Neoadjuvant Trastuzumab-rezetecan Plus Pertuzumab or Nab-Paclitaxel, Carboplatin, Trastuzumab, and Pyrotinib After Suboptimal Response to Neoadjuvant Dual HER2-Targeted Therapy Combined With Chemotherapy in HER2-Positive Early Breast Cancer

This is a prospective, response-guided, phase II study designed to evaluate individualized neoadjuvant treatment strategies in patients with HER2-positive early breast cancer. The study incorporates an adaptive treatment algorithm based on early response assessment to an initial neoadjuvant dual HER2-targeted therapy combined with chemotherapy, with the aim of optimizing therapeutic efficacy while minimizing unnecessary treatment-related toxicity. All eligible patients initially receive neoadjuvant dual HER2-targeted therapy combined with chemotherapy according to the study protocol. Following completion of a predefined initial treatment phase, tumor response is systematically assessed using standardized clinical and radiologic criteria. Patients who achieve an adequate response continue the same neoadjuvant treatment to complete the planned course of therapy. In contrast, patients demonstrating a suboptimal response are assigned to an intensified investigational neoadjuvant strategy. The escalation regimens include either trastuzumab-rezetecan in combination with pertuzumab or a pyrotinib-based multi-agent regimen incorporating chemotherapy and HER2-directed therapy. Treatment selection and administration follow protocol-specified criteria and schedules. The response-guided escalation strategy is intended to address the unmet clinical need of patients who derive insufficient benefit from standard neoadjuvant dual HER2-targeted therapy combined with chemotherapy. By selectively intensifying treatment only in patients with suboptimal response, this study seeks to enhance pathologic response rates while avoiding overtreatment in patients who respond adequately to initial therapy. Primary and secondary objectives focus on evaluating pathologic response outcomes, safety and tolerability of the adaptive treatment strategies, and feasibility of response-guided treatment modification in the neoadjuvant setting. Exploratory analyses will assess potential biomarkers associated with treatment response and resistance, providing insights to inform future personalized neoadjuvant treatment approaches in HER2-positive early breast cancer.