Pyrotinib in Combination With Neoadjuvant Chemotherapy in HR+/HER2- HER4 High Expression Breast Cancer Patients: A Phase II Trial

  • End date
    Dec 31, 2028
  • participants needed
  • sponsor
    Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Updated on 12 May 2021


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 total pathological complete response (pCR) rate. Secondary endpoints include the pCR rate in breast only, objective response rate(ORR), event-free survival, overall survival, and toxicity. We will also explore potential prognostic and predictive biomarkers.


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 In HR+/HER2- tumor xenografts, Pyrotinib has been observed to inhibit tumor growth in a dose-dependent manner(unpublished data).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 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 24 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 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.

Condition Breast Cancer, Breast Cancer, Breast Cancer Diagnosis, Hormone Receptor Positive Breast Cancer, breast carcinoma, cancer, breast
Treatment cyclophosphamide, docetaxel, Placebo, Epirubicin, Pyrotinib, doxorubicin hydrochloride liposome injection, nab paclitaxel
Clinical Study IdentifierNCT04872985
SponsorSun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Last Modified on12 May 2021


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Inclusion Criteria

Presenting with histological(by core needle biopsy or by limited incisional biopsy) proven hormone receptor positive (ER10% 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): WBC3.0x109/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 cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) 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
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