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

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

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.

Study Overview

• Status: Recruiting
• Conditions: HER2-positive Breast Cancer
• Intervention / Treatment: Drug: THP Regimen (Taxane + Trastuzumab + Pertuzumab); Drug: Trastuzumab Rezetecan (SHR-A1811)

• Study Type: Interventional
• Enrollment (Estimated): 124
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hao Zhou; Phone Number: +8613862097709; Email: dlou515@163.com

Study Locations

• China
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • Recruiting
      • The First Affiliated Hospital of Soochow University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: THP Continuation Arm; All patients first receive 2 cycles of neoadjuvant THP (taxane + trastuzumab + pertuzumab). Patients with favorable response (≥50% tumor reduction or meeting PDO sensitivity threshold) continue with 4 additional cycles of THP.	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.
Experimental: SHR-A1811 Switch Arm; All patients first receive 2 cycles of neoadjuvant THP (taxane + trastuzumab + pertuzumab). Patients with inadequate response (<50% tumor reduction or failing PDO sensitivity threshold) switch to 4 cycles of trastuzumab rezetecan (SHR-A1811).	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response (tpCR) Rate	Proportion of patients achieving pathologic complete response (tpCR), defined as the absence of invasive carcinoma in both the breast primary lesion and axillary lymph nodes (ypT0/is ypN0) after neoadjuvant therapy and surgery. Ductal carcinoma in situ (DCIS) is allowed.	Perioperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Proportion of patients achieving complete response (CR) or partial response (PR) as assessed by the investigator according to RECIST version 1.1 criteria.	Up to 24 weeks
Event-Free Survival (EFS)	Time from study enrollment to the first occurrence of invasive disease recurrence (local, regional, or distant), death from any cause, or contralateral invasive breast cancer.	From study enrollment up to 3 years after the last patient is enrolled
Overall Survival (OS)	Time from study enrollment to death from any cause.	From study enrollment up to 5 years after the last patient is enrolled
3-Year Invasive Disease-Free Survival (iDFS) Rate	Proportion of patients alive and free from invasive breast cancer recurrence (local, regional, or distant) or contralateral invasive breast cancer at 3 years after study enrollment.	3 years after study enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	Incidence, nature, and severity of adverse events (AEs), including serious adverse events (SAEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Exposure to study treatment will also be summarized.	From the first dose of study treatment up to 30 days after the last dose

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Soochow University
• Investigators: Study Chair: Zhaoji Guo, The First Affiliated Hospital of Soochow University

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): December 1, 2031

Study Registration Dates

• First Submitted: June 3, 2026
• First Submitted That Met QC Criteria: June 9, 2026
• First Posted (Actual): June 15, 2026

Study Record Updates

• Last Update Posted (Actual): June 15, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Neoadjuvant therapy; HER2-positive; Trastuzumab rezetecan
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Trastuzumab; pertuzumab; taxane
• Other Study ID Numbers: 26-OBU-JS-BC-II-016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No