A Clinical Study on Hormone Receptor Positive HER2 Positive Breast Cancer of RCB1-2 After Neoadjuvant Treatment with Trastuzumab Combined with Parezumab

Research background: Neratinib is an irreversible pan HER tyrosine kinase inhibitor, which belongs to one of tyrosine kinase inhibitors (TKI). In the non pCR HER2 positive breast cancer patients after neoadjuvant therapy, there is no study on macromolecular anti HER2 drugs combined with TKI drugs to treat HER2 positive breast cancer patients after neoadjuvant therapy. In addition, there is no prospective randomized controlled study results of trastuzumab combined with patuzumab versus trastuzumab combined with TKI drugs for HER2 positive breast cancer patients with RCBI-II after new adjuvant treatment. To sum up, this study is intended to design and evaluate the efficacy and safety of trastuzumab combined with nelatinib in the treatment of hormone receptor positive HER2 positive breast cancer RCBI-II patients after the new adjuvant treatment of trastuzumab combined with patouzumab.

Objective: This study was designed to evaluate the efficacy and safety of trestuzumab combined with nelatinib in the adjuvant treatment of breast cancer patients with hormone receptor positive HER2 positive RCB I-II after the neoadjuvant treatment of trestuzumab combined with partuzumab.

Trial design: Single center, randomized controlled phase III clinical study.

Study content: Study content: The qualified subjects will be randomly (1:1) treated with the following scheme:

Treatment plan:

Experimental group: Trastuzumab combined with nelatinib

Control group: Trastuzumab combined with Parstuzumab

Nilatinib: Take 240 mg (6 tablets) orally once a day, which can be taken with food every 21 days as a cycle. After surgery, it starts to be used together with trastuzumab, and stops the next cycle when trastuzumab treatment is completed.

Trastuzumab: loading dose 8mg/kg, maintenance dose 6mg/kg, intravenous infusion, once every three weeks, with a total of 18 cycles during the new adjuvant treatment.

Patuzumab: loading dose 840mg/kg, maintenance dose 420mg, intravenous infusion, once every three weeks, with a total of 18 cycles during the new adjuvant treatment.

Observation index: main index: Invasive disease free survival (IDFS) refers to the time from randomization to the first occurrence of local or distant disease recurrence or death.

Secondary indicators: 1. Disease free survival (DFS): refers to the time from randomization to disease recurrence or death due to disease progression.

2. Overall survival (OS): the time from randomization to death from any cause.

3. Distant disease free survival (DDFS): the time when no metastatic lesion was found in other places except the primary lesion after treatment.

4. Incidence and severity of adverse events


Eligibility Criteria:
Inclusion Criteria:

1. Female patients ≥ 18 years old and ≤ 70 years old;
2. ECOG score 0-1;
3. The clinical staging at the time of initial diagnosis (according to the 8th edition of the American Joint Commission on Cancer \[AJCC\] Cancer Staging Manual): cT4/any N/M0, any cT/N2 - 3/M0 or cT1-3/N0-1/M0 (cT1mi/T1a/T1b/N0 patients are not eligible) at the time of initial diagnosis meets the new adjuvant treatment standard (NCCN2022 guidance of the National Comprehensive Cancer Network of the United States). The primary invasive lesions and lymph nodes of the breast must meet the following conditions: histologically confirmed invasive breast cancer; After receiving the new adjuvant treatment and completing the surgery, the pathology showed that there was residual invasive cancer in the breast or axillary lymph nodes and the RCB rating was 1-2; HER2 pathological test result is positive, which is defined as the result of immunohistochemistry (IHC) test is 3+or the result of in situ hybridization (ISH) is HER2 gene amplification (HER2/CEP17 ≥ 2.0 or average HER2 copy number/cell ≥ 6); There was no recurrence or metastatic disease before adjuvant treatment after operation.
4. Trastuzumab+Parstuzumab were applied in the new auxiliary stage and the treatment time was ≥ 12 weeks or 4 dosing cycles. No residual lesions were found at the resection margin of breast surgery specimen. Axilla can accept sentinel lymph node biopsy or axillary lymph node dissection (patients receiving axillary lymph node biopsy should meet the NCCN guidelines for sentinel lymph node biopsy after new adjuvant treatment). The operation and pathology showed that HER2 positive breast cancer patients did not reach complete pathological remission (non pCR) and RCB grade was 1-2. The time from initial operation to randomization was less than 12 weeks;
5. Hormone receptor positive (definition: immunohistochemistry estrogen receptor ≥ 1%, and/or progesterone receptor ≥ 1%), HER2 positive (definition: standard immunohistochemistry 3+or ISH positive);
6. The functional level of the main organs must meet the following requirements (no blood transfusion, no use of leukopenia and platelet raising drugs within 2 weeks before screening):

   Neutrophil (ANC) ≥ 1.5 × 109/L；

   Platelet count (PLT) ≥ 90 × 109/L；

   Hemoglobin (Hb) ≥ 90 g/L;

   Total bilirubin (TBIL) ≤ 1.5 × Upper limit of normal value (ULN);

   Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN；
7. After the completion of neoadjuvant therapy, echocardiography (ECHO) showed that the left ventricular ejection fraction (LVEF) in the screening period was ≥ 50% and the absolute decrease of LVEF was not more than 15% compared with that before chemotherapy. Or, if LVEF evaluation is not performed before chemotherapy, LVEF must be ≥ 55% in the screening period after completion of neoadjuvant therapy
8. Expected life ≥ 6 months
9. For female patients who have not undergone menopause or surgical sterilization: during the study treatment and within 8 weeks after the last administration of the drug during the study treatment, they agree to abstain or use effective non hormone contraceptive methods;
10. Volunteer to participate in the trial, sign the informed consent form, have good compliance and are willing to cooperate with follow-up.

Exclusion Criteria:

1. Recurrent disease of local or regional breast has occurred in the past;
2. The clinical staging of the tumor is stage IV (metastatic) breast cancer;
3. Bilateral breast cancer;
4. Any history of malignant tumors other than breast cancer in the past 5 years, excluding cured cervical carcinoma in situ, skin basal cell carcinoma or squamous cell carcinoma;
5. He has previously received treatment including pyrrolidine, lapatinib, neratinib or other tyrosine kinase inhibitors, entetrazumab (T-DM1), and other anti-tumor biological therapy or tumor immunotherapy;
6. At the same time, he received anti-tumor therapy in other clinical trials, including endocrine therapy, bisphosphonate therapy or immunotherapy;
7. Serious heart disease or discomfort, including but not limited to the following diseases: history of diagnosis of heart failure or systolic dysfunction (LVEF\<50%); High risk uncontrolled arrhythmia, such as atrial tachycardia, significant ventricular arrhythmia (such as ventricular tachycardia) or higher grade atrioventricular block; Angina pectoris requiring anti angina drugs; Valvular heart disease with clinical significance; ECG showed transmural myocardial infarction; The blood pressure of hypertensive patients was not well controlled by drugs (systolic blood pressure\>180 mmHg and/or diastolic blood pressure\>100 mmHg);
8. Inability to swallow, intestinal obstruction or other factors affecting drug administration and absorption;
9. Have a history of previously diagnosed neurological or mental disorders, including patients with involuntary behavior or mental illness;
10. Previous history of gastrointestinal diseases with diarrhea as the main symptom;
11. People who are known to have a history of allergy to the drug components of this protocol; Have a history of immunodeficiency, including HIV test positive, or other acquired or congenital immunodeficiency diseases, or have a history of organ transplantation;
12. Female patients in pregnancy and lactation, female patients with fertility and positive baseline pregnancy test;
13. Suffering from serious concomitant diseases or other concomitant diseases that will interfere with the planned treatment, including infectious diseases with active infection (including but not limited to active hepatitis B, active hepatitis C, active tuberculosis, active syphilis, etc.), or any other circumstances in which the researcher believes that the patient is not suitable to participate in the test.