Neoadjuvant SBRT Followed by Nab-Paclitaxel Combined With Toripalimab in HR+/HER2- Breast Cancer

Summary

The goal of this clinical trial is to evaluate the efficacy and safety of neoadjuvant radiotherapy followed by chemotherapy combined with immunotherapy in patients with previously untreated stage IIB-IIIC (cT3N0 or cT2-4N1-3) HR-positive and HER2-negative breast cancer. 27 enrolled patients will be assigned to receive stereotactic body radiotherapy followed by Nab-Paclitaxel combined with Toripalimab. The main question it aims th answer is that whether the combination therapy of radiotherapy, de-escalated chemotherapy, and immunotherapy could improve the pCR rate of HR-positive and HER2-negative breast cancer.

Eligibility

Inclusion Criteria:

1. Female patients aged ≥18 and ≤75 years at the time of signing informed consent.
2. ECOG PS status of 0-1.
3. Breast cancer assessed as non-metastatic (M0), meeting all of the following:

   1. Clinical stage: Stage IIB, IIIA, IIIB, or IIIC
   2. Required imaging assessments (within 28 days): Abdominal CT, ECT Bone scan, Chest CT and Brain MRI
4. Histologically or pathologically confirmed invasive carcinoma of no special type, with all of the following:

   1. Grade 2 or 3 (confirmed by central laboratory);
   2. ER-positive (\>1% staining) and/or PR-positive (\>1% staining) by IHC;
   3. HER2-negative (IHC 0/1+ or HER2/neu FISH ratio ≤1.8);
   4. Ki-67 ≥15%.
5. Patient deemed eligible for radiotherapy after MDT evaluation.
6. No prior antitumor therapy within 1 month before enrollment.
7. Organ Function Requirements (within 7 days prior to enrollment):

   1. Complete blood count (no transfusion or hematopoietic growth factors within 7 days): ANC ≥1.5×10⁹/L; ALC ≥0.5×10⁹/L; Platelets ≥100×10⁹/L; Hemoglobin ≥90 g/L; WBC ≥3.0×10⁹/L and ≤15×10⁹/L;
   2. Blood biochemistry (no transfusion/albumin within 7 days): ALT/AST ≤2.5×ULN; ALP ≤2.5×ULN；BUN/Cr ≤1.5×ULN; Cr≥60 mL/min (Cockcroft-Gault formula);
   3. Coagulation: PT/APTT ≤1.5×ULN; INR ≤1.5×ULN (if no anticoagulant therapy);
   4. Urinalysis: Urine protein \<2+; if ≥2+, 24-hour urine protein must be ≤1g;
   5. Thyroid function:TSH ≤1×ULN; if abnormal, normal T3/T4 levels required for eligibility.
8. Women of childbearing potential must:

   1. Have a negative serum pregnancy test within 7 days before treatment;
   2. Use highly effective contraception during the study and for 180 days after the last dose.
9. Voluntarily sign informed consent, demonstrate good compliance, and commit to follow-up.

Exclusion Criteria:

1. Inflammatory Breast Cancer.
2. Comorbidities/Medical History:

   1. Autoimmune disease: patients with any known or suspected autoimmune disease, except: hypothyroidism due to autoimmune thyroiditis managed with hormone replacement therapy only, stable type-1 diabetes with well-controlled blood glucose.
   2. Cardiovascular Diseases: poorly controlled hypertension despite medication (SBP \>140 mmHg or DBP\>90 mmHg). And with the history (within 6 months prior to enrollment) of myocardial infarction, severe/unstable angina, NYHA Class ≥2 heart failure, clinically significant arrhythmias as well as symptomatic congestive heart failure.
   3. Interstitial lung disease, non-infectious pneumonitis, or other uncontrolled systemic diseases (e.g., diabetes, pulmonary fibrosis, acute pneumonia);
   4. Vaccination: receipt of live attenuated vaccines within 28 days prior to enrollment or planned during the study;
   5. Infections: HIV/AIDS, active hepatitis(HBV-DNA ≥500 IU/mL; HCV-RNA above detection limit), or co-infection with HBV and HCV, severe infections within 4 weeks prior to enrollment (e.g., bacteremia, severe pneumonia requiring hospitalization), active infection requiring systemic antibiotics (CTCAE≥Grade 2) within 2 weeks prior to treatment, active tuberculosis within 1 year prior to enrollment;
   6. Unexplained fever \>38.5°C during screening (unless deemed tumor-related by the investigator);
   7. Malignancy History: other malignancies diagnosed within 5 years prior to enrollment (except adequately treated basal cell carcinoma, squamous cell skin cancer, or cervical carcinoma in situ);
   8. Surgery:Major surgery within 28 days prior to enrollment (diagnostic biopsies or PICC line placement are allowed);
   9. Transplant: Prior or planned allogeneic bone marrow or solid organ transplant;
   10. Neurological: peripheral neuropathy ≥Grade 2;
   11. Gastrointestinal: clinically significant bowel obstruction;
   12. Thrombotic Events: arterial/venous thrombosis within 6 months prior to enrollment (e.g., stroke, transient ischemic attack, DVT, pulmonary embolism);
   13. Bleeding Risk: hemoptysis (≥2.5 mL/day) within 2 months prior to enrollment, clinically significant bleeding within 3 months prior to enrollment (e.g. gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood≥++), and the known bleeding/thrombotic disorders (e.g., hemophilia, coagulopathy, thrombocytopenia, hypersplenism);
   14. Coagulation abnormalities (INR \>1.5×ULN or APTT \>1.5×ULN), or requiring long-term anticoagulation (warfarin/heparin) or antiplatelet therapy (aspirin≥300 mg/day or clopidogrel ≥75 mg/day).
3. Treatment-Related Exclusions:

   1. Prior systemic targeted therapy or immunostimulants (e.g., interferon, IL-2) within 4 weeks before treatment;
   2. Known allergy to the investigational drug (recombinant humanized anti-PD-1 mAb) or its excipients.
4. Clinical Trial Participation: participation in another drug trial within 4 weeks prior to enrollment, or within 5 half-lives of the last investigational drug dose.
5. Substance Abuse: history of drug/alcohol abuse or dependency.
6. Pregnancy/Lactation: pregnant, breastfeeding, or planning pregnancy during the study.
7. Investigator' s Discretion: other conditions that may compromise subject safety or study integrity (e.g., severe lab abnormalities, social factors).

Conditions2

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