A Phase Ⅱ Trial of Pyrotinib Combination With CDK4/6 Inhibitor SHR6390 in Patients Prior Trastuzumab-treated Advanced HER2-Positive Breast Cancer

Inclusion Criteria:

1. Metastatic HER2-Positive breast cancer prior trastuzumab-treated;

2. 18-70 Years, female;

3. HER2-positive breast cancer(according to 2018 ASCO/CAP HER2 test guideline IHC 3+ orIHC 2+ and FISH, SISH or CISH+);

4. Status of hormone receptor is known, Estrogen receptor(ER) or Progesteronereceptor(PR) positive is defined as the percentage of cells positive for ER or PRexpression ≥ 10%;

5. ECOG performance status 0 or 1;

6. Life expectancy is not less than 12 weeks;

7. At least one measurable lesion according to RECIST 1.1;

8. Patients treated with systemic treatment for advanced / metastatic breast cancer≤1line;

9. Natural postmenopausal or OFS in Arm A;

10. Adequate function of major organs meets the following requirements (no bloodcomponents have been used within 7 days and cell growth factors have been used within 14 days before randomization):

• Neutrophils ≥ 1.5×10^9/L

• Platelets ≥ 100×10^9/L

• Hemoglobin ≥ 90g/L

• Total bilirubin≤ 1.5 × the upper limit of normal (ULN)

• ALT and AST ≤ 2.5 × ULN (ALT and AST≤5×ULN if liver metastasis)

• BUN and Cr ≤ 1.5 × ULN

• Left ventricular ejection fraction (LVEF) ≥ 50%

• QTcF ≤ 470 ms

Exclusion Criteria:

1. Patients with central nervous system metastasis (Excluding asymptomatic brainmetastases or CNS metastases stable by local treatment);

2. Unable to swallow, chronic diarrhea and intestinal obstruction, gastrointestinalabsorption disorders that interfere with drug absorption;

3. Patients who received radiotherapy, chemotherapy, surgery (excluding local puncture)or molecular targeted therapy within 4 weeks before admission; those who receivedanti-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.) havebeen used or are being used in the past;

6. Previously received any CDK4/6 inhibitor treatment;

7. Previously received Capecitabine in HR- patients;

8. Patients with other malignant tumors within 5 years or at the same time( except forcured skin basal cell carcinoma and cervical carcinoma in situ);

9. Patients receive any anti-tumor treatments other than the regimen;

10. Have a history of allergies to the drug components of this regimen,; history ofimmunodeficiency, including HIV positive, or other acquired or congenitalimmunodeficiency disease, history of organ transplantation;

11. Have severe heart disease;

12. According to the judgement of the researchers, any serious coexisting disease might beharmful to the patient's safety or avoid the patients from accomplishing thetreatment(e.g serious hypertension, diabetes, thyroid dysfunction,active infectionetc.);

13. Female patients during pregnancy and lactation, fertile women with positive baselinepregnancy tests or women of childbearing age who are unwilling to take effectivecontraceptive measures throughout the trial;

14. History of neurological or psychiatric disorders, including epilepsy or dementia;

15. Any other situation evaluated by researchers.