Phase II test of SHR-A1811 for ultra-low HER2 advanced breast cancer

Inclusion Criteria:

1. Female subjects, aged ≥18 years and ≤75 years;
2. ECOG performance status 0-1;
3. Expected survival of no less than 3 months;
4. Histologically documented breast cancer:

   1. Advanced or metastatic breast cancer
   2. History of ultra-low HER2 expression: histopathology confirms ultra-low HER2 expression, defined as incomplete, faint membranous staining in ≤10% of invasive tumor cells.

      * If multiple historical/local HER2 test results are available for a subject, the most recent result derived from metastatic or advanced disease should be adopted.
      * If local HER2 testing only classifies the subject's tumor as HER2-negative without available IHC status, the result must be re-confirmed by the Department of Pathology of Tianjin Medical University Cancer Institute and Hospital.
5. Have radiographic or objective evidence of disease progression at or after the last prior systemic therapy before initiation of study treatment;
6. For hormone-receptor-positive breast cancer: subjects have received 1-2 lines of endocrine therapy in the advanced-disease setting. Progression during adjuvant endocrine therapy or within 12 months after completion of adjuvant endocrine therapy counts as 1 prior line;
7. For hormone-receptor-negative breast cancer: subjects have received 1-2 lines of prior systemic therapy. Progression during adjuvant therapy or within 12 months after completion of adjuvant therapy counts as 1 prior line;
8. Have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1;
9. Adequate major organ and bone marrow function meeting the following criteria:

   1. . Hemoglobin ≥90 g/L (no blood transfusion within 14 days);
   2. . Absolute neutrophil count ≥1.5×10⁹/L;
   3. . Platelet count ≥90×10⁹/L;
   4. . Total bilirubin ≤1.5 × upper limit of normal (ULN);
   5. . Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; in the presence of liver metastases, ALT and AST ≤5 × ULN;
   6. . Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min (calculated by the Cockcroft-Gault formula);
   7. . International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN;
   8. . Left ventricular ejection fraction (LVEF) ≥50%; QTc interval \<470 ms for female subjects;
10. Female subjects of child-bearing potential must agree to use highly effective contraception from study screening through 7 months after the last dose of study drug and agree not to breast-feed. A negative serum pregnancy test must be obtained within 7 days prior to the first study drug administration;
11. No radiotherapy, chemotherapy, molecular-targeted therapy, immunotherapy or surgery within 4 weeks prior to enrollment; toxicities from prior therapies have recovered to Grade ≤1 (wounds fully healed if surgery was performed). No endocrine therapy within 14 days prior to enrollment.
12. Subjects voluntarily participate in the study and provide written informed consent, with anticipated good compliance to follow protocol-required study procedures.

Exclusion Criteria:

1. According to ASCO/CAP guidelines, subjects whose tumor has never been reported as HER2-positive (IHC 3+ or ISH-amplified);
2. HR-positive patients who have received systemic chemotherapy in the advanced-disease setting;\<br/\>Prior anti-HER2 therapy; prior or ongoing treatment with antibody-drug conjugates containing exatecan derivatives (topoisomerase I inhibitors), including DS-8201a, Sacituzumab govitecan (SG), etc.;
3. Known history of severe hypersensitivity to the drug substance, inactive ingredients in the pharmaceutical formulation, or other monoclonal antibodies;
4. Received local radiotherapy, endocrine therapy, or oral small-molecule targeted anti-tumor therapy within 14 days prior to first study drug administration;
5. received anti-tumor immunotherapy, macromolecular anti-tumor agents, or chemotherapy within 28 days prior to first study drug administration OR five half-lives (whichever is shorter). For oral fluoropyrimidines, folinic acid agents and weekly paclitaxel chemotherapy, the wash-out period shall be ≥14 days; for nitrosoureas and mitomycin, the wash-out period shall be ≥42 days. Underwent major surgery (e.g., trans-abdominal, trans-thoracic surgery; excluding diagnostic puncture, infusion-device implantation, biliary stent implantation and other minor procedures) within 28 days prior to first study drug administration, or anticipated to require major surgery during the study period
6. Meningeal metastasis or active parenchymal brain metastasis. Subjects with clinically stable parenchymal brain metastasis may be enrolled, including asymptomatic brain metastases without prior local therapy; or subjects with previously treated CNS metastases (radiotherapy or surgery), provided radiological stability has been maintained for at least 4 weeks AND symptomatic treatment (including corticosteroids, mannitol, etc.) has been discontinued for more than 2 weeks.

   * Active brain metastasis: newly-diagnosed brain lesions without local therapy (surgery or radiotherapy), or radiologically progressive brain metastasis after prior treatment.
   * Stable brain metastasis: brain metastasis with no radiological progression (no new lesions, no enlargement of existing lesions) for at least 4 weeks after local therapy (stereotactic radiotherapy, whole-brain radiotherapy or surgery);
7. Other malignancies within the past 5 years, except for cured carcinoma in-situ of cervix, basal-cell carcinoma or squamous-cell carcinoma of skin (no treatment required for at least the past 3 years);
8. Uncontrolled concurrent diseases, including but not limited to: persistent or active infection, uncontrolled or significant cardiovascular disease, severe chronic gastrointestinal disease accompanied by diarrhea, or psychiatric/social conditions that may compromise protocol compliance, substantially increase adverse-event risk, or impair the subject's ability to provide written informed consent;
9. Uncontrolled or significant cardiovascular disease, defined by any of the following:

   1. History of myocardial infarction or symptomatic congestive heart failure (NYHA Class II-IV) within 6 months before enrollment. Subjects with troponin above ULN (per manufacturer reference range) without myocardial-infarction-related symptoms at screening shall receive cardiology consultation prior to enrollment to rule out myocardial infarction.
   2. Uncontrolled hypertension;
   3. Uncontrolled and/or clinically significant arrhythmia;
   4. Mean QTcF interval (QT corrected by Fredericia formula) \>470 ms for female subjects, derived from three screening 12-lead ECGs;
10. History of non-infectious interstitial lung disease (ILD)/non-infectious pneumonitis requiring steroid therapy; current ILD / non-infectious pneumonitis; or suspected ILD / non-infectious pneumonitis that cannot be excluded by imaging at screening;
11. Clinically significant pulmonary comorbidities, including but not limited to underlying pulmonary diseases (i.e., pulmonary embolism within 3 months prior to screening, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, significant pleural effusion, etc.), autoimmune / connective-tissue / inflammatory diseases with pulmonary involvement (i.e., rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.), and/or prior complete pulmonary resection;
12. Use of immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes within 2 weeks before first study drug administration (dose \>10 mg/day prednisone or equivalent physiological dose of other corticosteroids); nasal or inhaled corticosteroids are excluded;
13. Active autoimmune disease, or history of autoimmune disease prone to relapse. Subjects with skin disorders not requiring systemic therapy (e.g., vitiligo, psoriasis, alopecia), well-controlled type 1 diabetes treated with insulin, or childhood-onset asthma fully resolved without adult-period intervention are eligible. Subjects requiring bronchodilator medical intervention for asthma are excluded;
14. Uncontrolled infection requiring intravenous antibiotics, antiviral or antifungal agents;
15. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, active hepatitis B (HBsAg-positive with HBV DNA ≥500 IU/mL), or active hepatitis C infection. Among subjects with positive hepatitis C antibody, only those with negative HCV RNA by PCR are eligible;
16. Received live-attenuated vaccine within 30 days prior to first study-drug administration (mRNA vaccines and non-replicating adenoviral vaccines are not regarded as live-attenuated vaccines). Note: If enrolled, subjects shall not receive live vaccines during the study and within 30 days after last study-drug dose;
17. Unresolved toxicity from prior anti-cancer therapy, defined as toxicity not recovered to ≤Grade 1 or baseline (alopecia excluded).

    Note: Subjects with chronic stable Grade 2 toxicity judged by investigator to be related to prior anti-cancer therapy (defined as no deterioration to ≥Grade 2 for at least 3 months before enrollment and manageable with standard care) may be enrolled, e.g., chemotherapy-induced neuropathy, fatigue. Residual toxicities from prior immuno-oncology therapy including Grade 1 or 2 endocrine disorders are allowed: (a) hypothyroidism / hyperthyroidism; (b) type 1 diabetes mellitus; (c) hyperglycemia; (d) adrenal insufficiency; (e) adrenalitis; (f) skin depigmentation (vitiligo);
18. Imaging demonstrates tumor encasement of major blood vessels, or investigator-judged high risk of tumor invasion into major blood vessels leading to life-threatening hemorrhage during treatment;
19. Non-healing wounds or fractures for prolonged periods; major surgical procedures or severe traumatic injury, fracture or ulcer within 4 weeks prior to enrollment;
20. Pregnant or lactating women; female subjects of child-bearing potential unwilling or unable to adopt effective contraceptive measures;
21. Any other conditions judged by the investigator that may interfere with study conduct or endpoint assessment.