Neoadjuvant Toripalimab Plus SBRT for Chemo-Resistant Triple-Negative Breast Cancer

Neoadjuvant Toripalimab Combined With Preoperative Radiotherapy for Initial Chemotherapy-Nonresponding Triple-Negative Breast Cancer Patients (NEOTRIO-2)

The goal of this clinical trial is to test whether a "rescue" strategy can turn chemotherapy-resistant triple-negative breast cancer (TNBC) into a curable state. Patients whose tumors fail to shrink after 2 cycles of standard neoadjuvant chemotherapy will receive a short, high-precision course of stereotactic body radiotherapy (SBRT, 24 Gy in 3 daily fractions) to the breast primary tumor, followed by 4 cycles of toripalimab (an anti-PD-1 antibody) combined with albumin-bound paclitaxel plus carboplatin. The main questions are:

Can this SBRT-immuno-chemo triplet raise the pathologic complete response (pCR; no invasive cancer in breast or nodes at surgery)? Can it produce an objective radiologic response (ORR) in at least half of the patients, allowing more breast-conserving operations and fewer mastectomies? Secondary objectives include safety, changes in tumor-infiltrating lymphocytes (TILs), event-free survival, and exploratory biomarkers (whole-exome and RNA-seq, PBMC immunoprofiling) to discover signatures of benefit. Participants will undergo image-guided core biopsies before and after SBRT, provide serial blood samples, and have definitive surgery 3-5 weeks after the last cycle.

This is a single-arm, single-center, phase II exploratory trial designed for chemotherapy-refractory, early-stage triple-negative breast cancer (Stage II-III). After two cycles of standard neoadjuvant chemotherapy (taxane ± anthracycline ± platinum), patients with stable disease (SD) or progressive disease (PD) by RECIST 1.1 are eligible.

Intervention sequence:

Day 1-3: SBRT 8 Gy × 3 fractions to the intact breast primary (total 24 Gy) under daily image guidance.

Day 4: first dose of toripalimab 240 mg IV. Day 21 (±3 d): start cycle 2 of toripalimab 240 mg d1 + albumin-bound paclitaxel 125 mg/m² d1,8 + carboplatin AUC 6 d1, q21 d × 4 cycles (immunotherapy always given first on day 1).

Surgery: within 3-5 weeks after cycle 4; sentinel-node or axillary dissection per institutional standard. Adjuvant radiation (standard whole-breast/chest-wall plus nodal fields) is delivered post-operatively, but no further boost to the primary tumour bed is required.

Endpoints Primary: pCR rate (ypT0/is ypN0) in the intent-to-treat population. Secondary: ORR by RECIST 1.1 after 4 cycles, change in TILs (H&E-based, % stromal area), safety (CTCAE v5.0), event-free survival, overall survival, and rate of breast-conserving surgery. Exploratory: genomic scars, PD-L1, interferon signature, TCR clonality, ctDNA dynamics.

Inclusion Criteria:

• Female, age 18-75 years, newly diagnosed invasive breast cancer.
• Histologically confirmed triple-negative phenotype: ER < 1 %, PR < 1 % by IHC, HER2 negative (IHC 0/1+ or IHC 2+ with ISH negative).
• Clinical stage II-III (T2-4 or N1-3, M0).
• Completed 2 cycles of standard neoadjuvant chemotherapy (taxane ± anthracycline ± platinum) and assessed as non-responder: stable disease (SD) or progressive disease (PD) by RECIST 1.1.
• ECOG performance status 0 or 1.
• Radiation oncologist confirms suitability for SBRT and subsequent standard post-operative radiotherapy.
• Adequate organ function within 14 days before enrollment: WBC ≥ 2 000/µL, ANC ≥ 1 500/µL, platelets ≥ 100 000/µL, Hb ≥ 9 g/dL; Serum creatinine ≤ 2 mg/dL or GFR ≥ 40 mL/min; AST/ALT ≤ 2.5 × ULN, total bilirubin ≤ ULN (≤ 3 mg/dL if Gilbert syndrome); INR ≤ 1.5 (on anticoagulation allowed if therapeutic range)
• Negative HIV, HBV surface antigen, and HCV antibody (or HBV DNA / HCV RNA negative if false-positive).

Exclusion Criteria:

• Inflammatory breast cancer.
• Any other malignancy requiring treatment within the past 3 years (except adequately treated basal-cell skin carcinoma or cervical CIS).
• Active autoimmune disease, immunodeficiency, or systemic steroids > 10 mg/day prednisone equivalent within 2 years.
• Clinically significant cardiovascular disease (unstable angina, NYHA III/IV heart failure, recent MI).
• Prior radiotherapy to the breast or chest wall.
• Active infection requiring systemic therapy.
• Known intolerance or hypersensitivity to toripalimab, paclitaxel, or carboplatin.
• Pregnant or lactating women.