A molecular subtype–guided, chemotherapy-free neoadjuvant strategy using SHR-A1811 plus pertuzumab for hormone receptor–positive/HER2-positive breast cancer: A phase II trial in progress.

TPS653 Background: Hormone receptor–negative/HER2-positive breast cancer achieves high pathological complete response (pCR) rates with chemotherapy-based HER2-targeted therapy, whereas hormone receptor–positive (HR+)/HER2-positive disease consistently demonstrates lower pCR rates and substantial chemotherapy-related toxicity, representing an unmet clinical need. Antibody–drug conjugates (ADCs) may address this gap by enhancing HER2-directed cytotoxic delivery while potentially avoiding conventional chemotherapy. SHR-A1811 (ruikang-trastuzumab) is a next-generation HER2-directed ADC conjugated to a topoisomerase I inhibitor with a high drug-to-antibody ratio (≈6) and has demonstrated superior preclinical activity compared with trastuzumab emtansine. HER2-directed ADCs may be particularly advantageous in HR-positive/HER2-positive tumors, including those with HER2 immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)–positive status, through bystander killing effects that may overcome heterogeneous or lower-level HER2 expression. Emerging evidence suggests that ADC activity is retained in HR-positive/HER2-positive breast cancer and may be enhanced when combined with pertuzumab, providing the rationale for evaluating neoadjuvant SHR-A1811 plus pertuzumab in this population. Methods: This prospective, open-label, single-arm phase II trial enrolls women aged > 18 and < 70 years with previously untreated stage II–III HR-positive/HER2-positive breast cancer. All patients receive neoadjuvant SHR-A1811 (4.8 mg/kg intravenously every 3 weeks) plus pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) for four cycles. Baseline BluePrint profiling classifies tumors as luminal or non-luminal. Treatment is adaptively tailored based on molecular subtype and RECIST v1.1 response after four cycles. Patients with luminal subtype and stable disease switch to a chemotherapy-free regimen of trastuzumab, pyrotinib (a HER2-directed tyrosine kinase inhibitor), dalpiciclib (a CDK4/6 inhibitor), and an aromatase inhibitor, while patients with luminal subtype achieving partial or complete response and all non-luminal tumors continue SHR-A1811 plus pertuzumab for two to four additional cycles before surgery. Circulating tumor DNA (ctDNA) is assessed at baseline, after four cycles, and preoperatively. The primary endpoint is pCR (ypT0/is ypN0); secondary endpoints include event-free survival, objective response rate, and safety, with exploratory analyses evaluating associations among molecular subtype, ctDNA dynamics, and treatment response. Clinical trial information: NCT07307287 .