An Open-Label, Randomized Phase III Study of Trastuzumab Rezetecan With or Without Bevacizumab in First to Third Line BLIS Subtype TNBC

A Randomized Phase III Study of Trastuzumab Rezetecan With or Without Bevacizumab as First- to Third-Line Treatment for Basal-like Immune-suppressed Triple-Negative Breast Cancer

This study is a prospective, open-label, phase III, randomized controlled clinical trial. It is planned to screen patients with inoperable locally advanced or metastatic triple-negative breast cancer of the BLIS subtype. A total of 140 patients are planned to be enrolled.

Inclusion Criteria:

1. Female patients aged ≥18 years and ≤70 years;

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1;

3. Life expectancy of at least 3 months;

4. Histologically confirmed invasive triple-negative breast cancer (defined as breast cancer with estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER-2] all determined to be negative by pathological testing. Specifically: ER-negative: IHC <1%; PR-negative: IHC <1%; HER2-negative: IHC -/+ or IHC ++ with FISH/CISH negative. All specimens must be verified as the BLIS subtype of the Fudan quadruple molecular classification by the Precision Medicine Center/Department of Pathology at the study's participating center);

5. Tumor stage: recurrent or metastatic breast cancer; for locally recurrent disease, radical surgical resection must be confirmed by the investigator to be not feasible. Number of prior lines of therapy in the advanced setting ≤2;

6. Patients must have at least one lesion (measurable and/or non-measurable) that has not been previously irradiated, can be accurately assessed at baseline by CT/MRI, and can be repeatedly evaluated according to RECIST 1.1;

7. Adequate major organ function, meeting the following criteria:

   Hematological parameters: hemoglobin (HB) ≥90 g/L (without blood transfusion within 14 days); absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count (PLT) ≥75×10⁹/L;Biochemical parameters: total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN; in the presence of liver metastases, ALT and AST ≤5×ULN; serum creatinine (Cr) ≤1×ULN, and calculated creatinine clearance >50 mL/min (Cockcroft-Gault formula);

8. No prior radiotherapy, endocrine therapy, molecular targeted therapy, or surgery within 3 weeks before study initiation, and recovery from acute toxicities of prior treatment (if surgery was performed, the wound must be completely healed); no peripheral neuropathy or only grade I peripheral neurotoxicity;

9. Female subjects of childbearing potential must agree to use a medically accepted contraceptive method during the study treatment period and for at least 3 months after the last dose of study drug;

10. Subjects must voluntarily participate in this study, sign the informed consent form, have good compliance, and be willing to cooperate with follow-up.

Exclusion Criteria:

• Patients with any of the following criteria will be excluded from this study:

  1. Known central nervous system (CNS) metastases or a history of CNS metastases prior to screening. For patients with clinically suspected CNS metastases, contrast-enhanced CT or contrast-enhanced magnetic resonance imaging (MRI) must be performed within 28 days before the first dose to rule out CNS metastases;
  2. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina pectoris, myocardial infarction within the past 6 months, or ventricular arrhythmias;
  3. Persistent adverse events of Grade ≥1 resulting from prior treatment. Exceptions to this are alopecia or conditions that the investigator deems should not preclude enrollment. Such cases should be clearly documented in the investigator's notes;
  4. Major surgery (excluding minor procedures such as placement of vascular access) within 3 weeks before the first cycle of study treatment;
  5. Pregnant or lactating patients;
  6. Other malignancies within the past 5 years, excluding cured cervical carcinoma in situ, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin;
  7. Presence of third-space fluid accumulation (e.g., massive pleural effusion or ascites) that cannot be controlled by drainage or other methods;
  8. Participation in another anti-tumor drug clinical trial within 3 weeks before the first use of the study drug;
  9. Long-term unhealed wounds or incompletely healed fractures;
  10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or HBV DNA ≥500 IU/mL, or chronic hepatitis with abnormal liver function;
  11. History of allergic constitution, known allergy to any component of the study drug regimen, or history of allergy to other monoclonal antibodies;
  12. History of gastrointestinal bleeding within the past 6 months, or clear evidence of a tendency for gastrointestinal bleeding, such as esophageal varices at risk of bleeding, active local ulcerative lesions, or fecal occult blood test ≥ (++). Patients with fecal occult blood test (+) should undergo gastroscopy;
  13. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to study enrollment;
  14. Urinalysis showing urine protein ≥ (++), or confirmed 24-hour urine protein quantification >1.0 g;
  15. Hypertension that cannot be controlled to within normal range with antihypertensive medication (systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg);
  16. Prior use of anti-angiogenic agents or prior exposure to an antibody-drug conjugate (ADC) with a topoisomerase I inhibitor as the payload