Overview

To evaluate the efficacy and safety of toripalimab in combination with investigator-selected chemotherapy in patients with recurrent or metastatic HER2-negative breast cancer who have failed prior systemic therapy.

Eligibility

Inclusion Criteria:

1. Voluntary participation: the subject must give written informed consent, be compliant, and agree to attend all follow-up visits.
2. Age ≥ 18 years.
3. ECOG performance-status score ≤ 1 and life expectancy ≥ 3 months.
4. Histologically or cytologically confirmed HER2-negative breast cancer (HER2-negative is defined as either IHC 0, IHC 1+, or IHC 2+ with a negative in-situ-hybridisation \[ISH\] result).
5. For subjects with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC):

   \- Must have experienced progression during/after at least one prior systemic regimen for recurrent/metastatic disease (recurrence ≤ 12 months after neoadjuvant/adjuvant therapy counts as first-line failure).

   \- Cohort assignment by prior immune-checkpoint-inhibitor (ICI) exposure:

   1. Cohort A - ICI-pretreated:
      • If ICI was given in adjuvant setting, recurrence must occur ≥ 12 months after completion of immunotherapy.
      • If ICI was given in neoadjuvant or metastatic setting, best overall response must have met clinical-benefit criteria (PR, CR, or SD \> 24 weeks).
   2. Cohort B - ICI-naïve: no prior anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or any other antibody targeting T-cell co-stimulatory or checkpoint pathways.
6. For subjects with hormone-receptor-positive (HR+) breast cancer:
   • Must have progressed after ≥ 2 prior endocrine regimens in the recurrent/metastatic setting (unless investigator judges no endocrine benefit), and
   • Must have progressed after ≥ 1 prior systemic chemotherapy for recurrent/metastatic disease (recurrence ≤ 12 months after adjuvant/neoadjuvant therapy counts as first-line failure).
7. At least one measurable lesion per RECIST v1.1.
8. Adequate organ function, defined as:

   Haematology (no transfusion within 14 days):

   1. Haemoglobin ≥ 9 g/dL
   2. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
   3. Platelet count ≥ 100 × 10⁹/L . Serum chemistry:

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1. Total bilirubin ≤ 1.5 × ULN, or if total bilirubin \> ULN then direct bilirubin ≤ ULN
2. ALT and AST ≤ 2.5 × ULN
3. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min 9. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test within 7 days before first dose and must use highly effective contraception from first dose until 6 months after last dose.

WOCBP is defined as any sexually mature female who has not undergone hysterectomy or bilateral oophorectomy and who has not experienced natural amenorrhoea for ≥ 24 consecutive months (including women with treatment-induced amenorrhoea).Men whose partners are WOCBP must also use effective contraception during the same period.

Exclusion Criteria:

1. Uncontrolled central-nervous-system metastases (symptomatic or requiring corticosteroids or mannitol for symptom control).
2. Clinically significant or uncontrolled cardiac disease within 6 months before first dose, including congestive heart failure, angina, myocardial infarction, or ventricular arrhythmia.
3. Malignancy within 5 years before first dose, except adequately treated basal-cell carcinoma of the skin or carcinoma in situ of the cervix.
4. Active autoimmune disease requiring systemic therapy within 2 years before first dose, except vitiligo, type-1 diabetes, or residual hypothyroidism due to autoimmune thyroiditis managed with hormone replacement only.
5. Uncontrolled pleural, pericardial, or ascitic fluid requiring repeated drainage.
6. Documented human immunodeficiency virus (HIV) infection.
7. Documented hepatitis-B infection or active hepatitis-C infection.
8. Prior hypersensitivity to any component or excipient of the investigational product(s).
9. Any condition judged by the investigator to render the patient unsuitable for trial participation.