Phase II Study of SHR-A1811 for Ultra-Low HER2 Advanced Breast Cancer

Prior treatment

• 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.;
• Received local radiotherapy, endocrine therapy, or oral small-molecule targeted anti-tumor therapy within 14 days prior to first study drug administration;
• 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
• 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);
• 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;
• 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;
• 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;
• 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;
• 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;
• 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);
• Non-healing wounds or fractures for prolonged periods; major surgical procedures or severe traumatic injury, fracture or ulcer within 4 weeks prior to enrollment;

Other illness

• Known history of severe hypersensitivity to the drug substance, inactive ingredients in the pharmaceutical formulation, or other monoclonal antibodies;
• 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);
• 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;
• Uncontrolled infection requiring intravenous antibiotics, antiviral or antifungal agents;
• 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;
• 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;
• Any other conditions judged by the investigator that may interfere with study conduct or endpoint assessment.

Lab values

• Uncontrolled or significant cardiovascular disease, defined by any of the following:
  • 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.
  • Uncontrolled hypertension;
  • Uncontrolled and/or clinically significant arrhythmia;
  • Mean QTcF interval (QT corrected by Fredericia formula) \>470 ms for female subjects, derived from three screening 12-lead ECGs;

Other

• According to ASCO/CAP guidelines, subjects whose tumor has never been reported as HER2-positive (IHC 3+ or ISH-amplified);
• Pregnant or lactating women; female subjects of child-bearing potential unwilling or unable to adopt effective contraceptive measures;

• Female subjects, aged ≥18 years and ≤75 years;
• ECOG performance status 0-1;
• Expected survival of no less than 3 months;
• Histologically documented breast cancer:
  • Advanced or metastatic breast cancer
  • 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.
• Have radiographic or objective evidence of disease progression at or after the last prior systemic therapy before initiation of study treatment;
• 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;
• 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;
• Have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1;
• Adequate major organ and bone marrow function meeting the following criteria:
  • . Hemoglobin ≥90 g/L (no blood transfusion within 14 days);
  • . Absolute neutrophil count ≥1.5×10⁹/L;
  • . Platelet count ≥90×10⁹/L;
  • . Total bilirubin ≤1.5 × upper limit of normal (ULN);
  • . Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; in the presence of liver metastases, ALT and AST ≤5 × ULN;
  • . Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min (calculated by the Cockcroft-Gault formula);
  • . International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN;
  • . Left ventricular ejection fraction (LVEF) ≥50%; QTc interval \<470 ms for female subjects;
• 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;
• 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.
• Subjects voluntarily participate in the study and provide written informed consent, with anticipated good compliance to follow protocol-required study procedures.