To Evaluate the Efficacy and Safety of Disitamab Vedotin Combined With Toripalimab Sequential Chemotherapy as Neoadjuvant Treatment in Patients With HR-positive, HER2-low Breast Cancer

This is a single-arm, open-label, multicenter phase II clinical trial to evaluate the efficacy and safety of Disitamab Vedotin combined with Toripalimab sequential chemotherapy as neoadjuvant treatment in patients with HR-positive, HER2-low breast cancer

Inclusion criteria

• Voluntarily agree to participate in the study and sign the informed consent;
• Age ≥18 years old (including the threshold value);
• Histologically confirmed invasive breast cancer with clinical stage T1c-T2(≥2cm)cN1-2M0 or T3cN0-2M0;
• As assessed by the research Center, the subjects can tolerate and plan to undergo radical surgery for breast cancer and have not previously received any anti-tumor systemic therapy for breast cancer;
• Invasive breast tumor tissue with low HER2 expression confirmed by the central laboratory is defined as IHC 1+ or IHC 2+ expression of HER2 protein detected by immunohistochemistry (IHC), and no amplification detected by in situ hybridization (ISH) (according to the Breast Cancer HER2 Detection Guidelines 2019); Primary tumor specimens (wax pieces, slices or fresh tissues) can be provided for HER2 detection;
• According to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2020 guidelines, tumor tissue estrogen receptor (ER) and progesterone receptor (PgR) expression ≥ 1%;
• Histological grade (Nottingham grading system) G3 or G2 with ER expression
• ECOG physical status 0 or 1;
• At least one measurable lesion according to RECIST v1.1 standard;
• Heart function:

• New York Heart Association (NYHA) Grade < 3;
• left ventricular ejection fraction ≥50%;
• Bone marrow or organ function should meet the following criteria within 7 days before the study dose:

Hemoglobin ≥ 90g/L; Absolute neutrophil count (ANC) ≥1.5×109/L; Platelet ≥ 100 ×109/L; Serum total bilirubin ≤ 1.5 times the upper limit of normal value (ULN); Aspartate aminotransferase (AST) and glutamic pyruvic transaminase (ALT) ≤ 2.5 times the upper limit of normal value; International normalized ratio (INR) and activated partial thrombin time ≤ 1.5×ULN; Serum creatinine ≤ 1.5×ULN or creatinine clearance (CrCl) ≥ 50 mL/min according to Cockcroft-Gault formula method;

• Fertile female subjects who meet the following conditions

• A serum pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of β-human chorionic gonadotropin [β-hCG]) must be negative within 72 hours before the first dosing of the study intervention. Subjects with false positive results who are confirmed not to be pregnant are eligible for study.
• Must agree to contraception for the duration of the study and for at least 6 months after the last dose of investigational drug.
• Must agree not to breastfeed or donate eggs from the time of signing the informed consent until 6 months after the last dose of investigational drug.
• If sexually active and likely to result in pregnancy, continuous use of at least 2 acceptable forms of contraception, at least 1 of which must be highly effective from the time of the informed consent and continue until at least 6 months after the last dosing of the investigational drug.
• Fertile male subjects who meet the following conditions

• Must agree not to donate sperm from the time of signing the informed consent until at least 4 months after the last dose of investigational drug.
• If sexual activity with a fertile person is likely to result in pregnancy, continuous use of at least 2 acceptable forms of contraception, at least 1 of which must be highly effective from the time of the informed consent and continue until at least 4 months after the last dosing of the investigational drug.
• If sexually active with a pregnant or breastfeeding patient, condom use must continue from informed consent until at least 4 months after the last dosing of the investigational drug.
• Able to understand trial requirements, willing and able to follow trial and follow-up procedures.

Exclusion criteria

• Bilateral invasive breast cancer;
• Previous history of invasive breast cancer;
• Previously had carcinoma in situ of the breast and received adjuvant endocrine therapy within 5 years of surgery;
• Use of the investigational drug or major surgery within 4 weeks prior to study dosing;
• Have received or plan to receive live or attenuated vaccine within 4 weeks before the start of study dose;
• Previous history of receiving allogeneic hematopoietic stem cell transplantation or organ transplantation;
• Previous treatment with PD-(L)1, PD-L2, CTLA4 inhibitors and other Antibody-Drug Conjugates;
• Uncontrolled or significant cardiovascular and cerebrovascular diseases
• Presence of other treatable or serious lung diseases, including but not limited to active tuberculosis, interstitial lung disease, etc.;
• Suffering from an active infection that requires systematic treatment;
• Have active autoimmune diseases requiring systemic treatment within the past 2 years, allowing for relevant replacement therapy;
• Have a clear past or present history of neurological or psychiatric disorders, including epilepsy or dementia;
• Persistent ≥ grade 2 sensory or motor neuropathy;
• In the judgment of the investigator, there is a serious concomitant disease that endangers the safety of the subject or interferes with the completion of the clinical study;
• Positive HIV test result; Patients with active hepatitis B or C; Persistent coronavirus (COVID-19) infection;
• Known hypersensitivity or delayed anaphylaxis to certain components of Disitamab Vedotin, and Toripalimab or Certain components of chemotherapy drugs or similar drugs used in the study;
• Suffering from another malignancy within 5 years prior to signing the informed consent