RC48 Combined With Chemotherapy in HER2-Positive Advanced Breast Cancer Patients With Prior TOP1i-ADC Failure

Prior treatment

• A history of arterial or venous thromboembolic events (e.g., cerebrovascular accident including transient ischemic attack, deep vein thrombosis, pulmonary embolism) within 3 years prior to the start of study treatment.
• Failure to recover from toxicities of prior anti-tumor therapy to CTCAE v5.0 Grade 0 or 1 (except for alopecia, hyperpigmentation, or other conditions deemed by the investigator not to increase the risk of study drug administration).
• A history of clinically significant or uncontrolled cardiac diseases, including severe ventricular arrhythmia, congestive heart failure, angina pectoris, or myocardial infarction within 6 months prior.

Other illness

• Uncontrolled systemic diseases, including diabetes mellitus, hypertension, pulmonary fibrosis, acute lung disease, liver cirrhosis, etc.
• Current active infection requiring systemic treatment.
• Known immediate or delayed hypersensitivity to RC48 or any of its components.
• A history of other malignancies within 3 years prior (except for bilateral breast cancer with HER2 positivity in both lesions, cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, papillary thyroid carcinoma with favorable prognosis, or carcinoma in situ of the lung or minimally invasive adenocarcinoma with favorable prognosis).
• Any other conditions that, in the investigator's judgment, make the subject unsuitable for participation in the study.

Other

• Unstable brain metastases, leptomeningeal metastases, or untreated brain metastases (excluding subjects with treated and stable brain metastases who have been asymptomatic for ≥ 4 weeks).
• Pregnant or lactating women.

• Female subjects aged ≥ 18 years.
• Histologically or cytologically confirmed HER2-positive (IHC 3+ or IHC 2+ with positive FISH) advanced breast cancer.
• Disease progression on or intolerance to prior treatment with a topoisomerase I inhibitor-conjugated antibody-drug conjugate (TOP1i-ADC).
• ≤ 3 lines of systemic therapy received in the recurrent or metastatic setting. Prior exposure to only one ADC agent.
• At least one extracranial measurable lesion according to RECIST v1.1 criteria.
• ECOG Performance Status (PS) of 0 or 1.
• Adequate function of major organs, meeting the following criteria:Hematological criteria:Hemoglobin (HB) ≥ 90 g/L (no blood transfusion within 14 days prior);Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L;Platelet count (PLT) ≥ 75 × 10⁹/L.Biochemical criteria:Total Bilirubin (TBIL) ≤ 1.5 × Upper Limit of Normal (ULN); Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3 × ULN; for subjects with liver metastases, ALT and AST ≤ 5 × ULN;Serum Creatinine (Cr) ≤ 1 × ULN, and calculated Creatinine Clearance Rate (Ccr) \> 50 mL/min (using the Cockcroft-Gault formula).
• Expected survival ≥ 3 months.
• No prior radiotherapy, chemotherapy, endocrine therapy, molecular targeted therapy or surgery within 3 weeks prior to the start of the study; complete recovery from acute toxicities of previous treatments (if surgery was performed, surgical wounds must be fully healed); no peripheral neuropathy or peripheral neurotoxicity of Grade 1 at most.
• Female subjects with childbearing potential must use a medically approved contraceptive method during the study treatment period and for at least 3 months after the last administration of the study drug.
• Voluntary participation in the study, provision of written informed consent, and good compliance with study procedures and follow-up schedules.