SHR-A1811 vs Pyrotinib/Capecitabine in Trastuzumab-Resistant HER2+ Advanced Breast Cancer: A Randomized Study

Efficacy and Safety of SHR-A1811 Versus Pyrotinib Plus Capecitabine in Patients With Trastuzumab Primary-Resistant HER2-Positive Advanced Breast Cancer：A Prospective, Multicenter, Open-Label, Randomized, Controlled Study

This is a prospective, multicenter, open-label, randomized, controlled Study. The purpose of this study is to evaluate the efficacy and safety of SHR-A1811 versus pyrotinib plus capecitabine in the treatment of trastuzumab primary-resistant HER2-positive advanced breast cancer.

Inclusion Criteria:

1. Age ≥18 years.

2. Histologically or cytologically confirmed HER2-positive advanced breast cancer (IHC 3+, or IHC 2+ with ISH amplification).

3. ECOG performance status 0-2.

4. Estimated life expectancy >12 weeks.

5. At least one measurable lesion per RECIST v1.1 criteria;

6. Patients with trastuzumab primary resistance is defined as follows:

   1. Progression during or within 12 months after treatment in neoadjuvant or adjuvant setting (at least 9 weeks of trastuzumab treatment);
   2. For patients with de novo stage IV disease, progression during or within 3 months after treatment for locally advanced or metastatic disease in the first-line setting (at least 6 weeks of trastuzumab treatment).

7. Adequate organ function as defined by the following laboratory criteria:

   1. Hematologic: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count (PLT) ≥100 × 10⁹/L, hemoglobin (HGB) ≥90 g/L.
   2. Hepatic: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN) (≤5 × ULN in patients with liver metastases); total serum bilirubin (TBIL) ≤1.5 × ULN; serum albumin ≥30 g/L.
   3. Renal: serum creatinine (Cr) ≤1.5 × ULN or calculated creatinine clearance ≥50 mL/min using the Cockcroft-Gault formula.
   4. Coagulation: prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤1.5 × ULN.
   5. Cardiac: left ventricular ejection fraction (LVEF) ≥50%.

8. Women of childbearing potential must have a negative pregnancy test at screening, and subjects of reproductive potential must agree to use effective contraception from study start until 6 months after the last dose of study treatment..

9. Voluntary participation with written informed consent obtained prior to any study-related procedures.

Exclusion Criteria:

1. Prior or current exposure to antibody-drug conjugates (ADCs) containing a topoisomerase I inhibitor, including but not limited to fam-trastuzumab deruxtecan (DS-8201a).
2. Active brain metastases or leptomeningeal metastases (patients with asymptomatic/inactive brain metastases are allowed to be enrolled);
3. Other malignancy diagnosed within 5 years prior to enrollment, excluding cured non-melanoma skin cancer, cervical carcinoma in situ, ductal carcinoma in situ, or stage I grade 1 endometrial cancer;
4. Radiotherapy, any anti-HER2 targeted therapy, or chemotherapy within 4 weeks prior to enrollment; endocrine therapy within 2 weeks prior to enrollment;
5. Positive for human immunodeficiency virus (HIV);
6. Known hypersensitivity to any study drug or its excipients, or to humanized monoclonal antibody products (e.g., trastuzumab, pertuzumab, etc.);
7. Clinically significant cardiovascular disease, such as severe/unstable angina, symptomatic congestive heart failure (NYHA Class ≥II), clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention, myocardial infarction within 6 months prior to first dose, or cerebrovascular accident (including transient ischemic attack).
8. Participants known or suspected to interstitial lung disease.
9. Concurrent participation in any other interventional drug clinical trial.
10. Refusal to comply with protocol-mandated follow-up. Presence of any additional severe physical or psychiatric disorder, or any laboratory abnormality that, in the investigator's judgment, could increase the subject's risk, confound study results, or render the patient unsuitable for enrollment.