Neoadjuvant SHR-A1811 Combined With Pertuzumab in HER2-Positive Breast Cancer: An Exploratory Clinical Study.

Overview

This is a multicenter, two-arm, exploratory clinical study designed to evaluate the efficacy and safety of a response-guided neoadjuvant treatment strategy in patients with HER2-positive early or locally advanced breast cancer. Breast cancer is the most common malignancy in women worldwide, and HER2-positive disease accounts for approximately 15-20% of cases and is associated with aggressive tumor biology and a higher risk of recurrence. The introduction of HER2-targeted therapies, including trastuzumab and pertuzumab, has significantly improved patient outcomes. However, a proportion of patients exhibit suboptimal response to standard neoadjuvant therapy, highlighting the need for more effective treatment strategies. In this study, approximately 100 eligible patients will be enrolled. All patients will initially receive 2 cycles of standard neoadjuvant therapy with trastuzumab, pertuzumab, and chemotherapy (THP or TCbHP). Tumor response will be assessed according to RECIST version 1.1 criteria. Patients with tumor reduction greater than 40% will continue the same regimen for an additional 4 cycles. Patients with tumor reduction of 40% or less will switch to an alternative regimen consisting of SHR-A1811, a novel HER2-targeted antibody-drug conjugate, in combination with pertuzumab for 4 cycles. SHR-A1811 is an investigational HER2-targeted antibody-drug conjugate designed to deliver a cytotoxic payload directly to tumor cells, potentially overcoming resistance to prior HER2-targeted therapies. Emerging clinical data have demonstrated promising anti-tumor activity and manageable safety in HER2-positive breast cancer. Clinical data, including baseline characteristics, imaging findings, and pathological markers such as Ki-67, will be collected throughout the study. Efficacy will be evaluated based on imaging assessments according to RECIST 1.1 criteria and pathological response at surgery, while safety will be monitored during treatment. The primary objective of this study is to explore whether switching to SHR-A1811 in combination with pertuzumab in patients with suboptimal early response can improve pathological complete response (pCR) rates. Secondary objectives include evaluation of safety and tolerability of the treatment strategies. This study aims to provide evidence for an individualized, response-adapted neoadjuvant treatment approach in HER2-positive breast cancer, and to optimize treatment outcomes for patients with inadequate response to standard therapy.

HER2-positive breast cancer is driven by overexpression or amplification of the HER2 receptor, leading to activation of downstream signaling pathways such as MAPK and PI3K/AKT that promote tumor growth and survival. Although dual HER2 blockade with trastuzumab and pertuzumab in combination with chemotherapy has become a standard neoadjuvant treatment, a subset of patients exhibit insufficient tumor response, indicating biological heterogeneity and potential resistance to therapy. Pathological complete response (pCR) after neoadjuvant treatment is associated with improved long-term outcomes in HER2-positive breast cancer. Therefore, early identification of patients with suboptimal response and timely treatment modification may represent an effective strategy to improve prognosis. Antibody-drug conjugates (ADCs) are designed to selectively deliver cytotoxic agents to tumor cells through antigen-specific targeting. SHR-A1811 is an investigational HER2-directed ADC composed of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload via a cleavable linker. Preclinical data have demonstrated potent anti-tumor activity in HER2-expressing models, including those with reduced sensitivity to prior HER2-targeted therapies. Emerging clinical evidence supports the antitumor activity and manageable safety profile of SHR-A1811 in HER2-positive breast cancer. Its mechanism of action suggests potential benefit in patients with inadequate response to standard HER2-targeted neoadjuvant regimens. This study is designed to investigate a response-adapted treatment strategy, in which early tumor response is used to guide subsequent therapy selection. By incorporating an alternative HER2-targeted approach for patients with suboptimal response, this study aims to explore strategies to improve treatment efficacy while maintaining an acceptable safety profile. The results of this study are expected to provide evidence to support individualized neoadjuvant treatment strategies for patients with HER2-positive breast cancer.