Efficacy and Safety of Tinengotinib Tablets Combined With Fulvestrant Injection in Patients With HR Positive and HER-2 Negative Recurrent or Metastatic Breast Cancer Who Have Failed Prior Treatment

Inclusion Criteria:

1. Histologically or cytologically confirmed breast cancer with evidence of local recurrence or distant metastasis and no indication for surgery or radiotherapy;
2. Breast cancer confirmed as HR+/HER2- negative or low expression by local laboratory testing based on the most recent tumor tissue sample (from either the primary or metastatic site, excluding bone lesions). HR-positive, HER2-negative or low expression as defined in this study refer to the Chinese Society of Clinical Oncology \[CSCO\] 2024 criteria;
3. Participants must meet at least one of the following criteria: a) prior bilateral oophorectomy, or age ≥60 years; b) age \<60 years, with natural amenorrhea (in the absence of medication or pathological conditions) for ≥12 months, and estradiol and FSH levels within the postmenopausal range; c) age \<60 years, currently undergoing ovarian suppression therapy (e.g., LHRH agonist) and requiring continued treatment during the study, with estradiol and FSH levels maintained within the postmenopausal range;
4. Participants who have previously failed 1-2 lines of endocrine therapy (including AI, SERD, and SERM) for recurrent or metastatic disease are eligible. Subjects with initial diagnosis showing weak ER positivity by IHC (tumor cells with nuclear staining accounting for 1%-10%) are not eligible for enrollment;
5. Participants must have experienced disease progression after prior treatment with at least one CDK4/6 inhibitor (CDK4/6i), including in the neoadjuvant, adjuvant, or systemic treatment settings;
6. Participants who have previously failed 0-2 lines of systemic chemotherapy (cytotoxic drugs) for recurrent or metastatic disease. Antibody-drug conjugates (ADCs) are not counted as systemic chemotherapy;
7. ECOG ≤ 1;
8. Participants must meet at least one of the following criteria (per RECIST v1.1): a) At least one measurable lesion as defined by RECIST v1.1 at baseline; if the only target lesion is a non-nodal lesion, its longest diameter must be ≥15 mm; b) When bone lesions are the only measurable lesions, lytic or mixed bone lesions may be selected as target lesions; subjects with only blastic bone lesions are not eligible for enrollment.
9. Adequate organ and bone marrow function;
10. Premenopausal participants receiving ovarian suppression therapy must agree to use adequate contraception to avoid pregnancy during the study and for at least 3 months after the end of treatment;
11. Able to sign informed consent and comply with the protocol.

Exclusion Criteria:

1. Participants who are pregnant or breastfeeding;
2. Conditions judged by the investigator as making the participant unsuitable for study drug treatment, including but not limited to: a history of severe allergy to the components or excipients of the study drug, prior treatment history with the study drug, or presence of complications that may be life-threatening in the short term (such as pleural, pericardial, or abdominopelvic effusions that cannot be controlled by drainage or other methods);
3. Uncontrolled hypertension (systolic blood pressure \>150 mmHg or diastolic blood pressure \>100 mmHg), allowing for the lowest value from up to two repeat measurements;
4. Participants with brain or central nervous system (CNS) metastases that have progressed as confirmed by imaging or clinically within 28 days before the start of treatment (e.g., evidence of new or enlarging brain metastases on imaging, new neurological symptoms attributable to brain/CNS metastases);
5. Participants with concurrent other malignancies or hematologic malignancies that are progressing or require active treatment (excluding basal cell carcinoma of the skin, other non-invasive or indolent malignancies, or cured tumors); Hormone replacement therapy is permitted (e.g., thyroxine replacement therapy post-thyroidectomy);
6. Participants who have received systemic treatment with corticosteroids (\>10 mg/day of prednisone or equivalent dose of other corticosteroids) or other immunosuppressive medications within 14 days prior to the initiation of the study drug;
7. Participants who have received other systemic anti-tumor therapies or treatment with investigational drugs prior to the initiation of the study drug, with a washout period of approximately 5 half-lives or 14 days, whichever is shorter;
8. Participants who have received extensive radiotherapy or major surgery within 4 weeks prior to the initiation of the study drug, or local palliative radiotherapy within 2 weeks. (If the investigator judges that this does not pose an additional safety risk, initiation of the study drug during the washout period may be permitted with sponsor agreement.)
9. Participants who have not yet recovered from adverse events resulting from prior anti-tumor therapy (excluding adverse events ≤ Grade 1 per CTCAE, or ≤ Grade 2 adverse events that the investigator judges do not pose a safety risk).
10. History of severe cardiac or cerebrovascular disease;
11. Participants who have severe gastrointestinal disease or gastrointestinal dysfunction that may lead to absorption, metabolism or excretion of the study drug, enrollment eligibility will be based on the investigator's judgment (including but not limited to total gastrotomy, short bowel syndrome).
12. Participants who have bleeding disorders or thrombotic disorders or therapeutic anticoagulant therapy requiring INR monitoring.
13. Participants who have received a strong CYP3A inhibitor and inducer before starting the study drug, within an interval of ≤ 2 weeks or 5 half-lives (whichever is shorter);
14. Tested positive for the human immunodeficiency virus (HIV);
15. Participants with active HBV infection and/or HCV infection;
16. Participants who are unable to swallow or tolerate oral medication.
17. The investigator determines that there are other reasons making the participant unsuitable for participation in the study.