Trastuzumab Rezetecan Followed by Pyrotinib, and Trastuzumab Combined With Capecitabine as First-line Treatment for Advanced HER2-positive Breast Cancer

Inclusion Criteria:

• Female participants aged 18 to 75 years (inclusive)

• Breast cancer must meet the following criteria:

  • HER2-positive breast cancer confirmed by histology or cytology (HER2 positivity defined as IHC 3+ or ISH+ in primary or metastatic lesions); locally advanced or metastatic breast cancer not amenable to curative surgery (participants eligible for curative treatment are excluded);
  • Clear HR status (HR-positive defined as ER and/or PR positive in primary or metastatic lesions, with ≥1% of tumor cells showing ER and/or PR staining);
  • No prior systemic anticancer therapy during the recurrent/metastatic phase (except ≤1 line of endocrine therapy allowed);
  • For patients receiving (neo)adjuvant therapy, the interval between completion of systemic therapy (excluding endocrine therapy) and detection of recurrence/metastasis must be >12 months.
• ECOG performance status of 0 or 1.
• Organ function deemed adequate for study drug administration by the investigator.

• Pregnancy and contraception:

  • Sexually active female participants (WOCBP) must agree to use highly effective contraception from the screening visit through 7 months after the last dose of investigational product, and must agree not to breastfeed.

• Participants must voluntarily enroll in the study, sign informed consent, demonstrate good compliance, and be willing to cooperate with all study visits and procedures.

Exclusion Criteria:

• Patients with active central nervous system metastases who have not undergone surgery or radiation therapy, except those whose condition has been stable for at least one month after treatment and who have discontinued corticosteroids for more than 2 weeks.
• A history of other malignancies within the past 5 years, excluding cured cases of cutaneous basal cell carcinoma, cervical carcinoma in situ, and papillary thyroid carcinoma.
• Presence of third-space fluid accumulation (e.g., large volume ascites, pleural effusion, pericardial effusion) that cannot be controlled by drainage or other means.
• Patients who have received surgery (defined as major cancer-related surgery), radiation therapy, chemotherapy, immunotherapy, molecularly targeted therapy, biological therapy, or participated in other drug clinical trials within 4 weeks prior to the first dose of study medication.
• Prior exposure to antibody-drug conjugates containing irinotecan derivatives as topoisomerase I inhibitors, such as T-DXd (DS-8201a).
• Administration of live or live-attenuated vaccines within 4 weeks prior to the first dose of study medication.
• History of immunodeficiency, including positive HIV test results, other acquired or congenital immunodeficiency disorders, or a history of organ transplantation.
• Clinically significant cardiovascular disease, such as severe/unstable angina, symptomatic congestive heart failure (NYHA ≥ II), clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention, or myocardial infarction occurring within 6 months prior to the first dose.
• Known or suspected interstitial lung disease; presence of moderate to severe pulmonary conditions within 3 months prior to the first dose that could significantly impair respiratory function or interfere with assessment or management of drug-related pulmonary toxicity, including but not limited to idiopathic pulmonary fibrosis, organizing pneumonia/obstructive bronchiolitis, pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease (COPD), obstructive/restrictive lung diseases, or cancerous lymphangitis; any autoimmune, connective tissue, or inflammatory disease involving the lungs, such as rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, or prior history of pneumonectomy. Patients with a prior history of interstitial lung disease grade ≥3 are excluded from this study.
• Known hereditary or acquired bleeding tendency (e.g., hemophilia, coagulation disorders).
• Active hepatitis B (HBsAg positive and HBV DNA ≥500 IU/mL), hepatitis C (HCV antibody positive and HCV RNA above the upper limit of normal), cirrhosis; or severe infections requiring intravenous antibiotics, antivirals, or antifungal agents for control.
• According to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0), patients whose toxicity from prior anticancer treatments has not recovered to ≤Grade 1 (except alopecia; certain tolerable chronic Grade 2 toxicities may be allowed at the investigator's discretion, such as Grade 2 peripheral neuropathy).
• Known hypersensitivity to any of the investigational drugs, their excipients, or other monoclonal antibodies.
• Other serious physical or psychiatric conditions or laboratory abnormalities that may increase the risk of participation in the study or interfere with study outcomes, or patients deemed unsuitable for participation by the investigator.