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):

• Absolute neutrophil count (ANC) ≥1.5×10⁹/L;
• Platelet count ≥100×10⁹/L;
• Hemoglobin ≥9 g/dL;
• Serum albumin ≥3.0 g/dL;
• Total bilirubin ≤1.5×upper limit of normal (ULN), alanine transaminase (ALT) and/or aspartate transaminase (AST) ≤2.5×ULN;
• Serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL/min (calculated according to the Cockcroft-Gault formula);
• 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:

• Major surgery or severe trauma within 4 weeks prior to the first dose of study drug;
• 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;
• Previous vaccination with anti-tumor vaccine, or vaccination with live vaccine within 4 weeks prior to the first dose of study drug;
• 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.