This is a prospective, randomized, 2-arm, multicenter study to compare the safety and
efficiency of anti-HER2 therapy (Trastuzumab ± Pertuzumab) plus fulvestrant versus anti-HER2
therapy (Trastuzumab ± Pertuzumab) plus capecitabine in women with hormone receptor positive
(HR+), human epidermal growth factor receptor 2 positive (HER2+), non-visceral metastases,
stage IV breast cancer. Subjects will be randomized into one of two treatment arms. Arm A
subjects will receive the anti-HER2 therapy plus fulvestrant. Arm B subjects will receive the
anti-HER2 therapy plus capecitabine. The use of Pertuzumab depends on patients' choices.
Inclusion Criteria:
1. Patients provided written informed consent
2. Postmenopausal or premenopausal or perimenopausal women aged 18-75 years:
1. ≥60 years, or bilateral ovariectomy was previously performed, or
2. <60 years, natural postmenopausal status (defined as a continuous period of at
least 12 months following spontaneous cessation without other pathological or
physiological causes), estrogen (E2) and follicle-stimulating hormone (FSH) are
present at postmenopausal levels
3. Premenopausal or perimenopausal women, willing to receive luteinizing hormone
(LHRH) stimulation during the study
3. Histologically or cytologically confirmed HR-positive (ER/PR≥10%), HER2-positive (IHC
3+ or ISH+) breast cancer
4. At least one measurable non-visceral metastatic lesion (liver, lung, pleura,
pericardium, peritoneum, kidney, adrenal, brain or leptomeningeal metastases are
excluded), HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+), (≥10 mm on
T1-weighted, gadolinium-enhanced MRI) (RECIST v1.1)
5. Previous treatment with HER2 inhibitors to be discontinued prior to first study
treatment administration (at least 14 days for trastuzumab and other antibodies, at
least 7 days for lapatinib)
6. Previous chemotherapy, biological or target therapy to recurrent or metastatic disease
are not allowed; Previous radiotherapy allowed, but radiotherapy must have been
discontinued at least 14 days prior to first study treatment administration.
7. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2
8. Life expectancy > 24 weeks
9. left ventricular ejection fraction (LVEF) of 50% or higher at baseline (within 42 days
before randomization)
10. Previous adjuvant chemotherapy treatment is allowed
11. Previous adjuvant trastuzumab treatment is allowed
12. Hormone therapy must have been discontinued at least 1 month prior to recruitment
13. Patients with good compliance
14. Patients must have recovered to baseline condition or to Common Terminology Criteria
for Adverse Events (CTCAE) version 5.0 grade = 1 from any acute CTCAE v. 5.0 grade =2
side effects of previous treatments
15. Without infection of human immunodeficiency virus (HIV) on central laboratory assay
results prior to randomization
16. Alanine aminotransferase (ALT) </= 2.5 × the upper limit of normal (ULN), Aspartate
aminotransferase (AST) </= 2.5 × ULN prior to randomization
17. Total bilirubin (TBIL) </= 1.25 × ULN
18. Alkaline phosphatase (ALK) </= 2.5 × ULN
19. Gamma glutamyl transpeptidase (GGT) </= 2.5 × ULN
20. Serum total bilirubin (TBil) </= 1.5 × ULN
21. Serum creatinine (Scr) </= 1.5 × ULN
22. WBC >/= 3×109/L, Blood neutrophil count >/= 1×109/L, Platelet count >/= 100×109/L, HB
>/= 9 g/dL
23. Albumin >/= 30g/L
24. Women of child-bearing age who had a negative serum pregnancy test (within 14 days
before randomization) should take effective contraceptive measures
Exclusion Criteria:
1. Primary and metastatic lesion lack of histological or cytological confirmation of
HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+)
2. Breast cancer with visceral metastases (liver, lung, pleura, pericardium, peritoneum,
kidney, adrenal, brain or leptomeningeal metastases)
3. Inflammatory breast cancer
4. Having a life-threatening metastatic visceral disease, defined as extensive liver
damage or brain or leptomeninges damage (past or present) or symptomatic pulmonary
lymphatic diffusion. Patients with discrete pulmonary parenchyma metastasis were
eligible if the investigators determined that their respiratory function was not
significantly impaired by the disease.
5. Disease progression or recurrence within 12 months after neo/adjuvant endocrine
therapy
6. Unable to tolerate endocrine therapy, including those who with symptoms, who have
spread to the viscera, and who are at risk for short-term life-threatening
complications (including uncontrolled thorax, pericardium, or abdominal cavity
exudation, pulmonary lymphangitis, and more than 50% liver damage).
7. CT or MRI confirmed the presence of brain or leptomeningeal metastases.
8. Any other current malignancy or malignancy diagnosed within the past five years (other
than breast cancer, carcinoma in situ of the cervix, skin basal cell carcinoma or
squamous cell carcinoma), unless radical treatment is performed and there is no
evidence of recurrence or metastasis within the last 5 years.
9. Non- visceral metastatic lesions cannot be evaluated by RECIST v1.1
10. Active infection with human immunodeficiency virus (HIV) prior to first study
treatment administration.
11. History of participating any other clinical trials within 30 days prior to
randomization
12. Known hypersensitivity (Grade 3 or 4) to Pertuzumab, Trastuzumab, Fulvestrant or
Capecitabine or the excipients of any of the trial drugs
13. Pregnancy or lactation
14. Uncontrolled illnesses including symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia requiring therapy, myocardial infarction within the past
6 months, or active infection
15. severe pulmonary and renal disease
16. Patients with GI tract disease resulting in an inability to take oral medication,
malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative
colitis)
17. Legal incompetence or limitation.
18. Considered unable to complete the study or sign the informed consent due to a medical
or mental disorder by the investigator.
