Induction Trastuzumab Rezetecan Followed by Maintenance Dalpiciclib and Endocrine Therapy as First-line Treatment of HR+/HER2 Low mBC

Inclusion Criteria:

• Female patients aged ≥18 years and ≤75 years (premenopausal or perimenopausal female patients must be willing to receive LHRH agonist therapy during the study period).
• Female breast cancer patients with pathologically confirmed HR-positive, HER2-low expression, with evidence of locoregional recurrence or metastasis, not suitable for curative-intent surgical resection or radiotherapy, and without clinical indication for chemotherapy:

HR-positive defined as: ER-positive and/or PR-positive, with positive staining tumor cells accounting for ≥1% of all tumor cells; HER2-low expression defined as: standard immunohistochemistry (IHC) 1+/2+ and ISH/CISH negative.

• No prior systemic anticancer therapy for locoregional recurrence or metastatic disease, or relapse >12 months after completion of (neo)adjuvant CDK4/6 inhibitor therapy (if the patient progressed during adjuvant AI therapy, the first-line treatment for advanced disease must use the dalpiciclib plus fulvestrant regimen).
• ECOG performance status score of 0-1.
• Adequate organ function meeting the following criteria (no blood components or cell growth factors used for corrective treatment within 14 days before the first dose):
• Female subjects of childbearing potential must have a negative pregnancy test result at screening and must agree to use highly effective contraceptive methods from the time of signing informed consent until 7 months after the last dose of investigational drug.
• Voluntary participation in the clinical study with signed informed consent, good compliance, and willingness to cooperate with visits and study-related procedures.

Exclusion Criteria:

• Uncontrolled active central nervous system metastases (defined as symptomatic or requiring glucocorticoids or mannitol to control symptoms). Patients with stable brain metastases are permitted to enroll.
• Disease progression or relapse during or within ≤12 months of completing neoadjuvant or adjuvant endocrine therapy.
• Patients judged by the investigator to be unsuitable for endocrine therapy, including those with symptomatic visceral dissemination or at risk of life-threatening complications in the short term (e.g., third-space fluid accumulation that cannot be controlled by drainage [massive ascites, pleural effusion, pericardial effusion], pulmonary lymphangitis, or liver involvement >50%).
• Prior treatment with dalpiciclib or any antibody-drug conjugate containing an exatecan derivative topoisomerase I inhibitor.
• Prior surgery (major surgery for cancer treatment), radiotherapy, chemotherapy, immunotherapy, molecular targeted therapy, biologic therapy, or other clinical investigational therapy within 4 weeks before the first dose.

Other malignancies within the past 5 years, excluding cured basal cell carcinoma of the skin and cervical carcinoma in situ.

• Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS); active hepatitis B (HBV DNA ≥1000 IU/mL); hepatitis C (positive hepatitis C antibody and HCV-RNA above the lower limit of detection of the assay); or co-infection with hepatitis B and hepatitis C. Liver cirrhosis, or severe infection requiring antibiotics, antivirals, or antifungals.
• History of any of the following cardiac diseases: (1) angina pectoris; (2) arrhythmia requiring medication or clinically significant arrhythmia; (3) myocardial infarction; (4) heart failure; (5) any other cardiac disease judged by the investigator to be unsuitable for participation in this trial.

History of clinically significant pulmonary disease, including but not limited to interstitial pneumonia, pneumonitis, pulmonary fibrosis, and radiation pneumonitis (except for radiation changes not requiring corrective treatment), or suspected presence of such conditions identified during screening.

• Severe infection within 4 weeks before the first dose (e.g., requiring intravenous antibiotics, antifungals, or antivirals per clinical practice guidelines), or unexplained fever >38.5°C during screening or before the first dose.
• Inability to swallow, intestinal obstruction, or other factors affecting drug administration and absorption.
• Known allergy to any investigational drug or any of its excipients.
• Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1 per NCI-CTCAE v6.0.
• Presence of any other serious physical or mental illness or laboratory abnormality that may increase the risk of participating in the study, interfere with study results, or render the patient unsuitable for participation in the investigator's judgment.