Cohort Study on Sequential ADC Therapy in HR-positive/HER2-negative Advanced Breast Cancer

Official title

Real-world Cohort Study on Sequential Therapy With ADC Drugs Following Progression of Endocrine Therapy Guided by Molecular Biomarkers in HR-positive/HER2-negative Advanced Breast Cancer

Overview

The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy is the standard first-line treatment for advanced HR+ (hormone receptor-positive)/HER2- (human epidermal growth factor receptor 2-negative) breast cancer. However, the optimal treatment strategy after CDK4/6i progression remains unclear. In recent years, antibody-drug conjugates (ADCs) such as sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) have demonstrated significant activity in HR+/HER2- breast cancer, providing new options post-CDK4/6i progression. Yet, the optimal sequencing of different ADCs (e.g., SG followed by T-DXd vs. T-DXd followed by SG) after CDK4/6i failure remains uncertain. Determining how to further optimize treatment selection to prolong survival and improve quality of life has become a key research focus in clinical practice. This study aims to explore the efficacy, safety, and potential resistance mechanisms of biomarker-guided sequential ADC therapy (e.g., SG→T-DXd vs. T-DXd→SG) following CDK4/6i progression. The findings may guide clinical decision-making and provide evidence for precision medicine.

Interventions

• Drug First-line T-DXd followed by SG upon disease progression
  Patients will be assigned to Cohort 1 (HER2 IHC 2+) based on different HER2 immunohistochemical expression levels, where they will first receive T-DXd treatment, followed by SG treatment upon disease progression.
• Drug First-line SG followed by T-DXd upon progression
  Patients will be assigned to Cohort 2 (HER2 IHC ≤1+) based on different HER2 immunohistochemical expression levels, where they will first receive SG treatment, followed by T-DXd treatment upon disease progression.

Primary outcome measures

• Progression-Free Survival (PFS1) [Time frame: From the date of signing the informed consent form until the date of first documented disease progression after initial ADC therapy or date of death from any cause (whichever occurs first), assessed up to 24 months.]

Secondary outcome measures (4)

• Progression-Free Survival 2 (PFS2) [Time frame: From the date of initiation of the second ADC therapy (ADC2) until the date of further documented disease progression or date of death from any cause (whichever occurs first), assessed up to 24 months.]
• Composite Progression-Free Survival (PFS-Total) [Time frame: From the date of signing the informed consent form until the date of the first documented disease progression (during ADC1 or ADC2 therapy) or date of death from any cause (whichever occurs first), assessed up to 36 months.]
• Overall Survival (OS) [Time frame: From the date of randomization until the date of death from any cause, assessed up to 60 months.]
• Objective Response Rate（ORR） [Time frame: At least 4 weeks after first documented response]

Eligibility criteria

Inclusion criteria

• Adult patients ≥18 years old;
• Histologically or cytologically confirmed HR+/HER2- (HER2 IHC 0/IHC 1+ or IHC 2+ with FISH-negative) locally advanced unresectable or metastatic breast cancer, as defined by ASCO/CAP guidelines;
• Prior treatment with CDK4/6i combined with endocrine therapy, with radiologically confirmed disease progression;
• Presence of evaluable lesions;
• Received ≤2 lines of chemotherapy for advanced disease;
• Adequate organ function and performance status (ECOG score ≤2);
• Signed informed consent.

Exclusion criteria

• Previous treatment with topoisomerase 1 (TOP-1) inhibitor-based therapy;
• Severe cardiac, hepatic, or renal dysfunction or other serious comorbidities;
• History of moderate to severe interstitial lung disease (ILD) with concurrent pulmonary insufficiency;
• Symptomatic brain metastases;
• History of allergy to key components of the investigational ADC drugs (e.g., payload, antibody, or linker);
• Patients with active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or a history of intestinal obstruction or gastrointestinal (GI) perforation;
• Uncontrolled cardiovascular diseases (e.g., NYHA Class III/IV heart failure, myocardial infarction within 6 months);
• Active infections (e.g., HIV, active HBV/HCV infection);
• Pregnant or lactating women.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Xi'an International Medical Center Hospital — Xi'an

Identifiers

NCT: NCT07162259 · IIT2025006

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗