* This study was an open, multicenter phase II clinical trial that enrolled 118 patients with HR+/HER2- with recurrent or progressive advanced breast cancer treated with CDK4/6 inhibitors; * The study adopted the Simon phase 2 design, and all 20 eligible patients were treated with entinostat + fulvestrant; The study was terminated if no more than 2 patients achieved objective response and continued to enter Phase 2 if no more than 3 patients achieved objective response. In Phase 2, qualified patients were randomly assigned at a ratio of 1:1.5 to either the entestasta + fluvestrus group (Group 1) or the anlotinib + entestasta + fluvestrus group (Group 2), with 39 patients enrolled in group 1 and 59 patients enrolled in group 2; All patients were treated until the subjects' treatment would continue until the subjects experienced disease progression, intolerable toxicity, active withdrawal from treatment, or other conditions specified in the protocol, whichever occurred first. * During the study period, efficacy evaluations will be conducted every 8 weeks in accordance with the Solid Tumor Efficacy Evaluation Criteria (RECIST) v1.1 until disease progression, the initiation of a new anti-tumor treatment by the subject, or the withdrawal of informed consent, whichever occurs first. * Continuous safety evaluations will be conducted during the study treatment period. All subjects who have received at least one study treatment will be required to undergo end-of-treatment visits and safety follow-up visits within 7 days and 30±2 days after the last study treatment, respectively. * The end of the study was defined as the occurrence of disease progression or the end of the study treatment in all subjects, or the early termination of the study for other reasons, whichever occurred first.
Sign an informed consent form;
Female, aged 18 or above;
The patient's Eastern Tumor Collaboration Group (ECOG) physical status is 0-1;
The patient's expected survival time is ≥3 months;
Symptomatic visceral metastases or other conditions, visceral crisis, or the investigator deems it inappropriate to use endocrine therapy;
The patient has a past or present central nervous system metastases, or leptomeningeal disease, brain metastases;
Previous use of selective estrogen receptor degraders (SERD, such as fulvestrant) or histone deacetylase (HDAC) inhibitors (such as entectamine, chidamide, etc.) or small molecule multi-target tyrosine kinase inhibitors (such as apatinib, anlotinib, etc.) or PAM pathway inhibitors (such as PI3K inhibitor Alpelisib, AKT inhibitor Capivasertib, MTOR inhibitor everolimus, etc.
Known allergy to SERD, entinostat, or other drugs with a benzamide structure (such as typapride, remopilib, cloprapride, etc.), anlotinib;
Parallel
entinostat
DrugEntinostat tablets, orally once a week (5 mg); Each treatment cycle lasts for 28 days. Treatment will continue until the subject experiences disease progression, intolerable toxicity, voluntary withdrawal, or any other condition specified in the protocol, whichever occurs first.
Fulvestrant
DrugFulvestrant, intramuscular injection, 500 mg each time, administered on d1 and d15 of the first cycle, and on d1 of each subsequent cycle. Each treatment cycle lasts for 28 days. Treatment will continue until the subject experiences disease progression, intolerable toxicity, voluntary withdrawal, or any other condition specified in the protocol, whichever occurs first.
Anlotinib
DrugAnlotinib, 10mg each time, once daily, orally before breakfast. Take the drug for 2 consecutive weeks and then stop for 1 week, that is, 3 weeks (21 days) as one course of treatment.
ORR
To evaluate the objective response rate (ORR) of entinostat combined with fulvestrant in the treatment of HR+/HER2- advanced breast cancer that has recurred or progressed after CDK4/6 inhibitor therapy. Objective response rate was defined as number of patients with complete response (CR) or partial response (PR) divided by all randomized patients. Responses were evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline. CR was defined as disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameters), and/or persistence of one or more non-target lesion(s).
PFS
To evaluate progression-free survival (PFS),of entinostat with or without anlotinib + fulvestrant in treatment of relapsed or advanced HR+/HER2- breast cancer treated with CDK4/6 inhibitors Progression-free survival (PFS) was defined to be time from randomization to the earliest documented disease progression as defined by the RECIST criteria, new primary breast cancer, or death without progression. The distribution of PFS will be estimated using the Kaplan- Meier method, with 95% confidence intervals calculated using Greenwood's formula. In the primary analysis of PFS, differences in treatment effect will be tested using stratified log rank tests, stratifying on the randomization stratification factors. Stratified univariate and multivariable Cox proportional-hazard models will be built to estimate the hazard ratios (HRs) for treatment effect for PFS as a supportive analysis. In all analyses, P-values will be two-sided.
CBR
To evaluate clinical benefit rate (CBR) of entinostat with or without anlotinib + fulvestrant in treatment of relapsed or advanced HR+/HER2- breast cancer treated with CDK4/6 inhibitors Percentage of Participants Who Achieve a Best Overall Response of CR, PR or Stable Disease for Greater than or Equal to (≥) 24 Weeks
DoR
To evaluate duration of response (DoR) of entinostat with or without anlotinib + fulvestrant in treatment of relapsed or advanced HR+/HER2- breast cancer treated with CDK4/6 inhibitors
ORR of anlotinib+entinostat+fulvestrant
The objective response rate(ORR) of entesustat combined with anlotinib + fulvestrant in treatment of recurrent or progressive HR+/HER2- advanced breast cancer treated with CDK4/6 inhibitors Percentage of Participants Who Achieve a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)
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