Phase II Study of HLX43 Monotherapy or Combined With Immune Checkpoint Inhibitors in Patients With Locally Advanced, Recurrent, or Metastatic Triple-negative Breast Cancer.

A Phase II Study to Evaluate the Efficacy and Safety of HLX43 (an Anti-PD-L1 ADC) as a Monotherapy or in Combination With Immune Checkpoint Inhibitors in Subjects With Locally Advanced, Recurrent or Metastatic Triple-negative Breast Cancer (TNBC).

The study is being conducted to explore the reasonable dosage and evaluate the efficacy, safety and tolerability of HLX43 (Anti-PD-L1 ADC) as a monotherapy or in combination with immune checkpoint inhibitors in Subjects with locally advanced, recurrent or metastatic triple-negative breast cancer (TNBC).

Inclusion Criteria:

1. Voluntary written informed consent obtained before any study procedures.

2. Age ≥ 18 years at consent; no gender restriction.

3. Histopathologically confirmed TNBC: ER < 1%, PR < 1%, HER2 IHC 0/1+/2+ with no FISH amplification.

   • Phase I: Recurrent or metastatic TNBC after ≥1 prior line of standard systemic therapy.
   • Phase II: Unresectable locally advanced, recurrent, or metastatic TNBC with no prior systemic anti-cancer therapy for this stage (palliative radiotherapy to metastases allowed; neoadjuvant/adjuvant therapy permitted if completed ≥6 months before recurrence/metastasis).

4. At least one RECIST v1.1-measurable lesion documented within 4 weeks before randomization.

   Note: Target lesions must not be in irradiated fields or the CNS. If only measurable lesion is irradiated, imaging must confirm progression post-radiotherapy.

5. Archival FFPE tumor tissue (≤6 months old, ≤2 years max) for PD-L1 testing; fresh biopsy acceptable if archival tissue is unavailable or inadequate.

   Note: Specimens must be non-irradiated FFPE blocks/slides with pathology report confirming malignancy and adequacy.

6. Washout: ≥3 weeks (or 5 half-lives, whichever is shorter) after major surgery, radiotherapy (except palliative bone RT), chemotherapy, targeted therapy, or immunotherapy; ≥1 week after minor surgery or anti-tumor TCM. All treatment-related AEs resolved to CTCAE v6.0 Grade ≤1 (stable Grade 2 peripheral neuropathy and alopecia exempted).

7. ECOG PS 0-1, assessed ≤7 days before randomization.

8. Life expectancy >3 months.

9. Adequate hematologic, hepatic, and renal function per labs ≤7 days before randomization.

Exclusion Criteria:

1. Prior topoisomerase I-targeting therapy (e.g., irinotecan, topotecan, or ADCs).
2. Second primary malignancy within 2 years before randomization (except cured carcinoma in situ or stage I tumors).
3. Prior grade ≥3 immune-related adverse event during immunotherapy.
4. Uncontrolled, recurrent malignant pleural, pericardial, or ascitic effusions requiring repeated drainage.
5. Active CNS metastases, spinal cord compression, or carcinomatous meningitis.
6. Clinically significant pulmonary impairment.
7. Uncontrolled cardiovascular or cerebrovascular disease .
8. Active systemic infection requiring IV antibiotics within 2 weeks before randomization.
9. Moderate or strong CYP2D6/CYP3A inhibitor or inducer use within 2 weeks before randomization.
10. Systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressants within 2 weeks before randomization .
11. Active or suspected autoimmune disease .
12. Live or attenuated live vaccine within 4 weeks before randomization.
13. Hypersensitivity to mAbs, large-molecule biologics, or drug formulation excipients.
14. Active pulmonary tuberculosis.
15. Known immunodeficiency.
16. Active HBV , HCV , or HBV/HCV co-infection.
17. Pregnancy or lactation.
18. Participation in another interventional trial within 30 days before consent .
19. Any condition posing unacceptable safety risk or interfering with study conduct per investigator judgment.