Maintenance Therapy in HER2-Positive Unresectable Locally Recurrent or Metastatic Breast Cancer: A Phase II Study

A Multicenter, Open-Label, Phase II Trial of Exploring the Maintenance of Trastuzumab Plus Pyrotinib or Trastuzumab Plus Dalpiciclib and Endocrine Therapy Based on HR Status Following Trastuzumab Rezetecan as Induction Treatment for HER2 Positive Unresectable Locally Recurrent or Metastatic Breast Cancer

This is a phase II trial exploring the maintenance therapy with trastuzumab combined with pyrotinib or dalpiciclib and endocrine therapy in HER2-positive advanced breast cancer based on different hormone receptor (HR) statuses following trastuzumab rezetecan (T-DXh, SHR-A1811) as induction treatment for HER2-positive unresectable locally recurrent or metastatic breast cancer (MBC) patients.

Inclusion Criteria:

To be eligible to participate in this trial, an individual must meet ALL the following criteria:

1. Patient must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.

2. Female patients ≥ 18 years of age at the time of signing ICF.

3. Breast Cancer Requirements:

   1. Histologically or cytologically confirmed HER2-positive(IHC 3+ or ISH+) unresectable locally advanced or metastatic breast cancer (Note: Patients eligible for curative-intent treatment are excluded).
   2. Documented hormone receptor (HR) status.
   3. No prior systemic anti-tumor therapy for recurrent/metastatic disease (≤1 line of endocrine therapy is permitted*).
   4. For patients who received (neo)adjuvant therapy: >12 months between the end of systemic treatment (excluding endocrine therapy) and recurrence/metastasis.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

5. Adequate Organ Function.

6. Pregnancy and Contraception: Women of childbearing potential (WOCBP) must agree to use highly effective contraception from screening until7 months after the last dose of study treatment and must refrain from breastfeeding.

Exclusion Criteria:

An individual who meets ANY of the following criteria will be excluded from participation in this trial:

1. Known active CNS metastases not treated with surgery or radiotherapy, except for those who have achieved stable disease for ≥1 month after treatment and have discontinued corticosteroids for >2 weeks.

2. Received major cancer-related surgery, radiotherapy, chemotherapy, immunotherapy, molecular targeted therapy, biologic therapy, or investigational drug therapy within 4 weeks prior to the first dose of study treatment.

3. Previous treatment with antibody-drug conjugates containing exatecan derivative topoisomerase I inhibitors.

4. Presence of clinically significant cardiovascular conditions, including:

   1. Severe/unstable angina
   2. Symptomatic congestive heart failure (NYHA class ≥II)
   3. Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention
   4. Myocardial infarction within 6 months before the first dose

5. Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

6. Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, contraindicate patient participation.