Fulvestaciclib Combined With Anti-HER2 and Endocrine Therapy for HR+/HER2+ Advanced Breast Cancer

Inclusion criteria

• Age ≥ 18 years, with inoperable locally advanced or recurrent/metastatic breast cancer not amenable to curative-intent therapy.
• Histologically or cytologically confirmed hormone receptor-positive (HR+) and HER2-positive (HER2+) breast cancer. HR+ is defined as estrogen receptor (ER) and/or progesterone receptor (PR) positivity with ≥1% of invasive tumor cells positive by immunohistochemistry (IHC). HER2+ is defined as IHC 3+ or IHC 2+ with in situ hybridization (ISH) positivity.
• No prior systemic therapy for advanced breast cancer, including endocrine therapy, chemotherapy, anti-HER2 therapy, or any CDK4/6 inhibitor.
• Patients may have received neoadjuvant or adjuvant therapy. If prior endocrine therapy was received in the neoadjuvant/adjuvant setting, the disease-free interval from completion of endocrine therapy to randomization must be ≥12 months. If prior anti-HER2 therapy was received, the disease-free interval from completion of anti-HER2 therapy to randomization must be ≥6 months.
• Patients with stable central nervous system (CNS) metastases (meeting all the following criteria: no disease progression on screening imaging after local therapy; at least 3 weeks from completion of local CNS therapy to Cycle 1 Day 1; no requirement for medication to control symptoms) or asymptomatic CNS metastases are eligible.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Any menopausal status. Postmenopausal status is defined as: a. bilateral oophorectomy; b. age ≥60 years; c. age <60 years with amenorrhea for >1 year in the absence of chemotherapy, tamoxifen, toremifene, or ovarian function suppression, and with serum FSH and estradiol levels within the postmenopausal range. For patients <60 years on tamoxifen or toremifene with amenorrhea, serum FSH and estradiol levels must be within the postmenopausal range on consecutive measurements.
• At least one evaluable lesion per RECIST 1.1 (measurable and/or non-measurable lesion).
• For women of childbearing potential: negative serum or urine pregnancy test within 7 days prior to randomization, and agreement to use adequate contraception during study treatment and for 6 months after the last dose of fulvestaciclib.
• Voluntarily sign the informed consent form (ICF), understand the study, and be willing to comply with all study procedures and follow-up.
• Adequate bone marrow and organ function defined as:

Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; Hemoglobin ≥90 g/L (no red blood cell transfusion within 14 days prior to randomization); Platelet count ≥75 × 10⁹/L; Serum total bilirubin ≤1.5 × upper limit of normal (ULN); AST and ALT ≤3 × ULN (or ≤5 × ULN in the presence of liver metastases); Serum creatinine ≤1 × ULN or calculated creatinine clearance >50 mL/min (Cockcroft-Gault formula); Baseline left ventricular ejection fraction (LVEF) ≥50%.

Exclusion criteria

• Inflammatory breast cancer.
• Leptomeningeal disease.
• Active brain metastases (patients with asymptomatic brain metastases, or clinically stable and not requiring steroids or other CNS-directed therapy for ≥4 weeks are eligible).
• Diagnosis of any other malignancy, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix that has been definitively treated.
• Known severe hypersensitivity to any component of the study drugs.
• Myocardial infarction within 6 months prior to first dose; uncontrolled cardiac arrhythmias (QTc interval ≥470 ms by Fridericia's formula); New York Heart Association (NYHA) Class III-IV cardiac insufficiency; LVEF <50% on echocardiography; or clinically significant pleural effusion, pericardial effusion, or ascites requiring intervention.
• Dysphagia, active gastrointestinal disease, major gastrointestinal surgery, malabsorption syndrome, or any other condition that may interfere with the absorption of study drugs.
• Known active infection, including hepatitis B (HBsAg positive with HBV DNA ≥1×10⁴ copies/mL or ≥2000 IU/mL), hepatitis C, syphilis, or human immunodeficiency virus (HIV) infection.
• Major surgery, radiotherapy, tumor immunotherapy, monoclonal antibody therapy, or other systemic antitumor therapy within 30 days prior to the first dose, or any therapy that the investigator considers may interfere with the efficacy of study drugs.
• Concurrent use of other investigational drugs or therapies.
• Planned or prior organ or bone marrow transplantation.
• Known history of substance abuse or drug addiction.
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for participation in this study.