Treatment of Dalpiciclib Combined With Pyrotinib for Trastuzumab-sensitive HER2+ Advanced Breast Cancer(DAP-Her-02)

Based on different HR status, we explored the efficacy and safety of Pyrotinib and Dalpiciclib Isethionate Tablets based combination regimen in the first-line treatment of HER2 + MBC.

Cyclin D-CDK4/6-RB-E2F signaling pathway regulates the transformation of breast cancer cells from stage G1 to S, and plays an important role in the proliferation of breast cancer cells. HER2 protein regulates proliferation of breast cancer cells through PI3K/AKT signaling pathway. HER2 positive breast cancer patients need anti HER2 therapy. Data indicate that HER2 positive breast cancer patients often express cyclin D1 and E1, suggesting that anti HER2 therapy can synergy with CDK4/6 inhibitors.

A preclinical study shows that the combination of CDK4/6 inhibitor Dulcie and anti HER2 drug pyrrolidone can effectively reduce the phosphorylation of AKT and HER3, thereby promoting the apoptosis of HER2 positive breast cancer cells and achieving the purpose of inhibiting tumor.

In the clinical study of na-phere 2, piperacillin combined with trastuzumab, patuzumab and fluvestrant can significantly inhibit the expression of Ki67. MonarcHER study shows that the treatment of patients with advanced HR+HER2+ breast cancer after the failure of anti HER2+ is better than conventional chemotherapy plus anti HER2 therapy. The successful challenge of traditional chemotherapy is the opening of a new chapter in the treatment of HR+/HER2+. In 2021, ESMO 276P reported the interim data of darcilil combined with pyrroltinib in the first-line / second-line treatment of MBC. HR -, HER2 + MBC ORR can reach 81.8%, and the safety is controllable.

Based on different HR status, we explored the efficacy and safety of Pyrotinib and Dalpiciclib Isethionate Tablets based combination regimen in the first-line treatment of HER2 + MBC.

Eligibility Criteria:
Inclusion Criteria:

1. Premenopausal / perimenopausal / postmenopausal women who aged ≥ 18 years
2. Suffering from non resectable locally advanced recurrent breast cancer or metastatic breast cancer
3. group A: Women who have breast cancer histopathologically confirmed by positive estrogen receptor (ER; \>10%), positive progesterone receptor (PR; \>1%), and positive human epidermal growth factor receptor 2 (HER2) according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) guideline. The pathological laboratory confirmed that the immunohistochemical (IHC) score was 3 +, or 2 +, and the in situ hybridization (ISH) test was positive (ISH amplification rate ≥ 2.0); (New) the end of trastuzumab treatment in the adjuvant treatment stage \> 12 months, recurrence and metastasis, or no trastuzumab treatment in the early stage; No adjuvant endocrine therapy or postoperative adjuvant endocrine therapy \> 24 months; Premenopausal or perimenopausal patients need to be combined with ofs (OFS includes bilateral ovariectomy or GnRHa drugs); group B: Women who have breast cancer histopathologically confirmed by negative estrogen receptor (ER), negative progesterone receptor (PR; \<1%), and positive human epidermal growth factor receptor 2 (HER2) according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) guideline. The pathological laboratory confirmed that the immunohistochemical (IHC) score was 3 +, or 2 +, and the in situ hybridization (ISH) test was positive (ISH amplification rate ≥ 2.0); (New) the end of trastuzumab treatment in the adjuvant treatment stage \> 12 months, recurrence and metastasis, or no trastuzumab treatment in the early stage;
4. No previous systematic treatment for advanced diseases
5. at least one measurable lesion or only bone metastasis according to RECIST 1.1.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0～1.
7. The patient must be able to swallow oral drugs
8. The functional level of organs must meet the following requirements:

   a) Bone marrow function i) Absolute neutrophil count（ANC）≥1.5×109/L (no use of growth factor within 14 days) ii) Platelet count（PLT）≥100×109/L (no corrective treatment within 7 days) iii) Hemoglobin level（Hb）≥100 g/L (no corrective treatment within 7 days) b) Liver and kidney function i) Total bilirubin（TBIL）≤1.5 upper limit of normal value (ULN) ii) Alanine transaminase (ALT) and aspartate transaminase (AST) ≤3×ULN iii) Blood urea nitrogen (BUN) and creatinine ≤1.5×ULN and creatinine clearance≥50 mL/min (Cockcroft-Gault formula); c) Color Doppler echocardiography: Left ventricular ejection fraction ≥50% d) 12-lead electrocardiography: QTc interval ≤480 ms
9. Volunteers to participate in the study, provision of signed informed consent, good compliance and willingness to cooperate with follow-ups.

Exclusion Criteria:

1. Patients with symptomatic brain metastasis;
2. Unable to swallow, chronic diarrhea and intestinal obstruction, there are many factors affecting drug use and absorption;
3. patient who received radiotherapy, chemotherapy, surgery (excluding local puncture) or molecular targeted therapy within 4 weeks before admission; those who received anti-tumor endocrine therapy after screening period;
4. Participated in other drug clinical trials within 4 weeks before admission;
5. Tyrosine kinase inhibitors targeting HER2 (Neratinib, Lapatinib, pyrotinib, etc.) have been used or are being used in the past;
6. Patients previously treated with any CDK4 / 6 inhibitor;
7. Those who have other malignant tumors (with the exception of healed cervical carcinoma in situ) occurring in the past 5 years;
8. Those who are known to have a history of allergy to the component of study drugs; those who have a history of immunodeficiency, including positive detection of human immunodeficiency virus, hepatitis C virus, active hepatitis B or other acquired, congenital immunodeficiency diseases, or organ transplantation;
9. Those who had suffered from any heart disease, including arrhythmia which requires drug treatment or is of clinical significance; myocardial infarction; heart failure; and any other heart disease judged by the investigator as unsuitable for this trial;
10. Pregnant and lactating women; fertile women who provide positive results of baseline pregnancy test; women of childbearing age who are unwilling to take effective contraceptive measures during the whole study period;
11. If the accompanying diseases (including, but not limited to, severe hypertension, severe diabetes, and active infection, which cannot be controlled by drugs) that would be a potential hazard to participant's health, or affect the completion of the study as per investigator's judgement;
12. Moderate infection occurs within 4 weeks before the first administration (e.g. intravenous drip of antibiotics, antifungal or antiviral drugs according to clinical criteria), fever（\> 38.5 ℃） of unknown origin occurs during the screening period/before the first administration.
13. A clear history of neurological or psychiatric disorders, including epilepsy or dementia.
14. Researchers believe that patients are not suitable for any other situation in this study.