A Study of SKB264 Versus Investigator's Choice of Chemotherapy in Subjects With Unresectable Locally Advanced, Relapsed, or Metastatic HR+/HER2- Breast Cancer Who Have Previously Failed Endocrine Therapy

A Randomized, Open-label, Multicenter Phase III Clinical Study of SKB264 Versus Investigator's Choice of Chemotherapy in Subjects With Unresectable Locally Advanced, Relapsed, or Metastatic Hormone Receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2-negative (HER2-) Breast Cancer Who Have Previously Failed Endocrine Therapy

The purpose of this study is to evaluate the efficacy and safety of SKB264 in patients with unresectable locally advanced, recurrent, or metastatic HR+/HER2- breast cancer who have previously failed endocrine therapy.

This is a randomized, open-label, multicenter phase 3 clinical study to evaluate the efficacy and safety of SKB264 monotherapy versus investigator's choice of chemotherapy (ICC) in subjects with unresectable locally advanced, recurrent, or metastatic HR+/HER2- breast cancer who had failed at least one line of systemic chemotherapy and have not recieved systemic chemotherapy for locally advanced, relapsed, or metastatic stages.

Inclusion Criteria:

1. Aged ≥ 18 and ≤ 75 years at the time of signing the ICF, male or female;
2. Histologically and/or cytologically confirmed HR+/HER2- BC based on pathological reports from the most recent biopsy or other pathological specimens;
3. Subjects must have radiologically documented disease progression during or after the most recent treatment prior to enrollment;
4. No prior systemic chemotherapy for locally advanced, relapsed, or metastatic stages. Subjects who previously received adjuvant/neoadjuvant chemotherapy and progressed >6 months after completion of the last chemotherapy treatment will be allowed for study inclusion;
5. The investigator assessed that the patient could not continue to benefit from endocrine therapy and was suitable for receiving first-line chemotherapy;
6. Able to provide recently newly obtained or archival tumor tissue sections at or after diagnosis of relapsed or metastatic tumor within the recent prior to randomization;
7. At least one measurable lesion per RECIST v1.1；
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 with no worsening within 2 weeks prior to randomization;
9. Life expectancy of ≥ 12 weeks;
10. Suitable to receive one of the chemotherapy regimens listed in the investigator's choice of chemotherapy (paclitaxel, nab-paclitaxel, capecitabine) as assessed by the investigator;
11. Adequate organ and bone marrow function;
12. Having recovered from all toxicities due to prior treatment;
13. Use of effective medical contraception during study treatment and for 6 months after the end of dosing for female subjects of childbearing potential and male subjects with partners of childbearing potential;
14. Willingness to participate in the study, sign the ICF, and comply with the protocol-specified visits and relevant procedures.

Exclusion Criteria:

1. Subjects with locally advanced breast cancer suitable for curative therapy at study enrollment;
2. Other malignancies (except those tumors cured by local treatment, such as basal cell carcinoma of skin, squamous cell carcinoma of skin, carcinoma in situ of the cervix) within 3 years prior to randomization;
3. Subiects with known meningeal metastases, brainstem metastases, spinal cord metastases and/or compression or active centralnervous system (CNS) metastases.
4. Presence of any serious cardiovascular and cerebrovascular diseases or cardiovascular and cerebrovascular risk factors;
5. History of (noninfectious) interstitial lung disease (ILD)/noninfectious pneumonitis requiring steroid therapy and current ILD/noninfectious pneumonitis, or suspected ILD/noninfectious pneumonitis at screening that cannot be excluded by imaging;
6. Clinically serious lung injuries caused by lung diseases;
7. Serious infection within 4 weeks prior to randomization, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia; active infection requiring systemic anti-infective therapy within 2 weeks prior to randomization;
8. Documented severe dry eye syndrome, severe meibomian gland dysfunction and/or blepharitis, or history of severe corneal disorders that prevent/delay corneal healing;
9. History of esophagogastric varices, severe ulcers, gastric perforation, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to randomization;
10. Active hepatitis B (hepatitis B surface antigen positive and HBV-DNA ≥ 500 IU/mL or above the ULN, whichever is higher) or hepatitis C (hepatitis C antibody positive and HCV-RNA above the ULN);
11. Positive result of human immunodeficiency virus (HIV) test or history of acquired immunodeficiency syndrome (AIDS); known active syphilis infection;
12. 12 Known hypersensitivity to SKB264 or investigator's choice chemotherapy or any of its excipients, including but not limited to polysorbate-20, or history of severe hypersensitivity reaction to other monoclonal antibodies;
13. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
14. Pregnant or lactating women;
15. Prior TROP2-targeted therapy or any treatment containing chemotherapeutic agents targeting topoisomerase I (including antibody-drug conjugates [ADCs]);
16. Live vaccines within 4 weeks prior to randomization or scheduled to receive live vaccines during study treatment;
17. Receipt of the following therapies prior to randomization: a)Major surgery within 4 weeks prior or expected major surgery during the study; b)Radiation therapy within 2 weeks prior (extensive radiation therapy including radiopharmaceuticals within 4 weeks prior); c)Any immunotherapy, biological therapy, or other investigational drugs within 4 weeks or 5 half-lives of prior drug use (whichever is shorter) (bisphosphonates or RANK-L inhibitors for bone metastases are permitted prior to randomization); or traditional Chinese medicine with approved anti-tumor indications, small molecule targeted therapy, or endocrine therapy within 2 weeks prior.
18. Rapid deterioration of the condition, e.g., significant changes in performance status, etc., during the screening process.