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

Overview

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.

Interventions

• Drug SHR- A1811
  SHR-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 pro

Primary outcome measures

• Pathologic complete response (pCR) [Time frame: At the time of definitive surgery, approximately 24 weeks after study entry]

Secondary outcome measures (3)

• 5-year Event-free survival (EFS) [Time frame: 60 weeks]
• Objective response rate (ORR) [Time frame: 18 weeks]
• Safety and tolerability [Time frame: From enrollment to the end of treatment at 8 weeks]

Eligibility criteria

Inclusion criteria

• 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.
• At least one measurable lesion per RECIST v1.1 criteria.
• ECOG performance status 0-1.
• 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.

Exclusion criteria

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07307287 · OBU-BC-II-280

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗