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

Yan Xue

Status and phase: Not yet enrolling; Phase 4

Conditions: Breast Neoplasms

Treatments: Drug: First-line T-DXd followed by SG upon disease progression; Drug: First-line SG followed by T-DXd upon progression

Study type: Interventional

Funder types: Other

Identifiers

NCT07162259

IIT2025006

Details and patient eligibility

About

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.

Enrollment: 40 estimated patients

Sex: Female

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Adult patients ≥18 years old;
2. 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;
3. Prior treatment with CDK4/6i combined with endocrine therapy, with radiologically confirmed disease progression;
4. Presence of evaluable lesions;
5. Received ≤2 lines of chemotherapy for advanced disease;
6. Adequate organ function and performance status (ECOG score ≤2);
7. Signed informed consent.

Exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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40 participants in 2 patient groups

Cohort 1 (HER2 IHC 2+)

Experimental group

Description:

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

Treatment:

Drug: First-line T-DXd followed by SG upon disease progression

Cohort 2 (HER2 IHC ≤1+)

Experimental group

Description:

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.

Treatment:

Drug: First-line SG followed by T-DXd upon progression