Culmerciclib Combined With Letrozole and Dual HER2 Blockade as Neoadjuvant Therapy for HR+/HER2+ Breast Cancer

A Single-Arm, Prospective, Multicenter Phase II Study of Culmerciclib Plus Letrozole and Trastuzumab (TQB211)/Pertuzumab (TQB2440) as Neoadjuvant Therapy in Patients With HR-Positive/HER2-Positive Early or Locally Advanced Breast Cancer

This is a single-arm, prospective, multicenter, phase II clinical study evaluating the efficacy and safety of a chemotherapy-free neoadjuvant regimen in patients with HR-positive/HER2-positive (HR+/HER2+) early or locally advanced breast cancer.

Approximately 33 treatment-naive patients with stage II-III (AJCC 8th edition) HR+/HER2+ breast cancer will receive 5 cycles of neoadjuvant treatment with culmerciclib (a CDK4/6 inhibitor) plus letrozole, trastuzumab (TQB211) and pertuzumab (TQB2440), followed by definitive breast surgery.

The primary endpoint is breast pathological complete response rate (bpCR, ypT0/is ypN0). Secondary endpoints include objective response rate (ORR), residual cancer burden (RCB), Ki67 change rate, patient-reported outcomes, and safety assessed per CTCAE v5.0.

HR-positive/HER2-positive breast cancer accounts for approximately 10% of all breast cancers and shows lower pathological complete response rates to neoadjuvant therapy compared with the HR-negative/HER2-positive subtype. Crosstalk between HER2 and ER signaling pathways contributes to resistance to endocrine and anti-HER2 therapy. Preclinical evidence suggests that CDK4/6 inhibitors synergize with anti-HER2 therapy and may restore tumor sensitivity to HER2 blockade.

Eligible patients receive:

• culmerciclib 180 mg orally once daily, in 28-day cycles, for 5 cycles;
• Letrozole 2.5 mg orally once daily, in 28-day cycles, for 5 cycles;
• Trastuzumab (TQB211) 8 mg/kg loading dose followed by 6 mg/kg intravenously every 3 weeks, for 6 doses;
• Pertuzumab (TQB2440) 840 mg loading dose followed by 420 mg intravenously every 3 weeks, for 6 doses.

Tumor response is assessed by imaging (ultrasound, mammography, and MRI) according to RECIST 1.1. After completion of 5 cycles of neoadjuvant treatment, patients undergo definitive breast cancer surgery, and postoperative pathology is evaluated for bpCR and RCB. Adverse events are assessed per CTCAE v5.0. Exploratory analyses will investigate correlations between biomarkers and treatment response.

Inclusion Criteria:

• Histologically confirmed HR-positive (ER >=50%, PR >=10%) and HER2-positive (IHC 3+ or ISH+) breast cancer;
• Clinical stage II-III (AJCC 8th edition);
• Treatment-naive: no prior systemic anti-tumor therapy for breast cancer;
• ECOG performance status 0-1;
• Adequate organ function;
• Signed informed consent.

Exclusion Criteria:

• Distant metastasis (stage IV disease);
• Prior chemotherapy, endocrine therapy, or anti-HER2 therapy for the current breast cancer;
• Severe cardiac dysfunction or left ventricular ejection fraction (LVEF) below the institutional lower limit of normal;
• Pregnancy or lactation;
• Any other condition that, in the investigator's opinion, makes the patient unsuitable for the study.