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NCT Number: NCT07162259

Cohort Study on Sequential ADC Therapy 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.

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Key information

Conditions

Breast Neoplasms Breast Diseases Neoplasms Neoplasms by Site Skin Diseases Skin and Connective Tissue Diseases

Age range

18 year–85 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 4

Primary location

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

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

Drug

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.

First-line SG followed by T-DXd upon progression

Drug

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 outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. 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.

  3. 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.

  4. Objective Response Rate（ORR）

    Time frame: At least 4 weeks after first documented response

Study contacts

Contact information is provided by the study sponsor or research team.

Junmei Zhang

CONTACT

[email protected]

008618092309080

Sponsors and collaborators

Lead sponsor

Yan Xue

Other

Registry information

Official study 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

Important dates

Study start
2025
Primary completion
2027
Study completion
2027
First posted
Sep 9, 2025
Registry last updated
Sep 9, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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