A Multicohort Study of Toripalimab in Combination With Investigator-Selected Chemotherapy for Advanced HER2-Negative Breast Cancer

Prior treatment

• Uncontrolled central-nervous-system metastases (symptomatic or requiring corticosteroids or mannitol for symptom control).
• Clinically significant or uncontrolled cardiac disease within 6 months before first dose, including congestive heart failure, angina, myocardial infarction, or ventricular arrhythmia.
• Prior hypersensitivity to any component or excipient of the investigational product(s).

Other illness

• Malignancy within 5 years before first dose, except adequately treated basal-cell carcinoma of the skin or carcinoma in situ of the cervix.
• 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.
• Documented human immunodeficiency virus (HIV) infection.
• Documented hepatitis-B infection or active hepatitis-C infection.
• Any condition judged by the investigator to render the patient unsuitable for trial participation.

Other

• Uncontrolled pleural, pericardial, or ascitic fluid requiring repeated drainage.

• Voluntary participation: the subject must give written informed consent, be compliant, and agree to attend all follow-up visits.
• Age ≥ 18 years.
• ECOG performance-status score ≤ 1 and life expectancy ≥ 3 months.
• 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).
• 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:
  • 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).
  • 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.
• 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).
• At least one measurable lesion per RECIST v1.1.
• Adequate organ function, defined as:
  • Haematology (no transfusion within 14 days):
  • Haemoglobin ≥ 9 g/dL
  • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
  • Platelet count ≥ 100 × 10⁹/L . Serum chemistry:
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  • Total bilirubin ≤ 1.5 × ULN, or if total bilirubin \> ULN then direct bilirubin ≤ ULN
  • ALT and AST ≤ 2.5 × ULN
  • Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min
• 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.