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

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

• Aged ≥ 18 and ≤ 75 years at the time of signing the ICF, male or female;
• Histologically and/or cytologically confirmed HR+/HER2- BC based on pathological reports from the most recent biopsy or other pathological specimens;
• Subjects must have radiologically documented disease progression during or after the most recent treatment prior to enrollment;
• 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;
• The investigator assessed that the patient could not continue to benefit from endocrine therapy and was suitable for receiving first-line chemotherapy;
• 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;
• At least one measurable lesion per RECIST v1.1；
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 with no worsening within 2 weeks prior to randomization;
• Life expectancy of ≥ 12 weeks;
• 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;
• Adequate organ and bone marrow function;
• Having recovered from all toxicities due to prior treatment;
• 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;
• Willingness to participate in the study, sign the ICF, and comply with the protocol-specified visits and relevant procedures.

Exclusion criteria

• Subjects with locally advanced breast cancer suitable for curative therapy at study enrollment;
• 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;
• Subiects with known meningeal metastases, brainstem metastases, spinal cord metastases and/or compression or active centralnervous system (CNS) metastases.
• Presence of any serious cardiovascular and cerebrovascular diseases or cardiovascular and cerebrovascular risk factors;
• 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;
• Clinically serious lung injuries caused by lung diseases;
• 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;
• Documented severe dry eye syndrome, severe meibomian gland dysfunction and/or blepharitis, or history of severe corneal disorders that prevent/delay corneal healing;
• History of esophagogastric varices, severe ulcers, gastric perforation, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to randomization;
• 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);
• Positive result of human immunodeficiency virus (HIV) test or history of acquired immunodeficiency syndrome (AIDS); known active syphilis infection;
• 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;
• Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
• Pregnant or lactating women;
• Prior TROP2-targeted therapy or any treatment containing chemotherapeutic agents targeting topoisomerase I (including antibody-drug conjugates [ADCs]);
• Live vaccines within 4 weeks prior to randomization or scheduled to receive live vaccines during study treatment;
• 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.
• Rapid deterioration of the condition, e.g., significant changes in performance status, etc., during the screening process.