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

September 5, 2025 updated by: Yan Xue

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
      • Xi'an, China
        • Xi'an International Medical Center Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Cohort 1 (HER2 IHC 2+)
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.
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.
Experimental: Cohort 2 (HER2 IHC ≤1+)
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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
PFS1 is defined as the time from signing the informed consent form to the first documented disease progression after initial ADC therapy or death from any cause, whichever occurs first.
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

Outcome Measure
Measure Description
Time Frame
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.
PFS2 is defined as the time from the initiation of the second ADC therapy (ADC2) after progression on the first ADC therapy to the date of further disease progression or death from any cause, whichever occurs first.
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.
PFS-Total is defined as the time from signing the informed consent form to the earliest occurrence of disease progression or death from any cause, regardless of whether it occurs during the first ADC therapy (ADC1), the second ADC therapy (ADC2) following progression, or thereafter.
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.
OS is defined as the time from randomization to death due to any cause.
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
At least 4 weeks after first documented response

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yan Xue

Investigators

  • Principal Investigator: Yan Xue, Xi'an International Medical Center Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

October 1, 2025

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2027

Study Registration Dates

First Submitted

August 18, 2025

First Submitted That Met QC Criteria

September 5, 2025

First Posted (Estimated)

September 9, 2025

Study Record Updates

Last Update Posted (Estimated)

September 9, 2025

Last Update Submitted That Met QC Criteria

September 5, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IIT2025006

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Since the research data involves patient privacy and intellectual property protection from collaborating institutions, the original data will not be publicly shared at this time. Summarized results will be published in academic papers.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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