Phase II Exploratory Study of Toripalimab Combined With SBRT in HER2-Negative Breast Cancer Patients With Insensitivity to Neoadjuvant Chemotherapy

Inclusion Criteria:

* The patient voluntarily participates in this study, has signed the informed consent form, with good compliance and willingness to cooperate with follow-up.
* Aged ≥18 years, male or female.
* Histologically confirmed unilateral primary invasive breast cancer, meeting the criteria of cT2-4N0-2M0.
* HER-2 expression negative by immunohistochemistry (IHC); for patients with HER-2 2+ expression, HER-2 gene non-amplification must be confirmed by in situ hybridization (ISH).
* Patients with stable disease (SD) assessed after 2 cycles of neoadjuvant chemotherapy.
* At least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
* Eastern Cooperative Oncology Group (ECOG) performance status score: 0-1.
* Expected survival ≥3 months.
* At least one tumor tissue biopsy specimen of the primary tumor obtained during screening must be provided to the central laboratory.
* Function of vital organs meets the following requirements (administration of any blood components or cell growth factors is not allowed within 2 weeks before the start of screening tests):

  1. Absolute neutrophil count (ANC) ≥1.5×10⁹/L;
  2. Platelet count ≥100×10⁹/L;
  3. Hemoglobin ≥9 g/dL;
  4. Serum albumin ≥3.0 g/dL;
  5. Total bilirubin ≤1.5×upper limit of normal (ULN), alanine transaminase (ALT) and/or aspartate transaminase (AST) ≤2.5×ULN;
  6. Serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL/min (calculated according to the Cockcroft-Gault formula);
  7. International Normalized Ratio (INR) and activated partial thromboplastin time (APTT) ≤1.5×ULN (screening is permitted for patients receiving stable-dose anticoagulant therapy \[e.g., low-molecular-weight heparin or warfarin\] with INR within the expected therapeutic range for the anticoagulant).
* Female subjects of childbearing potential must undergo a urine or serum pregnancy test within 72 hours prior to the first administration of the study drug with a negative result, and agree to use an effective contraceptive method during the trial and for 6 months after the last dose. Male subjects whose partners are women of childbearing potential must use an effective contraceptive method during the trial and for 6 months after the last dose.

Exclusion Criteria:

* A history of invasive malignancy within 5 years prior to signing the informed consent form, except for adequately treated basal/squamous cell skin cancer or carcinoma in situ of the cervix.
* Receipt of any of the following treatments:

  1. Major surgery or severe trauma within 4 weeks prior to the first dose of study drug;
  2. Receipt of any non-neoadjuvant anti-tumor therapy (including chemotherapy, radiotherapy, immunotherapy, targeted therapy, biotherapy, or tumor embolization) within 12 months prior to the first dose of study drug;
  3. Previous vaccination with anti-tumor vaccine, or vaccination with live vaccine within 4 weeks prior to the first dose of study drug;
  4. Requirement for systemic therapy with corticosteroids (\>10 mg prednisone equivalent per day) or other immunosuppressants within 2 weeks prior to the first dose of study drug.
* A current or historical diagnosis of any active autoimmune disease (e.g., interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, nephritis, hyperthyroidism, hypothyroidism); excluding vitiligo, or patients with childhood asthma/allergies that have resolved and require no intervention in adulthood. Patients with autoimmune-mediated hypothyroidism on a stable dose of thyroid replacement hormone and patients with type 1 diabetes on a stable dose of insulin are eligible for enrollment.
* A history of immunodeficiency, including positive HIV test results, other acquired/congenital immunodeficiency diseases, or a history of organ transplantation or allogeneic bone marrow transplantation.
* Uncontrolled clinical cardiac symptoms or diseases, including: (1) heart failure of NYHA Class Ⅱ or higher; (2) unstable angina pectoris; (3) myocardial infarction within 1 year; (4) clinically significant supraventricular/ventricular arrhythmias requiring clinical intervention.
* Severe infection (CTCAE Grade \>2) within 4 weeks prior to the first dose of study drug (e.g., severe pneumonia, bacteremia, infectious complications requiring hospitalization); active pulmonary inflammation indicated by baseline chest imaging; signs and symptoms of infection requiring oral/intravenous antibiotic therapy within 2 weeks prior to the first dose of study drug (prophylactic antibiotic use is excluded); active pulmonary tuberculosis confirmed by medical history or CT scan, a history of active pulmonary tuberculosis within 1 year prior to enrollment, or a history of active pulmonary tuberculosis more than 1 year prior to enrollment without standard treatment.
* Active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10⁴ copies/mL) or active hepatitis C (positive anti-HCV antibodies with HCV-RNA above the lower limit of detection of the assay).
* Known hypersensitivity or intolerance to toripalimab, chemotherapy drugs used in the study, or their excipients.
* Pregnant or lactating women; subjects of childbearing potential who are unwilling or unable to adopt effective contraceptive measures.
* Current participation in another clinical study or participation within the previous 4 weeks.
* Any other condition that, in the investigator's judgment, makes the subject unsuitable for participation in the study.