Adjuvant Trastuzumab Plus Neratinib in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer After Neoadjuvant Trastuzumab Plus Pertuzumab

A Randomized, Open-Label, Phase III Trial Comparing Adjuvant Trastuzumab Plus Neratinib Versus Trastuzumab Plus Pertuzumab in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer With Residual Cancer Burden 0/I After Neoadjuvant Trastuzumab Plus Pertuzumab

Neratinib is an irreversible pan-HER tyrosine kinase inhibitor (TKI). Currently, no studies have investigated the use of macromolecular anti-HER2 agents combined with TKIs for the treatment of non-pCR HER2-positive breast cancer following neoadjuvant therapy. Furthermore, there are no prospective randomized controlled trials comparing trastuzumab plus pertuzumab versus trastuzumab plus TKIs in HER2-positive breast cancer patients with residual cancer burden class (RCB) I or II after neoadjuvant trastuzumab and pertuzumab. Therefore, this study aimed to evaluate the efficacy and safety of adjuvant trastuzumab plus neratinib in patients with hormone receptor-positive/HER2-positive breast cancer and RCB 0/I following neoadjuvant trastuzumab and pertuzumab therapy.

Study Overview

• Status: Recruiting
• Conditions: HER2-positive Breast Cancer; Early-stage Breast Cancer; Adjuvant Treatment After Trastuzumab; RCB Classification 1-2; Neratini
• Intervention / Treatment: Drug: Trastuzumab and Pertuzumab; Drug: Trastuzumab and neratinib

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: chang Gong; Phone Number: 13925089353; Email: gchang@mail.sysu.edu.cn

Study Locations

• China
  • Guangzhou, China
    • Recruiting
    • Sun Yat-sen University Sun Yat-sen Memorial Hospital
    • Contact: chang Gong; Phone Number: 13925089353; Email: gchang@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female patients aged 18-70 years;
2. Eastern Cooperative Oncology Group performance status of 0 or 1;
3. Clinical stage at initial diagnosis (per the 8th edition of the American Joint Committee on Cancer Staging Manual): cT1-4/N1-3/M0 (cT1mi/N0 or cT1a-b/N0 are eligible), meeting the criteria for neoadjuvant therapy as per NCCN 2022 guidelines;
4. Histologically confirmed hormone receptor-positive (estrogen receptor ≥1% and/or progesterone receptor ≥1%) and HER2-positive (immunohistochemistry 3+ or fluorescence in situ hybridization-positive) invasive breast cancer;
5. Completion of ≥4 cycles of neoadjuvant therapy with trastuzumab and pertuzumab, without recurrence or metastatic disease prior to adjuvant treatment; residual cancer burden class 0 or I after neoadjuvant therapy; time from initial surgery to randomization ≤12 weeks;

6. Adequate organ function within 2 weeks prior to screening (without transfusion or use of growth factors):

   • Absolute neutrophil count ≥1.5 × 10⁹/L;
   • Platelet count ≥90 × 10⁹/L;
   • Hemoglobin ≥90 g/L;
   • Total bilirubin ≤1.5 × upper limit of normal (ULN);
   • Alanine aminotransferase and aspartate aminotransferase ≤1.5 × ULN;
7. Post-neoadjuvant therapy echocardiography showing left ventricular ejection fraction (LVEF) ≥50% during screening, with an absolute decrease of ≤15% compared to pre-chemotherapy values; if no pre-chemotherapy LVEF assessment is available, LVEF must be ≥55% during screening;
8. Life expectancy ≥6 months;
9. For premenopausal or non-sterilized female patients: agreement to abstain from sexual activity or use effective non-hormonal contraception during study treatment and for 8 weeks after the last dose;
10. Willingness to participate voluntarily, provide signed informed consent, demonstrate good compliance, and cooperate with follow-up.

Exclusion Criteria:

1. History of local or regional breast cancer recurrence;
2. Clinical stage IV (metastatic) breast cancer;
3. Bilateral breast cancer;
4. History of other malignant tumors within the past 5 years, except for curatively treated cervical carcinoma in situ, basal cell carcinoma, or cutaneous squamous cell carcinoma;
5. Prior treatment with pyrotinib, lapatinib, neratinib, or other tyrosine kinase inhibitors; trastuzumab emtansine; or any antitumor biological or immunotherapy;
6. Concurrent participation in another clinical trial involving antitumor therapy, including endocrine therapy, bisphosphonate therapy, or immunotherapy;

7. Significant cardiac disease, including:

   • Heart failure or systolic dysfunction (LVEF < 50%);
   • Poorly controlled arrhythmias (e.g., atrial tachycardia, significant ventricular arrhythmia, or high-grade atrioventricular block);
   • Angina requiring antianginal medication;
   • Clinically significant valvular heart disease;
   • Electrocardiographic evidence of transmural myocardial infarction;
   • Poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg) despite medication;
8. Impaired drug absorption due to dysphagia, intestinal obstruction, or other gastrointestinal disorders;
9. History of neurological or psychiatric conditions that may compromise compliance or informed consent;
10. Chronic gastrointestinal disorders with predominant diarrhea;
11. Known hypersensitivity to any study drug components; history of immunodeficiency (e.g., HIV positivity, congenital or acquired immunodeficiency disorder), or prior organ transplantation;
12. Pregnancy, lactation, or positive pregnancy test at baseline in women of childbearing potential;
13. Severe comorbidities that may interfere with treatment, including active infections (e.g., hepatitis B, hepatitis C, tuberculosis, syphilis) or any other condition deemed by the investigator to render the patient unsuitable for trial participation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Trastuzumab combined with Pertuzumab; Trastuzumab (8 mg/kg IV loading dose, followed by 6 mg/kg IV once every 3 weeks), and pertuzumab (840 mg IV loading dose, followed by 420 mg IV once every 3 weeks). This regimen will be repeated for a total of 18 cycles,encompassing both the preoperative and adjuvant phases.	Drug: Trastuzumab and Pertuzumab; Trastuzumab (8 mg/kg IV loading dose, followed by 6 mg/kg IV once every 3 weeks), and pertuzumab (840 mg IV loading dose, followed by 420 mg IV once every 3 weeks). This regimen will be repeated for a total of 18 cycles,encompassing both the preoperative and adjuvant phases.
Experimental: Trastuzumab combined with neratinib; Trastuzumab (8 mg/kg IV loading dose, followed by 6 mg/kg IV once every 3 weeks), and neratinib 240 mg orally once daily. The trastuzumab treatment will be continued for a total of 18 cycles, encompassing both the preoperative and adjuvant phases, while neratinib will be maintained throughout the adjuvant period.	Drug: Trastuzumab and neratinib; Trastuzumab (8 mg/kg IV loading dose, followed by 6 mg/kg IV once every 3 weeks), and neratinib 240 mg orally once daily. The trastuzumab treatment will be continued for a total of 18 cycles, encompassing both the preoperative and adjuvant phases, while neratinib will be maintained throughout the adjuvant period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Invasive disease free survival, IDFS	The time from random assignment until the first occurrence of invasive disease recurrence, distant recurrence, or death from any cause.	During the 3 years after random assignment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival, DFS	The time from random assignment until recurrence, the development of a second cancer, or death from any cause.	During the 3 years after random assignment
Overall survival, OS	The time from randomization to death from any cause.	During the 3 years after random assignment
Distant disease free survival, DDFS	The time from random assignment until the first occurrence of distant recurrence or death from any cause.	During the 3 years after random assignment
Incidence and severity of adverse events	The incidence and severity of adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).	From signing the informed consent form until 28 days after completion of adjuvant treatment

Collaborators and Investigators

• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2023
• Primary Completion (Estimated): February 16, 2028
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: February 26, 2023
• First Submitted That Met QC Criteria: February 26, 2023
• First Posted (Actual): March 8, 2023

Study Record Updates

• Last Update Posted (Estimated): September 25, 2025
• Last Update Submitted That Met QC Criteria: September 21, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: adjuvant therapy; targeted therapy; Hormone receptor positive HER2 positive breast cancer
• 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; neratinib
• Other Study ID Numbers: SYSKY-2023-075-03

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
• product manufactured in and exported from the U.S.: No