To evaluate the efficacy and safety of Serplulimab in combination with Trastuzumab Restuzumab for the neoadjuvant treatment of triple-negative breast cancer, aiming to provide evidence for optimizing the strategy of combining immunotherapy with ADC drugs in the neoadjuvant setting.

This is a prospective, single-arm, open-label, Phase II clinical trial investigating the efficacy and safety of a non-chemotherapy regimen comprising Serplulimab (an anti-PD-1 monoclonal antibody) and Trastuzumab Restuzumab (SHR-A1811, an antibody-drug conjugate) as neoadjuvant therapy for early-stage triple-negative breast cancer.

Primary Objective:To assess the pathological complete response rate, defined as the absence of invasive carcinoma in both the breast and sampled regional lymph nodes (ypT0/Tis ypN0), following neoadjuvant treatment with serplulimab plus SHR-A1811.

Secondary Objectives:

To evaluate invasive disease-free survival, event-free survival, and the objective response rate according to RECIST 1.1 criteria.

To determine the rate of breast-conserving surgery. To characterize the safety and tolerability profile of the combination regimen, including the incidence and severity of adverse events.

Study Design:

This study employs a Simon's two-stage, single-arm design. Approximately 84 treatment-naïve female patients with early-stage TNBC (clinical stage T1cN1-2 or T2-4N0-2) will be enrolled. Participants will receive six cycles of serplulimab and SHR-A1811 prior to definitive surgery. The primary endpoint will be centrally assessed on the surgical pathology specimen.

Interventions:

Serplulimab: Administered intravenously at a protocol-specified dose every three weeks for six cycles.

SHR-A1811: Administered intravenously at a protocol-specified dose every three weeks for six cycles.

Statistical Methods:

The study is designed to test the hypothesis that the combination regimen will increase the pCR rate from a historical benchmark of 30% to 40%. With a one-sided alpha level of 0.05 and 80% statistical power, a minimum of 75 evaluable patients is required. Allowing for an estimated 10% dropout rate, a total of 84 patients will be enrolled. The primary efficacy analysis of the pCR rate will be conducted on the full analysis set using an exact binomial test. The 95% confidence interval for the pCR rate will be calculated via the Clopper-Pearson exact method. Time-to-event endpoints will be analyzed using the Kaplan-Meier method.

Inclusion Criteria:

• Female patients aged 18 to 70 years, inclusive.

• Histologically confirmed, treatment-naïve, early-stage triple-negative breast cancer (TNBC), defined as estrogen receptor (ER) and progesterone receptor (PR) expression <1% by immunohistochemistry (IHC), and human epidermal growth factor receptor 2 (HER2)-negative (IHC 0/1+ or IHC 2+ with negative in situ hybridization confirmation) per current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines.

• Clinical stage T1cN1-2 or T2-4N0-2 according to the American Joint Committee on Cancer (AJCC) staging system, 8th edition.

• At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Adequate hematologic, hepatic, renal, and cardiac function within 14 days prior to enrollment:

  • Hematologic: Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; platelet count ≥100 × 10⁹/L; hemoglobin ≥90 g/L (without transfusion or growth factor support within 14 days).
  • Hepatic: Total bilirubin ≤1.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.
  • Renal: Serum creatinine and blood urea nitrogen (BUN) ≤1.5 × ULN.
  • Cardiac: Left ventricular ejection fraction (LVEF) ≥50% measured by echocardiogram; corrected QT interval (QTc) <470 ms on 12-lead electrocardiogram (ECG).

• Willingness to provide archival or fresh tumor tissue sample for programmed death-ligand 1 (PD-L1) biomarker analysis using the 22C3 pharmDx assay.

• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Evidence of metastatic (Stage IV) disease or bilateral breast cancer at diagnosis.
• Prior systemic anticancer therapy (including chemotherapy, endocrine therapy, immunotherapy, or biological therapy) for any malignancy within 4 weeks before the first dose of study treatment.
• Diagnosis of any other malignancy within the past 5 years, except for adequately treated non-melanoma skin cancer, basal cell carcinoma, or carcinoma in situ of the cervix.
• Known active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV-DNA ≥500 IU/mL), or hepatitis C virus (detectable HCV-RNA).
• Active autoimmune disease requiring systemic immunosuppressive therapy within the past 2 years.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic antibiotic therapy within 2 weeks, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements.
• History of allogeneic hematopoietic stem cell or solid organ transplantation.
• Pregnant or lactating women, or women of childbearing potential who are unwilling to use a highly effective method of contraception during the treatment period and for at least 7 months after the last dose.
• Known hypersensitivity to any component of serplulimab or SHR-A1811.
• Any condition that, in the opinion of the investigator, would compromise patient safety or interfere with the completion of the study procedures.