SKB264 Combined With KL-A167 Neoadjuvant Therapy for Early-stage, High-risk ER+/HER2- Breast Cancer

This is a single-arm, multi-center, phase II clinical trial to evaluate the efficacy and safety of SKB264 combined with KL-A167 as neoadjuvant treatment for early-stage high-risk ER+HER2- breast cancer. Eligible patients receive intravenous injections of 5mg/kg SKB264 and 900mg KL-167 every 2 weeks, with a total duration of 18 weeks for neoadjuvant therapy.

During neoadjuvant therapy, tumor assessments will be conducted every 6 weeks, followed by surgery after neoadjuvant therapy is completed. Following surgery, participants have the option to receive additional adjuvant therapy at the discretion of the treating physician. Participants will be followed at least every 6 months initially as per standard clinical practice.

The primary endpoint is to determine the pCR rate of SKB264 combined with KL-A167. Secondary endpoints include ORR, EFS, OS, and safety profile. Safety was evaluated by measuring the occurrence and severity of adverse effects by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.

Inclusion criteria

• Females aged 18-70 years;
• Pathologically confirmed invasive ductal breast cancer and untreated previously；
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1;
• Life expectancy ≥3 months;
• Have at least 1 measurable disease defined by RECIST v1.1;
• T1c-T2 (tumor size ≥2 cm), clinical node stage (cN)1-cN2, or T3-T4, cN0-cN2;
• Has confirmed ER+/HER2-：ER≥1%、HER2 IHC 0、1+ or 2+/ISH-）;
• Tumor Grade 3 of ductal histology, Or Tumor Grade 2 of ductal histology having an ER expression level percentage between 1-10%
• Tissue or blood available for biomarker assessment;
• Adequate organ function;
• Patients with negative serum pregnancy test and those with fertility potential must agree to use effective contraception during the treatment period and for at least 3 months after the last dose of study drugs;
• Patients must voluntarily participate in this study, sign an informed consent form, exhibit good compliance, and be willing to cooperate with follow-up procedures；

Exclusion criteria

• Inflammatory BC；
• Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants of the breast).
• Has bilateral invasive breast cancer.
• Has metastatic (stage IV) breast cancer.
• Has left ventricular ejection fraction (LVEF) of <50% or below the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
• Has received prior treatment for breast cancer.
• Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137).
• Has received prior treatment for targeting TROP2 and/or topoisomerase I;
• Patients who have had other malignancies within the past five years will be excluded from the study, with exceptions for those who have been successfully treated for cervical carcinoma in situ, skin basal cell carcinoma, or squamous cell carcinoma of the skin;
• Has hypersensitivity to any of the components or excipients used in the study treatments.
• History of allogeneic organ transplantation;
• Patients with a history of non-infectious interstitial lung disease (ILD) or non-infectious pneumonia requiring steroid treatment, those currently diagnosed with ILD or non-infectious pneumonia, or those with suspected ILD or non-infectious pneumonia that cannot be ruled out by imaging at the time of screening, will be excluded. Additionally, patients suffering from clinically severe pulmonary damage due to pulmonary comorbidities will also be excluded. This includes, but is not limited to, any underlying pulmonary disease (such as pulmonary embolism within the past three months, severe asthma, advanced chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion) or any autoimmune, connective tissue, or inflammatory conditions potentially affecting the lungs (such as rheumatoid arthritis, Sjögren's syndrome, sarcoidosis), as well as those who have undergone a pneumonectomy.
• Patients with active autoimmune diseases requiring systemic treatment within the past two years will be excluded from the study. Systemic treatment does not include hormone replacement therapy, such as insulin therapy for Type 1 Diabetes, thyroid hormone replacement for hypothyroidism, or physiological doses of glucocorticoids for adrenal or pituitary insufficiency.
• Patients with active infection requiring systemic therapy.
• According to the investigator's judgment, there are concomitant diseases that seriously endanger the patient's safety or affect the patient's completion of the study, including but not limited to high blood pressure beyond the control of drugs, serious diabetes, active infection, etc.
• Patients for whom participation in the study was deemed to be inappropriate by the investigator for any other reason were also excluded.