A Phase Ⅲ Study of Hemay022 in Combination With AI In Advanced Breast Cancer

Inclusion Criteria:

1. Age ≥18 years old；

2. Subjects must give informed consent to the study before the study entry andvoluntarily sign a written informed consent form;

3. Breast cancer subjects diagnosed by pathology（histology or cytology）;

4. ER positive and HER2 over-expression (immunohistochemical IHC test 3+ and/or in situhybridization ISH test positive)；Previous test results are acceptable.

5. Advanced/metastatic breast cancer that has previously received treatment failurewith trastuzumab (or trastuzumab biosimilar) regimen;Or (new) adjuvant therapyduring treatment with trastuzumab (or trastuzumab biosimilar) or within 12 monthsafter the end of treatment, disease recurrence or progression；Patients withfirst-line systemic treatment for relapse (previously received trastuzumab ortrastuzumab biosimilars)；Or patients who are not suitable for trastuzumabtreatment；Patients who have failed previous anti-HER2-ADC drug therapy can also beincluded.

6. At least one lesion (measurable and/or non-measurable) that can be evaluated byCT/MRI and meets the reproducible evaluation requirements of RECIST V1.1;

7. ECOG Performance Status of 0-1;

8. The estimated survival time is more than 3 months;

9. Postmenopausal women Postmenopausal is defined as meeting any one of the following four conditions: Past bilateral oophorectomy; Age ≥60 years old; Age <60 years old, natural menopause ≥12 months, in the past 1 year without chemotherapy, tamoxifen, toremifene orovarian castration, the level of follicle stimulating hormone (FSH) and estradiolWithin the postmenopausal range (use the reference range of the local laboratory). Patients younger than 60 years old who are taking tamoxifen or toremifene, their FSHand estradiol levels are within the postmenopausal range (use the reference range ofthe local laboratory); Premenopausal or perimenopausal women who do not meet theabove-mentioned menopausal criteria can also be included in this study, but theymust also receive ovarian suppression therapy that meets the standards of medical orsurgical castration treatment. Drug ovarian suppression therapy has been started atleast 21 days before the start of this program, and Must be continued during thetreatment plan;

10. Adequate bone marrow, liver, kidney, and coagulation Bone Marrow Function (No bloodtransfusion or adjuvant leukocyte or platelet augmentation drugs were used within 1week before screening) Absolute value of neutrophils (ANC) ≥1.5×109/L Hemoglobin (HB) ≥90g/L (transfusion allowed) Platelet (PLT) ≥80×109/L Liver function Liverfunction grade Child-Pugh A/B (≤9 points) Alanine transferase (ALT) or aspartateaminotransferase (AST) ≤2.5 ULN in the absence of liver metastasis; ALT or AST≤ 5xULN with liver metastasis Renal function: serum creatinine ≤1.5 times ULN;

11. All previous treatment-related toxicities must be CTCAE (version 5.0) ≤ Grade 2 atthe time of randomization, except for hair loss, pigmentation, and long-termtoxicity caused by radiotherapy (which cannot be recovered by the investigator'sjudgment)；

12. Women patients of childbearing age (including their partners) have no pregnancy planand voluntarily take effective contraceptive measures from the signing of theinformed consent form to 3 months after the last medication.

Exclusion Criteria:

1. Patients with visceral crisis（Visceral crisis is defined as the dysfunction ofseveral organs confirmed by symptoms, signs, laboratory tests, and rapid diseaseprogression.Visceral crisis does not simply refer to the presence of visceralmetastases, but to critical visceral conditions that require rapid and effectivetreatment to control the disease progression, especially when the opportunity forchemotherapy is lost after progression）

2. Patients with the presence of spinal cord compression or brain, meningeal metastases

3. Patients who have been treated with a small molecule HER2 tyrosine kinase inhibitor (HER2-TKI) (medication course ≤2 weeks is excluded)

4. Have received radiotherapy within 4 weeks prior to study；

5. Have received chemotherapy for advanced breast cancer> 1 lines (the subjects whohave used chemotherapy drugs must have stopped the chemotherapy drugs for ≥ 4 weeksbefore being enrolled in this study);

6. Patients with parenteral nutrition; malabsorption syndrome; or any conditionpossibly affecting drug absorption or inability to tolerate oral medications;

7. Use of any drug that inhibits or induces hepatic metabolism of Hemay022 within 2weeks prior to study and entire study duration, for example CYP3A4 strong inhibitorsor strong inducers;

8. Patients who are known to have a history of allergies to Hemay022, lapatinib、AI (letrozole, exemestane) capecitabine or similar drugs.

9. Left ventricular ejection fraction (LVEF) <50％ as measured by echocardiogram or MUGAscan.

10. Positive blood for human immunodeficiency virus (HIV antibody); Positive hepatitis Bsurface antigen and HBV-DNA>upper limit of normal; Active hepatitis C virus (HCV)infection

11. Patients with active infection requiring intravenous anti-infective treatment

12. Arrhythmias requiring treatment , including atrial fibrillation, supraventriculartachycardia ,ventricular tachycardia, ventricular fibrillation, or patients withcoronary heart disease have symptoms requiring medicine treatment, myocardialinfarction within 1 year, congestive heart failure (CHF)

13. Confirmed QTc prolongation (≥500ms) (heart rate corrected according to Bazettformula or Fridericia formula)

14. People with a history of interstitial lung disease that needs treatment, a historyof radiation pneumonitis, or clinically active interstitial lung disease

15. Have received other clinical trial drugs within 4 weeks before the study

16. Major surgery or injury less than 4 weeks before the study

17. The study period must be accompanied by other antitumor therapy，such aschemotherapy, targeted therapy, hormone therapy, immunotherapy, radiotherapy (exceptsymptomatic local radiotherapy)

18. Any other malignant cancer within 5 years with the exception of adequately treatedcervical cancer in situ or basal and squamous cutaneous cell carcinomas

19. Any condition that would make the subject inappropriate for this study by theinvestigator's judgment