Classifying for HER2 Dependence to De-Escalate Neoadjuvant Chemotherapy in Patients With HER2+ Early Breast Cancer Undergoing HER2 Double-Blockade

Prescreening Eligibility Criteria (Molecular Assessment):

• Signed prescreening informed consent form (ICF); Women between 18-80 years of age attime of signing ICF.

• ECOG ≤ 1.

• HER2+ breast cancer with clinical stage at presentation: T1cN1, T2, N0-1

• HER2 3+ by IHC

• ER IHC ≤10%

• PR IHC negative (<1%)

• Patients must NOT have received any previous systemic therapy for treatment orprevention of breast cancer.

• Must be willing to provide a tumor tissue sample (archival or recently collected).

• Patients undergoing molecular prescreening will be centrally reviewed for HER2 andhormone receptor status by IHC. These results will be used to verify eligibility inthe interventional part of this study.

Inclusion Criteria:

• Signed ICF; Women between 18-80 years of age at time of signing ICF.

• ECOG ≤ 1

• HER2+ breast cancer with clinical stage at presentation: T1cN1, T2, N0-1

• HER2 3+ by IHC, with strongly positive staining for HER2 protein in ≥ 80% of cells,and absence of HER2 negative areas in the tumor

• ER IHC ≤10%

• PR IHC negative (<1%) or 0% of tumor cell nuclei

• Tumors must have at least 10mm measured by breast echography and be assessable forSUVMax (maximum standardized uptake value (SUVmax) ≥ 2.5) using 18FDG-PET-CT scan onbaseline imaging.

• Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block forcentral confirmation of HER2 and hormone receptor status and additional biomarkerresearch.

• Baseline LVEF ≥ 55% measured by echocardiogram (ECHO) or multiple-gated acquisitionscan (MUGA).

• For women of childbearing potential (WOCBP) who are sexually active: agreement toremain abstinent (refrain from heterosexual intercourse) or use one highly effectivenon-hormonal contraceptive method with a failure rate of < 1% per year, or twoeffective non-hormonal contraceptive methods during the treatment period and for 7months after the last dose of HER2-targeted therapy, and agreement to refrain fromdonating eggs during this same period.

• A negative serum pregnancy test must be available prior to randomization for WOCBP (premenopausal women and women < 12 months after the onset of menopause), unlessthey have undergone surgical sterilization (removal of ovaries and/or uterus)

Exclusion Criteria:

• Patients with metastatic disease.

• Any previous systemic chemotherapy or anti-HER2 targeted therapy directed to breastcancer.

• Patients with clinical N2 or N3 disease, T4, or inflammatory breast cancer.

• Concurrent serious diseases that may interfere with planned treatment.

• Patients with a history of concurrent or previously treated non-breast malignanciesexcept for appropriately treated 1) non-melanoma skin cancer and/or 2) in situcarcinomas, including cervix, colon, and skin. A patient with previous invasivenon-breast cancer is eligible provided he/she has been disease free for more than 5years.

• Patients who have received any previous systemic therapy (including chemotherapy,immunotherapy, HER2-targeted agents, endocrine therapy (selective estrogen receptormodulators, aromatase inhibitors, and antitumor vaccines) for treatment orprevention of breast cancer.

• Patients who have a history of ductal carcinoma in situ (DCIS) or lobular carcinomain situ (LCIS) if they have received any systemic therapy for its treatment, orradiation therapy to the ipsilateral breast. Patients are allowed to enter the studyif treated with surgery alone.

• Patients with high-risk for breast cancer who have received chemopreventive drugs inthe past are not allowed to enter the study.

• Patients with bilateral breast cancer.

• Patients who have undergone an excisional biopsy of primary tumor and/or axillarylymph nodes.

• Axillary lymph node dissection (ALND) or Sentinel lymph node biopsy (SLNB) prior toinitiation of neoadjuvant therapy. Patients with clinically negative axilla (byphysical examination and radiographic imaging) may undergo a core or needle biopsyprocedure prior to neoadjuvant systemic therapy.

• Treatment with any investigational drug within 28 days prior to randomization.

• Serious cardiac illness or medical conditions.

• Inadequate bone marrow function.

• Impaired liver function.

• Inadequate renal function.

• Current severe, uncontrolled systemic disease that may interfere with plannedtreatment (e.g., clinically significant cardiovascular, pulmonary, or metabolicdisease; wound-healing disorders).

• Any major surgical procedure unrelated to breast cancer within 28 days prior torandomization or anticipation of the need for major surgery during the course ofstudy treatment.

• Pregnant or breastfeeding, or intending to become pregnant during the study orwithin 7 months after the last dose of HER2-targeted therapy. Women of childbearingpotential must have a negative serum pregnancy test result within 7 days prior toinitiation of study drug.

• Any serious medical condition or abnormality in clinical laboratory tests that, inthe investigator's judgment, precludes the patient's safe participation in andcompletion of the study.

• Known active liver disease, for example, active viral hepatitis infection (i.e.,hepatitis B or hepatitis C), autoimmune hepatic disorders, or sclerosingcholangitis.

• Concurrent, serious, uncontrolled infections, or known infection with HIV.

• Known hypersensitivity to study drugs, excipients, and/or murine proteins.

• Current chronic daily treatment with corticosteroids (dose > 10 mgmethylprednisolone or equivalent excluding inhaled steroids).

• History of other malignancy within 5 years prior to screening, except forappropriately treated carcinoma in situ of the cervix, colon, skin, and/ornon-melanoma skin carcinoma.

• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias,such as structural heart disease (e.g., severe LVSD, left ventricular hypertrophy),coronary heart disease (symptomatic or with ischemia demonstrated by diagnostictesting), clinically significant electrolyte abnormalities (e.g., hypokalemia,hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or longQT syndrome.