medications with known and accepted associated risk of QT prolongation

Other

• Leptomeningeal metastases
• Patients who have difficulty undergoing trial procedures for geographic, social or psychological reasons
• Person deprived of liberty or under guardianship
• Participation in another interventional clinical trial.

• Molecular screening step: availability of a formalin-fixed paraffin-embedded (FFPE) block with >10% tumor tissue (it is recommended to provide the most recently collected tumor sample).
• Having received ≥ 2 previous chemotherapy lines for advanced breast cancer
• Class IV or V somatic ERBB3 mutation as determined on a tumor sample obtained during the molecular screening step
• ECOG performance status ≤ 2
• Evaluable disease, per RECIST v1.1 inclusion criteria
• Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment
• Adequate organ function: a.Creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines; b.Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients with known Gilbert’s disease, who may enroll if the conjugated bilirubin is ≤1.5 X ULN; c.Transaminases (aspartate aminotransferase and alanine aminotransferase) ≤ 2.5 X ULN (≤ 5 X ULN if the patient has liver metastases)
• Women of childbearing potential (WCBP) must have a negative serum pregnancy test < 7 days prior to first dose of treatment. A woman is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as the absence of menses for 12 months without an alternative cause.
• WCBP (as defined above) and men with partners of childbearing potential must agree to use a highly effective birth control method during the study and for 3 months after completion of investigational treatment.
• Patients should be eligible for the treatment step according to the investigator’s opinion.
• Patients must be covered by a health insurance plan.
• Molecular screening step: the tumor sample must have been obtained less than 5 years before inclusion
• Patients able to provide signed informed consent.
• Molecular screening step: prior signature of a written informed molecular screening consent.
• Molecular screening step: patients should be eligible for the treatment step according to the investigator’s opinion.
• Molecular screening step: patients must be covered by a health insurance plan.
• Molecular screening step: patients able to provide signed informed consent.
• Age ≥ 18 years
• Metastatic or unresectable breast cancer
• HER2-negative (defined as having an IHC 0+, IHC 1+, or IHC 2+ and ISH non-amplified, per ASCO/CAP guidelines) on last assessable tumor sample