Efficacy and Safety of Trastuzumab Rezetecan or Trastuzumab Deruxtecan in Advanced Breast Cancer

A Comparison of the Efficacy and Safety of Trastuzumab Rezetecan(SHR-A1811) Versus Trastuzumab Deruxtecan(DS-8201) in Patients With HER2-Positive Metastatic Breast Cancer Previously Treated With Trastuzumab

This study is a prospective, open-label, multicenter, randomized, parallel Phase II clinical trial. This study aims to investigate the efficacy and safety of trastuzumab rezetecan or trastuzumab deruxtecan in HER2 positive advanced/metastastic breast cancer

Inclusion Criteria:

• Female patients aged ≥18 and ≤75 years.
• Histologically or cytologically confirmed HER2-positive (IHC 3+ and/or ISH positive) unresectable or metastatic breast cancer.
• Prior treatment with trastuzumab and a taxane in the recurrent or metastatic setting. Or recurrence during or within 12 months (disease-free interval, DFI) after completing neoadjuvant/adjuvant chemotherapy and/or anti-HER2 targeted therapy.
• Documented radiological disease progression (during or after the most recent prior therapy).
• ECOG Performance Status of 0 or 1.
• At least one measurable lesion according to RECIST v1.1 criteria.
• Adequate organ function meeting the following criteria (without the use of any blood components, cytokines, or growth factors for correction within 14 days prior to the first dose):

Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; Platelet count (PLT) ≥100 × 10⁹/L; Hemoglobin (Hb) ≥90 g/L (9.0 g/dL); Albumin ≥3.0 g/dL;Total bilirubin ≤1.5 × ULN; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (≤5.0 × ULN for patients with liver metastases); Serum creatinine ≤1.5 × ULN OR creatinine clearance ≥60 mL/min (calculated using the Cockcroft-Gault formula); QTcF interval ≤470 ms; Left ventricular ejection fraction (LVEF) ≥50% as measured by echocardiography (ECHO) or multigated acquisition scan (MUGA)

• Female subjects of childbearing potential must have a negative pregnancy test at screening and must agree to use highly effective contraception methods from the signing of the informed consent form until 7 months after the last dose of the investigational product.
• Willing and able to provide written informed consent, with good compliance, and willing to cooperate with follow-up visits and study-related procedures.

Exclusion Criteria:

• Patients with known untreated spinal cord compression or active central nervous system (CNS) metastases, except for those who have been treated and have remained stable for at least 1 month and have discontinued corticosteroids for >2 weeks.
• History of other malignancies within the past 5 years, excluding cured basal cell carcinoma of the skin and carcinoma in situ of the cervix.
• Uncontrolled third-space fluid accumulation (e.g., massive ascites, pleural effusion, pericardial effusion) that cannot be managed by drainage or other methods.
• Having undergone major cancer-related surgery, radiotherapy, chemotherapy, immunotherapy, molecular targeted therapy, biotherapy, or other clinical investigational therapy within 4 weeks prior to the first dose.
• Prior treatment with an antibody-drug conjugate containing an exatecan derivative (a topoisomerase I inhibitor).
• Use of immunosuppressants or systemic corticosteroids for immunosuppressive purposes (at doses >10 mg/day prednisone or equivalent) within 2 weeks prior to the first dose, excluding topical, nasal spray, or inhaled corticosteroids.
• Presence of any active autoimmune disease or a history of autoimmune disease that may potentially recur.
• History of immunodeficiency, including a positive HIV test, other acquired or congenital immunodeficiency diseases, or a history of organ transplantation.
• Patients with known or suspected interstitial lung disease (ILD); or presence of other moderate-to-severe pulmonary diseases that may significantly impair respiratory function or interfere with the detection or management of drug-related pulmonary toxicity within 3 months prior to the first dose, including but not limited to idiopathic pulmonary fibrosis, organizing pneumonia/bronchiolitis obliterans, pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease (COPD), obstructive/restrictive lung disease, etc.; and any autoimmune, connective tissue, or inflammatory disorders involving the lungs, such as rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.; or history of pneumonectomy. Patients who experienced ≥Grade 3 ILD during prior treatment with immune checkpoint inhibitors are excluded.
• Presence of active hepatitis B (HBsAg positive and HBV DNA ≥500 IU/mL), hepatitis C (anti-HCV positive and HCV RNA above the upper limit of normal), or liver cirrhosis; or severe infections requiring systemic antibiotic, antiviral, or antifungal therapy.
• Toxicities from prior anti-tumor therapy that have not recovered to ≤ Grade 1 (according to NCI-CTCAE v6.0).
• Known hypersensitivity to any of the study drugs or their excipients.
• Any other severe physical or mental illness or abnormal laboratory finding that, in the investigator's judgment, may increase the risk associated with study participation, interfere with the study results, or make the patient unsuitable for participation in this study.