A Prospective, Single-arm, Single-center Phase II Clinical Study of Deruxtecan in Combination With ivonescImab in Hormone Receptor-positive HER2 Negative Advanced Breast Cancer
The UNITY study is a prospective, single-arm, single-center, Phase II clinical trial conducted by Fudan University Shanghai Cancer Center. It aims to evaluate the efficacy and safety of Trastuzumab Deruxtecan (T-DXd) combined with ivonescimab in patients with hormone receptor-positive (HR+), HER2-negative recurrent or metastatic breast cancer. Approximately 53 patients will be enrolled. Eligible participants must have histologically confirmed advanced HR-positive breast cancer with HER2-low or HER2-ultralow expression. They must have experienced recurrence, metastasis, or disease progression after prior treatment with a CDK4/6 inhibitor (including in the adjuvant setting) and have received at most one line of systemic chemotherapy for advanced disease. The study permits the enrollment of patients with central nervous system (CNS) metastases. The primary endpoint is the Overall Response Rate (ORR). Key secondary endpoints include Clinical Benefit Rate (CBR), Overall Survival (OS), Progression-Free Survival (PFS), safety, and patient-reported quality of life (assessed using EORTC QLQ-C30 and QLQ-BR23). Exploratory endpoints will involve the analysis of biomarkers from tumor and blood samples, as well as PAM50 molecular subtyping and its correlation with survival outcomes. This study seeks to explore the efficacy and safety of Trastuzumab Deruxtecan in combination with ivonescimab for patients with HR-positive, HER2-negative recurrent or metastatic breast cancer, with a particular focus on the subpopulation with CNS metastases.
• Age ≥ 18 years, any gender.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Histologically or cytologically confirmed Hormone Receptor-positive (HR+) and Human Epidermal Growth Factor Receptor 2 (HER2)-low or HER2-ultralow breast cancer, with evidence of locally recurrent or metastatic disease that is not amenable to curative-intent surgery or radiation therapy.
‣ HR positivity is defined as Estrogen Receptor (ER) positive (≥1% positive cells) and/or Progesterone Receptor (PR) positive (≥1% positive cells).
⁃ HER2-low or HER2-ultralow expression is defined as HER2 (0 with staining), HER2 (1+), or HER2 (2+) by immunohistochemistry (IHC) with a negative in-situ hybridization (ISH) result.
⁃ Fulfillment of these criteria from any single pathological assessment is sufficient for eligibility.
• Life expectancy of ≥ 3 months.
• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• History of recurrence or disease progression after prior treatment with a CDK4/6 inhibitor (including in the adjuvant setting). Patients have received a maximum of one line of chemotherapy for recurrent or metastatic disease. Recurrence or disease progression during or within 6 months after completion of neoadjuvant/adjuvant intravenous chemotherapy is counted as one line of therapy.
• Patients with Central Nervous System (CNS) metastases are eligible. Ventriculoperitoneal shunt to relieve intracranial pressure or use of mannitol, corticosteroids, or anticonvulsants is permitted prior to the first dose. However, the dose of such medications must be stable for at least 1 week without an increase, and neurological symptoms must be stable without worsening for at least 1 week. (Priority will be given to the enrollment of patients with CNS metastases.)
• Availability of an adequate tumor tissue sample for retrospective analysis of PD-L1 status.
• Adequate organ function, defined as follows:
‣ Hematology: Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L; Platelets (PLT) ≥ 75 × 10⁹/L; Hemoglobin (Hb) ≥ 90 g/L (transfusion or medical support to meet this level is permitted).
⁃ Hepatic and Renal Function: Total Bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3 × ULN (≤ 5.0 × ULN in the presence of liver metastases); Blood Urea Nitrogen (BUN) or Serum Creatinine (Cr) ≤ 1.5 × ULN, or Creatinine Clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula).
⁃ Coagulation: Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN; Prothrombin Time (PT) ≤ 1.5 × ULN.
⁃ Cardiac: QT interval corrected by Fridericia's formula (QTcF) \< 470 ms for females and \< 450 ms for males on a 12-lead electrocardiogram (ECG); Left Ventricular Ejection Fraction (LVEF) ≥ 50% by echocardiogram.
⁃ Voluntary participation in the study with signed informed consent, and willingness to comply with study procedures and follow-up.