Breast cancer is the most common malignancy in women, with approximately 20% classified as HER2-positive. Anti-HER2 blockade (trastuzumab plus pertuzumab) combined with chemotherapy constitutes the standard neoadjuvant regimen; however, the pathological complete response (pCR) rate in the HR-positive subgroup remains only 35-40%, and platinum-containing schedules are associated with significant hematologic toxicity. Antibody-drug conjugates (ADCs) integrate targeted delivery with potent cytotoxic payloads. SHR-A1811 (ruikang-trastuzumab), a domestically developed ADC by Hengrui Pharmaceutical, is conjugated with a topoisomerase I inhibitor (mean drug-to-antibody ratio \[DAR\] ≈ 6). Preclinical data demonstrate that SHR-A1811 exhibits superior efficacy to trastuzumab emtansine (T-DM1) in both trastuzumab-sensitive and resistant HER2-expressing tumor models, with a manageable safety profile.
This prospective, open-label, phase II trial will enroll patients with early-stage/locally advanced HR-positive/HER2-positive breast cancer, who will receive neoadjuvant SHR-A1811 plus pertuzumab. At baseline, BluePrint gene profiling will be performed to stratify participants into luminal and non-luminal subtypes: patients with luminal subtype who achieve stable disease (SD) after 4 cycles will switch to a regimen of trastuzumab, pyrotinib, dalpiciclib, and an aromatase inhibitor for an additional 4 cycles; all other patients will continue ADC-based dual-target therapy for 2-4 further cycles, followed by surgical resection. Circulating tumor DNA (ctDNA) dynamics will be dynamically monitored at baseline, after 4 cycles of treatment, and preoperatively to evaluate early treatment sensitivity.
The primary endpoint is the pCR rate. Secondary endpoints include event-free survival (EFS), objective response rate (ORR), and safety profiles. Exploratory analyses will investigate the correlation between molecular subtypes and treatment responses, aiming to establish a chemotherapy-free, precision neoadjuvant strategy for HR-positive/HER2-positive breast cancer.
Female, aged 18-70 years at the time of informed consent.
Histologically confirmed invasive breast cancer, with no prior systemic anti-cancer therapy.
Pathologically documented HR-positive (ER ≥ 1% and/or PR ≥ 1%) and HER2-positive disease, per the 2018 ASCO-CAP guidelines: IHC 3+ or IHC 2+ with ISH ratio ≥ 2.0.
Clinical stage II-III (cT2-cT4 or cN+, cM0) per the 8th edition of the AJCC Cancer Staging Manual.
Breast cancer not confirmed by histopathology.
Bilateral, inflammatory, or occult breast cancer.
Any prior anti-cancer therapy (chemotherapy, radiotherapy, targeted, endocrine, etc.); radical radiotherapy ≤ 4 weeks or palliative radiotherapy ≤ 2 weeks before first dose.
Concomitant anti-cancer therapy of any kind.
Single group
SHR- A1811
DrugSHR-A1811 4.8 mg/kg and pertuzumab 420 mg are administered intravenously every 3 weeks for 4 cycles as neoadjuvant therapy. Patients with luminal subtype and stable disease (SD) then switch to trastuzumab 6 mg/kg, pyrotinib 320 mg po daily, dalpiciclib 125 mg po days 1-21 of a 28-day cycle, plus an aromatase inhibitor for 4 additional cycles. All remaining patients (PR/CR luminal or any non-luminal) continue SHR-A1811 + pertuzumab for 2-4 more cycles before surgery. Treatment continues until progression, unacceptable toxicity, or surgical resection.
Pathologic complete response (pCR)
Percentage of patients with no invasive cancer in the breast and axillary lymph nodes (ypT0/is ypN0) at definitive surgery.
5-year Event-free survival (EFS)
5 years event-free survival after surgery
Objective response rate (ORR)
Proportion of patients achieving complete or partial response (CR + PR) by RECIST 1.1 after neoadjuvant therapy.
Safety and tolerability
Incidence and severity of adverse events graded by CTCAE v5.0 from first dose up to 30 days after last dose.
Exploratory biomarker analyses
1. Association between baseline molecular subtypes (luminal vs non-luminal); 2. Cell-free tumor DNA (ctDNA) will be dynamically monitored at baseline, following four cycles of treatment, and prior to surgery; 3. Multi-gene profiling for identifying genomic characteristics predictive of benefit from neoadjuvant SHR-A1811 plus pertuzumab in HR-positive/HER2-positive breast cancer.
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