SHR-A1811 Plus Pertuzumab as Neoadjuvant Therapy for Early or Locally Advanced HR-Positive HER2-Positive Breast Cancer: A Prospective, Open-Label, Phase II Study
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 30
- 主要终点
- Pathologic complete response (pCR)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
- •Clinical stage II-III (cT2-cT4 or cN+, cM0) per the 8th edition of the AJCC Cancer Staging Manual.
- •At least one measurable lesion per RECIST v1.1 criteria.
- •ECOG performance status 0-
- •Estimated life expectancy of ≥ 12 months.
- •Adequate organ function within 14 days prior to the first dose (without transfusion or growth factor support):
- •Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; platelets ≥ 100 × 10⁹/L; hemoglobin (Hb) ≥ 90 g/L
- •Albumin ≥ 3.0 g/dL; total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); alanine transaminase (ALT)/aspartate transaminase (AST) ≤ 2.5 × ULN; alkaline phosphatase (ALP) ≤ 2.5 × ULN; blood urea nitrogen (BUN) and creatinine ≤ 1.5 × ULN, or creatinine clearance (CrCl) ≥ 60 mL/min (per Cockcroft-Gault formula)
- •Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
- •Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiography
- •Fridericia-corrected QT interval (QTcF) ≤ 470 ms
- •Premenopausal women with reproductive potential must have a negative serum β-human chorionic gonadotropin (β-hCG) test within 7 days before treatment, use effective barrier contraception throughout the study period and for 6 months after the last dose, and not be breastfeeding.
- •Provision of signed written informed consent; willingness to comply with all study visits and procedures.
排除标准
- •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.
- •Other malignancies within 5 years (except cured basal-cell skin cancer or cervical carcinoma in situ).
- •Participation in another drug trial ≤ 4 weeks before enrolment.
- •Systemic immunosuppressive therapy (e.g., > 10 mg/day prednisone equivalent) ≤ 2 weeks before first dose (nasal/inhaled corticosteroids allowed).
- •Live or attenuated vaccines ≤ 4 weeks before first dose.
- •Major non-breast surgery ≤ 4 weeks before first dose or not fully recovered.
- •Active autoimmune disease or history of recurrent autoimmunity (e.g., autoimmune hepatitis, uveitis, colitis, hypophysitis, vasculitis, nephritis, hyper/hypothyroidism except stable hormone replacement). Controlled vitiligo, psoriasis, alopecia, insulin-dependent type 1 diabetes, or childhood asthma in complete remission allowed. Asthma requiring bronchodilators excluded.
- •Immunodeficiency (HIV positive, congenital/secondary), prior organ transplant.
- •Uncontrolled or significant cardiovascular/cerebrovascular disease, including within 6 months: NYHA III/IV heart failure, MI, stroke (except lacunar), pulmonary embolism, unstable angina, significant arrhythmia; cardiomyopathies; QTc > 470 ms (Fridericia, female), 2nd/3rd degree AV block, atrial fibrillation ≥ EHRA 2b, uncontrolled hypertension.
- •Interstitial lung disease or any moderate-severe pulmonary disorder that may interfere with drug-related lung toxicity assessment: idiopathic pulmonary fibrosis, organizing pneumonia/bronchiolitis obliterans, pulmonary embolism, severe asthma/COPD, restrictive/obstructive defects, autoimmune/connective-tissue lung involvement, prior pneumonectomy.
- •Active hepatitis B (HBsAg+ and HBV DNA ≥ 500 IU/mL), hepatitis C (anti-HCV+ and HCV RNA > ULN), cirrhosis, or severe infection requiring antibiotics/antivirals/antifungals.
- •Hereditary/acquired bleeding or thrombotic diatheses (e.g., hemophilia, coagulopathy).
- •Known hypersensitivity to study drugs or excipients.
- •Pregnant or lactating women; women of child-bearing potential with positive baseline pregnancy test or unwilling to use effective contraception throughout the study.
- •Any severe concomitant condition jeopardizing patient safety or compliance (e.g., uncontrolled hypertension, diabetes, active infection) or significant neurologic/psychiatric disorder (epilepsy, dementia) that, in the investigator's opinion, renders
研究组 & 干预措施
SHR-A1811 + Pertuzumab Neoadjuvant Therapy for HER2+ HR+ Breast Cancer
All patients to be included in the analysis must undergo Blueprint genomic profiling before neoadjuvant therapy to define luminal and non-luminal molecular subtypes. After completing four cycles of neoadjuvant therapy with ruikang-trastuzumab plus pertuzumab, response is assessed by RECIST 1.1:
- Patients with stable disease (SD) and luminal subtype switch to a quadruplet regimen of trastuzumab, pyrotinib, dalpiciclib, and an aromatase inhibitor for a further four cycles.
- Patients achieving partial or complete response (PR/CR) and luminal subtype, as well as all non-luminal patients, continue ruikang-trastuzumab plus pertuzumab for an additional 2-4 cycles, tailored to individual clinical response, before undergoing surgery
干预措施: SHR- A1811 (Drug)
结局指标
主要结局
Pathologic complete response (pCR)
时间窗: At the time of definitive surgery, approximately 24 weeks after study entry
Percentage of patients with no invasive cancer in the breast and axillary lymph nodes (ypT0/is ypN0) at definitive surgery.
次要结局
- 5-year Event-free survival (EFS)(60 weeks)
- Objective response rate (ORR)(18 weeks)
- Safety and tolerability(From enrollment to the end of treatment at 8 weeks)