Next-generation Site-specific human epidermal growth factor receptor 2 (HER2)-targeting Antibody-drug Conjugate (ARX788) is an antibody-conjugated drug. Results from the phase I safety, tolerability and pharmacokinetic trial of ARX788 single drug in Chinese patients with advanced HER2 breast cancer indicated a good safety of the test drug, and responses to anti-tumor therapy were observed in the target dose group. Phase II clinical trial is being carried out gradually. This trial is designed to observe the effectiveness and safety of pyrotinib maleate combined with ARX788 neoadjuvant treatment in stage II-III HER2-positive breast cancer patients experiencing a poor efficacy of trastuzumab and pertuzumab.

This study adopts a single-arm, multi-center, open design. As per the initial plan, 30 stage II-III human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who have received neoadjuvant therapy containing trastuzumab and pertuzumab and have been assessed as stable disease (SD) during the neoadjuvant treatment (an increase of 0-20%), disease progression (PD), inoperable or failing to meet the breast-conserving requirements will be enrolled to receive pyrotinib combined with Next-generation Site-specific HER2-targeting Antibody-drug Conjugate (ARX788) neoadjuvant therapy. The main purpose of the study is to observe the efficacy and safety of pyrotinib combined with ARX788 neoadjuvant treatment in stage II-III HER2-positive breast cancer.

Inclusion Criteria:

• Female patients aged ≥ 18 but ≤ 75 years (The maximal age of the subjects enrolled in the Phase 3 study of pyrotinib is 75 years old, and there is no safety data for the use of the drug in older people);
• Diagnosis of breast cancer meets the following criteria: Histologically confirmed invasive breast cancer; Tumor staging: Stage II-III patients who meet the 8th edition of AJCC Cancer Staging Manual; Patients who have undergone neoadjuvant therapy with trastuzumab and pertuzumab and have been assessed as SD (an increase of 0-20%), PD, inoperable or failing to meet the breast-conserving requirements; Failing to meet the breast-conserving requirements is defined as not meeting the following criteria: tumor size of T1 and T2 stage, proper breast volume, proper tumor-to-breast volume ratio, and able to maintain a good breast shape after surgery.
• HER2-positive breast cancer pathologically confirmed is defined as Immunohistochemical method (IHC3+) or FISH+;
• Eastern Cooperative Oncology Group (ECOG) level 0-1;
• The functional level of major organs must conform to the following requirements: Neutrophils (ANC) ≥ 1.5×109/L (with no use of growth factors within 14 days); Platelet count (PLT) ≥ 100×109/L (with no correct treatment within 7 days ); Hemoglobin (Hb) ≥ 90 g/L (with no correct treatment within 7 days ); Total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3×ULN; Urea nitrogen and creatinine ≤ 1.5×ULN and creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula); Cardiac color Doppler ultrasound: left ventricular ejection fraction (LVEF) ≥ 50%; 12-lead electrocardiogram: QT interval ≤ 480 ms;
• Able to receive needle biopsy;
• Patients who participate in the trial voluntarily, sign an informed consent, have good compliance and are willing to comply with the follow-up visit.

Exclusion Criteria:

• Patients who are concurrently receiving other anti-tumor therapy;
• Bilateral breast cancer, inflammatory breast cancer, or occult breast cancer;
• With a history of any malignancies other than breast cancer in the past 5 years, excluding cured cervical carcinoma in situ, non-melanoma skin cancer or other malignant tumors;
• Inability to swallow, chronic diarrhea and intestinal obstruction, and having many factors that affect drug administration and absorption;
• Cardiac insufficiency, including but not limited to congestive heart failure, transmural myocardial infarction, angina pectoris requiring medical treatment, clinically significant valvular disease and high-risk arrhythmia, or abnormal QTc in the ECG examination during the screening period (at rest, QTc > 450 ms in male or QTc > 470 ms in female after correction of ECG examination);
• Uncontrolled hypertension (at rest, systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg);
• Patients who are suffering severe or uncontrolled systemic diseases, such as unstable or uncompensable respiratory, heart, liver, or kidney diseases, as per the investigator's judgments;
• Female patients during pregnancy and lactation, or those who are fertile and positive for baseline pregnancy test or those of childbearing age who are unwilling to take effective contraceptive measures throughout the trial period;
• Serious concomitant diseases or other comorbid diseases that will endanger the safety of patients or interfere with the completion of the trial, including but not limited to severe hypertension, severe diabetes mellitus, and active infections that are out of control;
• Patients with known allergies to any active ingredients or excipients of ARX788, or with a history of protein drug allergy, a history of specific allergies (asthma, rheumatism, eczematous dermatitis), or a history of other severe allergic reactions, who are unsuitable for ARX788 treatment as per the investigator's judgments;
• With a history of interstitial pulmonary disease, drug-induced pulmonary interstitial disease, and radiation pneumonitis that require hormone therapy, or any clinically active pulmonary interstitial disease as suggested by any evidence;
• Patients who are currently suffering from keratitis, corneal disease, retinal disease, or active eye infection that require any interventions for the eyes.