Trastuzumab Rezetecan Neoadjuvant Therapy in THP-Insensitive HER2-Positive Early Breast Cancer

Official title

An Interventional, Multicenter Study of Trastuzumab Rezetecan as Neoadjuvant Therapy in Patients With THP-Insensitive HER2-Positive Early Breast Cancer

Overview

This study is a response-adapted, multicenter, interventional trial enrolling patients with HER2-positive early or locally advanced breast cancer. All enrolled patients will first receive 2 cycles of standard neoadjuvant THP regimen, consisting of a taxane, trastuzumab, and pertuzumab. After the initial 2-cycle treatment, tumor response will be evaluated by radiologic imaging and patient-derived organoid (PDO) drug sensitivity testing. Patients with an inadequate response to THP are defined as those with \<50% tumor size reduction on imaging, or failure to reach the PDO sensitivity threshold (\<80% tumor cell killing for HER2+/HR- tumors; \<60% for HER2+/HR+ tumors). These non-responders will switch to receive 4 cycles of trastuzumab rezetecan (SHR-A1811), a novel HER2-targeted antibody-drug conjugate (ADC). Patients with a favorable response (≥50% tumor reduction or meeting the PDO threshold) will continue with an additional 4 cycles of THP. The primary objective is to evaluate the pathologic complete response (pCR) rate in THP non-responders after switching to trastuzumab rezetecan. Secondary objectives include objective response rate (ORR), event-free survival (EFS), overall survival (OS), 3-year invasive disease-free survival (iDFS), and safety profiles of both treatment strategies. Outcomes in patients who continue THP will be described for exploratory purposes. A total of 124 patients will be enrolled. This response-adapted, individualized strategy aims to provide an effective option for HER2-positive breast cancer patients with an inadequate early response to conventional THP neoadjuvant therapy.

Interventions

• Drug THP Regimen (Taxane + Trastuzumab + Pertuzumab)
  Neoadjuvant combination therapy consisting of a taxane, trastuzumab, and pertuzumab. Administered as initial treatment to all patients, and continued for responders.
• Drug Trastuzumab Rezetecan (SHR-A1811)
  HER2-targeted antibody-drug conjugate (ADC). Administered to patients with inadequate response to initial THP therapy.

Primary outcome measures

• Pathologic Complete Response (tpCR) Rate [Time frame: Perioperative]

Secondary outcome measures (4)

• Objective Response Rate (ORR) [Time frame: Up to 24 weeks]
• Event-Free Survival (EFS) [Time frame: From study enrollment up to 3 years after the last patient is enrolled]
• Overall Survival (OS) [Time frame: From study enrollment up to 5 years after the last patient is enrolled]
• 3-Year Invasive Disease-Free Survival (iDFS) Rate [Time frame: 3 years after study enrollment]

Eligibility criteria

Inclusion criteria

• 1.Age ≥18 years. For premenopausal and perimenopausal patients, a negative pregnancy test is required, and the patient must agree to use effective contraception during treatment.
• 2.Pathologically confirmed invasive breast cancer, stage II-III according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system, with HER2-positive disease defined as: immunohistochemistry (IHC) 3+; or IHC 2+ with confirmed HER2 gene amplification by fluorescence in situ hybridization (FISH).
• 3.At least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
• 4.No prior chemotherapy, immunotherapy, endocrine therapy, radical surgery, or radiotherapy for breast cancer.
• 5.Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• 6.Ability to understand and provide written informed consent.
• 7.Adequate organ function as evidenced by the following laboratory values:
• Hemoglobin ≥90 g/L
• White blood cell count ≥3.5×10⁹/L
• Platelet count ≥100×10⁹/L
• Neutrophil count ≥1.5×10⁹/L
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3× upper limit of normal (ULN)
• Total bilirubin ≤1.5×ULN
• Serum creatinine ≤1.5×ULN
• 8.No evidence of myocardial ischemia on electrocardiogram (ECG); New York Heart Association (NYHA) functional class I; left ventricular ejection fraction (LVEF) ≥55% on echocardiogram; cardiac biomarkers (cardiac troponin I \[cTnI\] and B-type natriuretic peptide \[BNP\]) within normal limits.
• 9.All required baseline laboratory and radiologic examinations completed prior to neoadjuvant therapy.
• 10.No dysphagia.
• 11.Availability of complete clinical data.

Exclusion criteria

• 1.Male breast cancer or inflammatory breast cancer.
• 2.Metastatic breast cancer (Stage IV).
• 3.Presence of other concurrent malignancies or history of malignancy other than breast cancer within the past 5 years, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
• 4.Receipt of any other concurrent anti-cancer therapy or participation in another clinical trial.
• 5.Presence of severe non-malignant disease that would compromise patient compliance or place the patient at unacceptable risk.
• 6.Major surgical procedure within 4 weeks prior to initiation of study treatment, or anticipated need for major surgery during the study period.
• 7.Receipt of radiotherapy, chemotherapy, molecular targeted therapy, endocrine therapy, or major breast surgery for breast cancer within 4 weeks prior to study treatment; current or prior use of HER2-targeted monoclonal antibodies, HER2-targeted antibody-drug conjugates (ADCs), or tyrosine kinase inhibitors (TKIs).
• 8.History of hypersensitivity or contraindication to any component of the study drugs.
• 9.Poorly controlled cardiac symptoms or diseases, including: New York Heart Association (NYHA) Class II or higher heart failure; unstable angina; myocardial infarction within 1 year; clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention.

Dementia, intellectual disability, or any psychiatric disorder that impairs the ability to understand the informed consent form.

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

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital of Soochow University — Suzhou

Identifiers

NCT: NCT07647263 · 26-OBU-JS-BC-II-016

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗