The Efficacy and Safety of Trastuzumab Rezetecan (SHR-A1811) in HER2-Low Unresectable/Metastatic Breast Cancer Patients With Visceral Crisis

Prior treatment

• Have received treatment with new antibody-drug conjugates (ADCs) at any stage of breast cancer.
• Are deemed by the investigator as unsuitable for systemic chemotherapy.
• Have undergone major surgical procedures or suffered significant trauma within 4 weeks prior to randomization, or are expected to undergo major surgical treatment.

Other illness

• Have had other malignant tumors within the past 5 years, excluding cured carcinoma in situ of the cervix, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma (patients with other malignant tumors that occurred more than 5 years before randomization and were cured solely by surgery are eligible for enrollment).
• Have a known history of allergy to any component of the drugs in this protocol.
• Have a history of immunodeficiency, including HIV infection, or other acquired or congenital immunodeficiency diseases.
• Have a known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Have a known history of psychotropic substance abuse or drug addiction.
• Have severe diseases, other comorbidities that would interfere with the planned treatment, or any other conditions that make them unsuitable for participation in this study (e.g., active hepatitis B, pulmonary infection requiring treatment).

Lab values

• Have severe heart disease or cardiac discomfort, including but not limited to the following conditions：a) A history of heart failure or systolic dysfunction (left ventricular ejection fraction \[LVEF\] \< 50%)；b) High-risk angina pectoris requiring treatment or cardiac arrhythmias；c) Clinically significant valvular heart disease；d) ECG findings indicating transmural myocardial infarction；e) Poorly controlled hypertension.

Age

• Are pregnant or lactating women, or women of childbearing age who are unwilling to use effective contraceptive measures throughout the trial period and within 7 months after the last administration of the study drug.

• Age: ≥18 years old and ≤75 years old;
• Pathologically confirmed HER2-Low unresectable or metastatic breast cancer;
• Investigator-assessed visceral crisis. Visceral crisis includes clinical crisis and molecular crisis. Subjects must meet the criteria for either clinical crisis or molecular crisis.
  • Clinical crisis is defined as severe organ dysfunction as assessed by signs, symptoms and laboratory studies, resulting from rapid progression of neoplastic disease and indicative of substantial visceral compromise that may serve as an indication for more aggressive therapeutic intervention, including：a）Liver visceral crisis: rapidly increasing bilirubin \>1.5 × ULN in the absence of Gilbert's syndrome or biliary tract obstruction；b）Lung visceral crisis: rapidly increasing dyspnoea at rest, not alleviated by drainage of pleural effusion；c）Other visceral crises: the evaluation is conducted by the clinician based on the definition of visceral crisis specified in the ABC7 guideline.
  • Molecular crisis is defined as a baseline monocyte-derived cfDNA fraction \< 0.0581, as determined by cell-specific cfDNA methylation analysis of the patient's baseline plasma sample. All patients undergoing screening must provide plasma samples for cfDNA methylation testing.
• Patients whom investigators deem to have indications for single-agent chemotherapy.
• Sufficient bone marrow function, defined as follows：a) Neutrophil count (ANC) ≥ 1,500/mm³ (1.5 × 10⁹/L)；b) Platelet count (PLT) ≥ 80 ×10\^9/L；c) Hemoglobin (Hb) ≥ 80 g/L；
• Patients who have received ≤ 3 line of chemotherapy in the advanced stage are permitted.
• Patients who have received endocrine therapy in the advanced stage are permitted.
• Previous treatment with CDK4/6 inhibitors is permitted.
• Previous or concurrent local treatment for symptom relief is permitted.
• For female subjects who are premenopausal or not surgically sterilized:
  • A serum pregnancy test must be performed within 7 days before the first dose of study drug, with a negative result. They must agree to either abstain from sexual activity or use a medically approved highly effective contraceptive method from the time of signing the informed consent form, throughout the study period, and for 1 year after the last dose of study drug.
• Patients must voluntarily participate in this study, sign the informed consent form, have good compliance, and be willing to cooperate with follow-up.