Evaluate the safety and efficacy of Pyrotinib in the transition from low-dose to normal-dose regimen for HER2-positive advanced first-line breast cancer

This study is planned to include 102 patients with HER2-positive advanced breast cancer meeting the admission criteria between 2023-12-01 and 2024-11-01. Statistical software will be used by the randomization officers for 1:1 allocation to pyrotinib dose increasing trial group and normal pyrotinib dose control group .

The primary endpoint of this study was grade ≥3 treatment-emergent diarrhea incidence during the first 2 cycles according to Common Terminology Criteria for Adverse Events, version 5.0, and secondary endpoints were adverse effects of pyrotinib during the study, efficacy (progression-free survival and overall survival), and patient-reported outcome.

Inclusion Criteria:

1. The subjects voluntarily joins the study and signs the informed consent;
2. Subject is an adult female ≥ 18 years old and ≤ 70 years old at the time of informed consent.
3. HER2-positive advanced breast cancer confirmed by pathology (HER2-positive expression refers to those with at least one tumor cell immunohistochemical staining intensity of 3+ or 2+ positive by fluorescence in situ hybridization [FISH] in the pathological examination/review of the primary or metastatic lesion conducted by the pathology department of the Central Hospital)
4. Stage IV breast cancer according to American Joint Committee on Cancer(AJCC) staging system version 8.
5. Subjects did not receive systemic antitumor therapy at the stage of recurrence/metastasis;
6. At least one measurable lesion according to Response Evaluation Criteria In Solid Tumors version 1.1 criteria
7. When randomized, Eastern Cooperative Oncology Group(ECGO) physical fitness status is 0 or 1 point.
8. Vital organ function meets the following requirements (excluding the use of any blood components and cell growth factors during screening) : Absolute neutrophil (ANC) count ≥1.5×109/L; Platelet (PLT) ≥100×109/L; Hemoglobin (HB) ≥9g/dL; Serum albumin ≥3g/dL; Thyroid stimulating hormone (TSH) ≤ULN (if abnormal, T3 and T4 levels should be investigated at the same time, if T3 and T4 levels are normal, they can be included in the group); Bilirubin ≤1.5 ULN; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times ULN; Alkaline phosphatase (AKP) ≤ 2.5 times ULN; Serum creatinine (Cr) ≤1.5 times ULN or creatinine clearance ≥60mL/min.

Exclusion Criteria:

1. Any previous tyrosine kinase inhibitor therapy against HER2 target;
2. Patients with known active central nervous system metastases without surgery or radiation therapy, except those who have been stable for at least 1 month after treatment and have been off corticosteroids for >2 weeks;
3. Pial metastasis confirmed by MRI or lumbar puncture;
4. Inflammatory breast cancer or other malignancies within the previous 5 years, excluding cured basal cell carcinoma of the skin and carcinoma in situ of the cervix;
5. Any antitumor therapy within 4 weeks prior to enrollment;
6. Pregnant or breastfeeding women (women of childbearing age must have a negative pregnancy test within 14 days prior to the first dose, if positive, the pregnancy must be ruled out by ultrasound);
7. Patients with gastrointestinal insufficiency or gastrointestinal disease significantly affecting the absorption of the investigational drug (e.g., uncontrolled ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or resection of the small intestine);
8. Patients with ascites, pleural effusion and pericardial effusion accompanied by clinical symptoms requiring drainage at baseline, or patients with serosal effusion drainage within 4 weeks before the first medication;
9. Patients with a history of immunodeficiency, including HIV testing positive, other acquired or congenital immunodeficiency diseases, or a history of organ transplantation;
10. Patients with a major surgical procedure or significant trauma within 4 weeks before starting treatment, or expected to undergo major surgery;
11. Concomitant medical conditions (e.g., severe hypertension, diabetes, thyroid disease, co-active hepatitis B/C, and other active infections, etc.) that are deemed by the investigator to seriously endanger the patient's safety or to interfere with the patient's completion of the study;
12. Inability to understand or follow research instructions and requirements;
13. The investigator considers the patient unsuitable for entry into this study.

Patient is an adult female ≥ 18 years old and ≤ 70 years old at the time of informed consent.