HER2-PET: Predicting T-DXd Efficacy and HER2 Heterogeneity (PREDICT-HER)

Inclusion Criteria:

Age ≥ 18 years.

Histopathologically confirmed unresectable locally advanced or metastatic breast cancer, with documented prior immunohistochemistry (IHC) results indicating HER2-positive (IHC 3+, or IHC 2+ with positive FISH) or HER2-low (IHC 1+, or IHC 2+ with negative FISH) expression.

For patients with hormone receptor-positive (HR+), HER2-negative breast cancer, patients must have received prior treatment with a CDK4/6 inhibitor in the locally advanced or metastatic setting, or experienced disease recurrence during adjuvant intensified CDK4/6 inhibitor therapy or within 12 months after completing adjuvant intensified CDK4/6 inhibitor therapy. (HR-positive is defined as ≥ 1% of tumor cells demonstrating positive ER staining by IHC; HER2-negative is defined as IHC score 0 or 1+, or IHC score 2+ with no evidence of in situ hybridization [ISH] gene amplification, or no evidence of ISH gene amplification in the absence of an IHC test.)

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Documented radiological or objective evidence of disease progression on or after the most recent line of systemic therapy prior to initiating study treatment.

Life expectancy ≥ 12 weeks at the time of screening.

Presence of at least one lesion (measurable and/or non-measurable) that can be accurately evaluated at baseline by CT (or MRI if CT is contraindicated) and is suitable for repeated assessment according to RECIST v1.1.

Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days prior to randomization.

Adequate organ and bone marrow function within 14 days prior to randomization. For all laboratory parameters listed below, the most recently obtained values must meet the eligibility criteria:

1. Hemoglobin ≥ 9.0 g/dL;
2. Absolute neutrophil count (ANC) ≥ 1,500/mm³;
3. Platelet count ≥ 100,000/mm³;
4. At baseline, total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) in the absence of liver metastases, or < 3.0 × ULN in the presence of Gilbert's syndrome (unconjugated hyperbilirubinemia) or documented liver metastases;
5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN (< 5.0 × ULN for patients with liver metastases);
6. Serum albumin ≥ 2.5 g/dL;
7. Creatinine clearance (CrCl) ≥ 30 mL/min (calculated using the Cockcroft-Gault formula);
8. International Normalized Ratio (INR) or prothrombin time (PT), and partial thromboplastin time or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.

Female patients must refrain from donating eggs (oocytes) or retrieving/banking eggs for personal use from the screening period, throughout the entire study treatment period, and for at least 7 months after the final dose of study treatment. Breastfeeding must be discontinued during this period. Patients wishing to preserve eggs/fertility should consider undergoing these procedures prior to randomization in this study.

Exclusion Criteria:

1. Uncontrolled concurrent diseases, including but not limited to: persistent or active infections, uncontrolled or significant cardiovascular disease, severe chronic gastrointestinal disease with diarrhea, or psychiatric/social conditions that may limit compliance with study requirements, significantly increase the risk of adverse events (AEs), or impair the patient's ability to provide written informed consent.

2. Uncontrolled or significant cardiovascular disease, including any of the following:

   1. History of myocardial infarction or symptomatic congestive heart failure (CHF) (NYHA Class II to IV) within 6 months prior to randomization. Patients with troponin levels above the Upper Limit of Normal (ULN) (as defined by the manufacturer) at screening without any symptoms related to myocardial infarction should undergo cardiac consultation prior to randomization to rule out myocardial infarction;
   2. Uncontrolled hypertension;
   3. Uncontrolled and/or clinically significant arrhythmias.
3. History of (non-infectious) interstitial lung disease (ILD)/pneumonitis requiring steroid treatment, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
4. Patients who have used immunosuppressive agents within 14 days prior to the first dose of study drug, with the exception of those using intranasal and inhaled corticosteroids, or systemic corticosteroids at a dose less than 10 mg/day prednisone or an equivalent dose.
5. Clinically significant pulmonary-specific comorbidities, including but not limited to any underlying pulmonary disease (e.g., pulmonary embolism within three months prior to randomization, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, significant pleural effusion, etc.) and any autoimmune, connective tissue, or inflammatory disease with associated pulmonary involvement (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), and/or prior lung resection.
6. Uncontrolled infection requiring intravenous antibiotics, antiviral, or antifungal medications.
7. Spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated and symptomatic, or requiring corticosteroid or anticonvulsant treatment to control associated symptoms. Subjects with clinically non-active brain metastases may be included in this study. If subjects have received treatment for brain metastases, are no longer symptomatic, do not require corticosteroids or anticonvulsants, and have recovered from acute toxicities of radiotherapy, they may be enrolled in this study.
8. Active primary immunodeficiency, known Human Immunodeficiency Virus (HIV) infection, or active Hepatitis B or C infection. Among patients who are Hepatitis C antibody positive, only those with a negative polymerase chain reaction (PCR) for HCV RNA are eligible for study enrollment.

9. Unresolved toxicities from prior anti-cancer therapy, defined as toxicities not resolved to ≤ Grade 1 or baseline (excluding alopecia).

   Note: Subjects with chronic, stable Grade 2 toxicities (defined as not worsening to ≥ Grade 2 for at least 3 months prior to enrollment and manageable with standard treatment) that are deemed by the investigator to be related to prior anti-cancer therapy may be included, e.g., chemotherapy-induced neuropathy or fatigue; residual toxicity from prior immunosuppressive therapy: Grade 1 or 2 endocrine disorders.

10. Pregnant or lactating female patients, or patients planning pregnancy. Known history of severe hypersensitivity reaction to the active pharmaceutical ingredient (API), excipients in the drug formulation, or other monoclonal antibodies.
11. History of another primary malignancy within 3 years, with the exception of adequately treated non-melanoma skin cancer, cured in situ disease, other cured solid tumors, or contralateral breast cancer.
12. Substance abuse or any other medical condition that, in the opinion of the investigator, might interfere with the patient's participation in the clinical study or the evaluation of the clinical study results, e.g., psychiatric disorders.