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

Phase II Exploratory Study of Toripalimab Combined With Stereotactic Body Radiation Therapy in HER2-Negative Breast Cancer Patients With Insensitivity to Neoadjuvant Chemotherapy

The goal of this clinical trial is to evaluate the efficacy and safety of toripalimab combined with radiochemotherapy as perioperative therapy in HER2-negative breast cancer patients insensitive to neoadjuvant chemotherapy.

This was a multicohort, single-center exploratory clinical study. Eligible patients were initially administered standard neoadjuvant chemotherapy (TAC or TE regimen). Efficacy assessment was performed after 2 cycles of neoadjuvant chemotherapy, and only those evaluated as stable disease (SD) were formally enrolled. Enrolled patients were stratified into the HR-positive group and the triple-negative breast cancer (TNBC) group, with each group further divided into 3 arms receiving the following treatments respectively:

• Cohort 1: Continued the original neoadjuvant chemotherapy for 4 cycles, followed by surgical treatment within 5 weeks for eligible patients.
• Cohort 2: Received the original neoadjuvant chemotherapy regimen plus toripalimab for 4 cycles, followed by surgery within 5 weeks; toripalimab monotherapy was continued for an additional 13 cycles postoperatively.
• Cohort 3: Received the original neoadjuvant chemotherapy regimen plus toripalimab for 4 cycles combined with concurrent stereotactic body radiation therapy (SBRT, 25Gy/5f), followed by surgery within 5 weeks; toripalimab monotherapy was continued for an additional 13 cycles postoperatively.

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.