Pyrotinib Plus Neoadjuvant Chemotherapy in HR+/HER2-, HER4-High Breast Cancer

Efficacy and Safety of Pyrotinib in Combination With Neoadjuvant Chemotherapy in Stage II-III HR+/HER2-, HER4 High Expression Breast Cancer Patients: A Phase II, Single-center, Randomized, Double-Blinded, Placebo-Controlled Trial

This is a Phase II, single-center, double-blind, placebo-controlled, randomized study of Pyrotinib in combination with Doxorubicin/Epirubicin and Cyclophosphamide followed by Docetaxel/nab-Paclitaxel as neoadjuvant therapy for women with hormone receptor positive HER2-negative stage II to III breast cancer. Patients randomized to the study arm/control arm will receive standard neoadjuvant chemotherapy in combination with pyrotinib/placebo, respectively. The primary endpoint of the study is the residual cancer burden 0/I (RCB 0/I) and total pathological complete response (tpCR) rate. Secondary endpoints include the breast pCR (bpCR) rate, objective response rate(ORR), event-free survival (EFS), overall survival (OS), rate of change in the Ki-67 proliferation index, correlations between potential biomarkers and treatment efficacy, and toxicity.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer; Hormone-receptor Positive Breast Cancer
• Intervention / Treatment: Drug: Epirubicin; Drug: Doxorubicin Hydrochloride Liposome Injection; Drug: Cyclophosphamide; Drug: Docetaxel; Drug: Placebo; Drug: Pyrotinib; Drug: Nab paclitaxel

Detailed Description

Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI) with activity against epidermal growth factor receptor HER1(EGFR), HER2 and HER4. Improvement of the chemotherapy efficacy and good tolerability have been shown by several stage II and III clinical trials in both the neoadjuvant and metastasis setting in HER2-positive breast cancers. Yet, the anti-tumor effect of Pyrotinib by targeting HER4 has not been determined. Preclinical studies show that HER4 is relatively highly expressed in hormone receptor positive and HER2-negative(HR+/HER2-) breast cancers. In MCF7 cell lines, Pyrotinib effectively repressed phosphorylation of MAPK and Akt signal transduction pathways to inhibit tumor cell proliferation. In HR+/HER2- tumor xenografts, Pyrotinib has been observed to inhibit tumor growth in a dose-dependent manner (unpublished data). Taken together, the data support the rationale that Pyrotinib may be efficacious in HER4 high expressed HR+/HER2- breast cancer and in combination with chemotherapy may lead to a better RCB 0/I and pCR rate in the neoadjuvant setting.

The study is a two-arm design with a 1:1 allocation ratio (equal numbers of patients randomized to Arms 1, 2). The sample size will be up to 140 patients with about 70 evaluable patients in each arm. Accrual is expected to occur over 48 months. Patients will be randomized to one of the two neoadjuvant therapy regimens: Patients in Arm 1 will be assigned to receive 400 mg Pyrotinib orally once per day with four cycles of epirubicin (100 mg/m2) (or doxorubicin hydrochloride liposome injection 30mg/m2) and cyclophosphamide (600 mg/m2) intravenously, once every 3 weeks, followed by four cycles of docetaxel (100 mg/m2) intravenously, once every 3 weeks(or nab-paclitaxel 260mg/m2 q3w, or 12 cycles of weekly nab-paclitaxel 120 mg/m2) . Dosage reduction of pyrotinib is permitted from 400 mg to 320 mg or 240 mg if Pyrotinib-related AEs are experienced. In Arm 2 (control), Pyrotinib will be replaced by 400mg placebo provided by the same pharmacy company.

In all arms, clinical response will be evaluated by breast MRI. The primary endpoint will be assessed with the paraffin embedded pathological specimens collected from surgery. Submission of tumor samples for the correlative science studies will be optional for all patients. For patients who agree, pathological sections of core biopsy specimen before treatment (after the patient has signed the consent form and has been screened for eligibility) and pathological sections of surgery residual disease specimen after the completion of the treatment are collected. In addition, a blood sample collected after randomization (before the start of study therapy and after the completion of the neoadjuvant therapy) will also be required for the correlative studies.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510120
      • Sun-Yat-Sen Memorial Hospital of Sun-Yat-Sen University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Presenting with histological(by core needle biopsy or by limited incisional biopsy) proven hormone receptor positive (ER≥10% and/or PR ≥1%), HER2 negative(IHC ≤2+ and/or FISH-) , stage II/ III breast cancer.
• Have clinical indication for neoadjuvant therapy.
• HER4 IHC score ≥ 4.
• Measurable disease (breast and/or lymph nodes).
• The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1.
• Adequate bone marrow function (within 4 weeks prior to registration): WBC≥3.0x109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l.
• Adequate liver function (within 4 weeks prior to registration): bilirubin ≤1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL.
• Adequate renal function (within 4 weeks prior to registration): the calculated creatinine clearance should be ≥50 ml/min.
• Patients must have the ability to swallow oral medication.
• Without history of any kind of treatment to known malignancy (solid tumor or hematologic).
• Written informed consent.
• Accessible for treatment and follow-up.

Exclusion Criteria:

• Evidence of stage IV breast cancer.
• Contralateral invasive breast cancer or Inflammatory breast cancer.
• History of non-breast malignancies (except for in situ cervical cancers, basal cell carcinoma of the skin, squamous cell carcinomas of the skin or thyroid papillary carcinoma that had received curative treatment before enrollment) within 5 years prior to randomization.
• Known metastatic disease from any malignancy (solid tumor or hematologic).
• Serious other diseases as infections (hepatitis B, C and HIV), recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias or on screening, any of the following cardiac parameters: bradycardia (heart rate <50 at rest) or QTcF ≥450 msec.
• Known hypersensitivity reaction to any of the components of the treatment.
• Pregnancy or lactation at the time of randomization.
• Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Pyrotinib+ AC/EC followed by T; 400 mg Pyrotinib orally once per day with four cycles of epirubicin (100 mg/m2) (or doxorubicin hydrochloride liposome injection 30mg/m2) and cyclophosphamide (600 mg/m2) intravenously, once every 3 weeks, followed by four cycles of docetaxel (100 mg/m2) intravenously, once every 3 weeks (or 260mg/m2 nab-paclitaxel once every 3 weeks for 4 cycles, or 12 cycles of weekly nab-paclitaxel 120mg/m2 intravenously). Pyrotinib starts with a dose of 240 mg once daily for one week, followed by 320 mg once daily for the next week, before transitioning to 400 mg once daily as maintenance therapy.	Drug: Epirubicin; 100 mg/m2,q3W*4; Other Names: E; Drug: Doxorubicin Hydrochloride Liposome Injection; 30mg/m2, q3w*4; Other Names: A; Drug: Cyclophosphamide; 600 mg/m2, q3w*4; Other Names: C; Drug: Docetaxel; 100 mg/m2, q3w*4; Other Names: T; Drug: Pyrotinib; 400 mg orally once per day. Pyrotinib starts with a dose of 240 mg once daily for one week, followed by 320 mg once daily for the next week, before transitioning to 400 mg once daily as maintenance therapy.; Drug: Nab paclitaxel; 120mg/m2 qw*12 or 260mg/m2 q3w*4
Placebo Comparator: Arm 2: Placebo+ AC/EC followed by T; 400 mg placebo orally once per day with four cycles of epirubicin (100 mg/m2) (or doxorubicin hydrochloride liposome injection 30mg/m2) and cyclophosphamide (600 mg/m2) intravenously, once every 3 weeks, followed by four cycles of docetaxel (100 mg/m2) intravenously, once every 3 weeks (or 260mg/m2 nab-paclitaxel once every 3 weeks for 4 cycles, or 12 cycles of weekly nab-paclitaxel 120mg/m2 intravenously) .	Drug: Epirubicin; 100 mg/m2,q3W*4; Other Names: E; Drug: Doxorubicin Hydrochloride Liposome Injection; 30mg/m2, q3w*4; Other Names: A; Drug: Cyclophosphamide; 600 mg/m2, q3w*4; Other Names: C; Drug: Docetaxel; 100 mg/m2, q3w*4; Other Names: T; Drug: Placebo; 400 mg orally once per day; Drug: Nab paclitaxel; 120mg/m2 qw*12 or 260mg/m2 q3w*4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RCB 0/I (Residual cancer burden 0/I) rate	defined as the proportion of patients whose surgical specimens after neoadjuvant therapy were pathologically assessed as RCB 0 or RCB I.	At the time of surgery
tpCR (total pCR) rate	ypT0/isN0, number of participants with by no histologic evidence of invasive tumor cells in the surgical breast and axillary specimen.	At the time of surgery.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EFS (event-free survival) at 3 and 5 years	EFS is defined as the time from randomization to the date of progression(according to RECIST 1.1 ) of disease that precludes surgery, local relapse, regional relapse, distant relapse, second primary invasive breast cancer including contralateral breast cancer, or death due to any cause which ever occurred first.	EFS will be determined at 3 and 5 years after randomization
OS (overall survival) at 3 and 5 years	OS is defined as the time from randomization to date of death.	OS will be determined at 3 and 5 years after randomization
The correlation of potential biomarkers with EFS and OS.	We will used immunohistochemistry (IHC) method to assess the positive percentage of ER, PR, Ki67%, as well as the HER4 scores, and the status EGFR, HER3, and PD-L1 of the specimen from primary core biopsy at baseline, as well as the residual surgical specimen after neoadjuvant chemotherapy. The IHC4 score will be calculated using our modified method (Jin et al. Oncologist. 2020 Aug;25(8):e1170-e1180.). The correlation between these biomarkers with EFS and OS will be analyzed	The correlation with EFS and OS will be performed at 5 years after the enrollment of the last patient.
The correlation between NGS sequencing and ctDNA data with clinical outcomes(Optional).	NGS sequencing will be performed with the pathological section of primary core biopsy and surgery residual specimen, and the ctDNA will be extracted from the patients' serum at baseline and the date of surgery, if with the agreement of participants. The correlation between these biomarkers with clinical outcomes (pCR and EFS) will be assessed when possible.	The correlation with pCR will be assessed when the surgery is performed on the last enrolled patients. The correlation with EFS and OS will be performed at 5 years after the enrollment of the last patient.
bpCR (breast pCR)	ypT0/is, number of participants with by no histologic evidence of invasive tumor cells in the surgical breast specimen.	At the time of surgery.
ORR (objective response) rate	the percentage of patients with a final overall response of CR or PR relative to the appropriate analysis set. Clinical response will be evaluated by breast MRI.	At the time of surgery.
Rate of change in the Ki-67 proliferation index	defined as change of Ki-67 expression in the tumor tissue before and after neoadjuvant therapy	Baseline and at the time of surgery
The correlation of potential biomarkers with the RCB 0/I, tpCR, bpCR and ORR rate.	We will used immunohistochemistry (IHC) method to assess the positive percentage of ER, PR, Ki67%, as well as the HER4 scores, and the status EGFR, HER3, and PD-L1 of the specimen from primary core biopsy at baseline. The IHC4 score will be calculated using our modified method (Jin et al. Oncologist. 2020 Aug;25(8):e1170-e1180.). The correlation between these biomarkers with treatment efficacy (RCB 0/I, tpCR, bpCR and ORR) will be explored.	The correlation with RCB 0/I, tpCR, bpCR and ORR will be assessed when the surgery is performed on the last enrolled patients.
AE (Adverse Event) and SAE (Serious Adverse Event) rate	Toxicities are graded according to NCI CTCAE v4.03.	Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.

Collaborators and Investigators

• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Collaborators: Jiangsu HengRui Medicine Co., Ltd.
• Investigators: Principal Investigator: Erwei Song, MD.,Phd., Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2021
• Primary Completion (Estimated): February 27, 2026
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: April 29, 2021
• First Submitted That Met QC Criteria: April 29, 2021
• First Posted (Actual): May 5, 2021

Study Record Updates

• Last Update Posted (Estimated): January 6, 2026
• Last Update Submitted That Met QC Criteria: January 2, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Pyrotinib; HER4; Pan-HER TKI
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Organic Chemicals; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Taxoids; Cyclodecanes; Diterpenes; Health Care Economics and Organizations; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Anthracyclines; Naphthacenes; Aminoglycosides; Daunorubicin; Doxorubicin; Economics; Docetaxel; Cyclophosphamide; Epirubicin; pyrotinib; Taxes
• Other Study ID Numbers: MA-BC-II-018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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