Efficacy and Safety of Trastuzumab Rezetecan Followed by CDK4/6 Inhibitors and Endocrine Therapy in HR+/HER2-Low/Ultra-Low Advanced Breast Cancer

NCT07037199 | Recruiting Phase 2

• 1 other identifier: SDE-BRCA
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

This multicenter, prospective phase II clinical trial evaluates the efficacy and safety of sequential Trastuzumab rezetecan followed by dalpiciclib plus endocrine therapy (fulvestrant or aromatase inhibitors) in 45 patients with HR+/HER2-low/ultra-low advanced breast cancer. Enrolled patients will receive Trastuzumab rezetecan monotherapy for 6-8 cycles until clinical benefit, then transition to CDK4/6 inhibitors with endocrine therapy until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), overall survival (OS), and treatment-related adverse events (TRAEs). The study will be conducted at Sun Yat-sen Memorial Hospital and collaborating centers.

Conditions

Advanced Breast Cancer

Keywords

endocrine therapy; breast cancer; Trastuzumab rezetecan; CDK4/6 inhibitors

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

  Progression-free survival rate at 2 years, calculated from the date of randomization to the first documented disease progression (per RECIST 1.1) or death due to any cause, whichever occurred first

  2-year PFS

Secondary Outcomes (6)

• Objective Response Rate (ORR)

  ORR (CR+PR rate per RECIST 1.1) with ≥30% tumor reduction at 2 years post-enrollment, assessed by investigators

• Clinical Benefit Rate (CBR)

  CBR (CR+PR+SD≥24 weeks rate per RECIST 1.1) at 2 years post-enrollment, assessed by investigators.

• Disease Control Rate (DCR)

  DCR (CR+PR+SD rate per RECIST 1.1) at 2 years post-enrollment (investigator-assessed)

• Overall Survival (OS)

  OS (time from enrollment to death) at 2-year follow-up (primary endpoint)

• Treatment-Related Adverse Events (TRAEs)

  TRAEs (all AEs from first dose to 30 days post-treatment) graded by CTCAE v5.0, with causality assessment

Study Arms (1)

HR+/HER2-low/ultra-low advanced breast cancer

EXPERIMENTAL

Enrolled patients will be HR+/HER2-low/ultra-low advanced breast cancer patients and receive SHR-A1811 monotherapy for 6-8 cycles until clinical benefit, then transition to dalpiciclib with endocrine therapy until disease progression or unacceptable toxicity.

Drug: Trastuzumab rezetecan + CDK4/6 inhibitors + endocrine therapy

Interventions

Trastuzumab rezetecan + CDK4/6 inhibitors + endocrine therapy DRUG

sequential Trastuzumab rezetecan followed by CDK4/6 inhibitors (Dalpiciclib, Abemaciclib, Ribociclib, Palbociclib) plus endocrine therapy (fulvestrant or aromatase inhibitors)

HR+/HER2-low/ultra-low advanced breast cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet all of the following criteria:
• \. Female patients aged ≥18 years. 2. Pathologically confirmed HER2-low/ultra-low, HR-positive unresectable or metastatic breast cancer:
• HER2-low: IHC 1+ or IHC 2+/ISH-negative；HER2-ultra-low: IHC 0 with membranous staining (\>0 but \<1+). HR+: ≥10% tumor cells with ER/PR nuclear staining (verified by central pathology review).
• Disease stage: Recurrent/metastatic disease; locally recurrent cases must be deemed unresectable by investigators.
• \. Prior therapy:
• Disease progression after endocrine therapy (ET) + CDK4/6 inhibitor in the advanced/metastatic setting.
• Progression within 12 months of adjuvant ET + CDK4/6 inhibitor allowed.
• ≤1 line of prior ET and ≤1 line of chemotherapy for advanced disease. 4. Measurable disease per RECIST 1.1 (including lytic/mixed bone-only metastases).
• \. ECOG PS 0-1. 6. Adequate organ function (no transfusions/G-CSF within 2 weeks prior):
• Hematologic: ANC \>1.5×10⁹/L; platelets \>90×10⁹/L; Hb \>90 g/L.
• Hepatic: Total bilirubin ≤ULN (≤2×ULN if Gilbert's syndrome). ALT/AST ≤1.5×ULN (≤5×ULN with liver metastases). Alkaline phosphatase ≤2.5×ULN.
• Renal: BUN/Cr ≤1.5×ULN.
• Cardiac: LVEF ≥50%;
• QTcF \<470 ms. 7. Voluntary participation with signed informed consent.

You may not qualify if:

• Participants will be excluded if they meet any of the following conditions:
• Prior anti-HER2 therapy at any stage (including HER2-ADCs such as T-DM1 or T-DXd).
• Significant cardiac disease, including:
• \) Heart failure or systolic dysfunction (LVEF \<50%). 2) High-risk/treated angina or arrhythmias (e.g., Type II Mobitz II/third-degree AV block, ventricular tachycardia).
• \) Clinically significant valvular disease. 4) ECG-confirmed transmural myocardial infarction. 5) Uncontrolled hypertension (systolic \>150 mmHg and/or diastolic \>100 mmHg). 3. Interstitial lung disease (ILD)/pneumonitis:
• History of non-infectious ILD requiring steroids.
• Current ILD or suspected ILD that cannot be ruled out by imaging at screening. 4. Impaired drug absorption due to:
• \) Dysphagia, chronic diarrhea, intestinal obstruction, or other factors affecting oral medication intake.
• \. Uncontrolled third-space effusions (e.g., pleural/peritoneal effusions) not manageable by drainage.
• \. Pregnancy, lactation, or unwillingness to use effective contraception during and for 7 months post-treatment.
• Severe comorbidities interfering with treatment (e.g., active HBV, pulmonary infections requiring therapy).
• Any condition deemed unsuitable by investigators.

Sponsors & Collaborators

• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University: lead

Study Sites (1)

Sun Yat-sen Memorial Hospital

Guangzhou, Guangdong, 510120, China

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

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

Study Officials

• JianLi Zhao, PhD

  Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

JianLi Zhao, PhD

CONTACT

008615920589334; zhaojianli1988@126.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Breast cancer center

Model Details: HR+/HER2-low/ultra-low advanced breast cancer

Study Record Dates

• First Submitted: June 13, 2025
• First Posted: June 25, 2025
• Study Start: August 18, 2025
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2030
• Last Updated: December 31, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)