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

NCT ID: NCT07037199

Last Updated: 2025-12-31

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-08-18
• Study Completion Date: 2030-06-30

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

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.

Group Type: EXPERIMENTAL

Trastuzumab rezetecan + CDK4/6 inhibitors + endocrine therapy

Intervention Type: DRUG

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

Interventions

Trastuzumab rezetecan + CDK4/6 inhibitors + endocrine therapy

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Participants must meet all of the following criteria:

1. Female patients aged ≥18 years. 2. Pathologically confirmed HER2-low/ultra-low, HR-positive unresectable or metastatic breast cancer:

1. 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).

2. Disease stage: Recurrent/metastatic disease; locally recurrent cases must be deemed unresectable by investigators.

3. Prior therapy:

1. Disease progression after endocrine therapy (ET) + CDK4/6 inhibitor in the advanced/metastatic setting.

2. Progression within 12 months of adjuvant ET + CDK4/6 inhibitor allowed.

3. ≤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).

5. ECOG PS 0-1. 6. Adequate organ function (no transfusions/G-CSF within 2 weeks prior):

1. Hematologic: ANC >1.5×10⁹/L; platelets >90×10⁹/L; Hb >90 g/L.

2. 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.

3. Renal: BUN/Cr ≤1.5×ULN.

4. Cardiac: LVEF ≥50%;

5. QTcF <470 ms. 7. Voluntary participation with signed informed consent.

Exclusion Criteria

Participants will be excluded if they meet any of the following conditions:

1. Prior anti-HER2 therapy at any stage (including HER2-ADCs such as T-DM1 or T-DXd).

2. Significant cardiac disease, including:

1) 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).

3) 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:

1. History of non-infectious ILD requiring steroids.

2. Current ILD or suspected ILD that cannot be ruled out by imaging at screening. 4. Impaired drug absorption due to:

1) Dysphagia, chronic diarrhea, intestinal obstruction, or other factors affecting oral medication intake.

5. Uncontrolled third-space effusions (e.g., pleural/peritoneal effusions) not manageable by drainage.

6. Pregnancy, lactation, or unwillingness to use effective contraception during and for 7 months post-treatment.

7. Other exclusions:

1. Severe comorbidities interfering with treatment (e.g., active HBV, pulmonary infections requiring therapy).

2. Any condition deemed unsuitable by investigators.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

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

OTHER

Sponsor Role: lead

Responsible Party

Jianli Zhao

Breast cancer center

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

JianLi Zhao, PhD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

Sun Yat-sen Memorial Hospital

Guangzhou, Guangdong, China

Site Status: RECRUITING

Countries

China

Central Contacts

JianLi Zhao, PhD

Role: CONTACT

Phone: 008615920589334

Email: zhaojianli1988@126.com

Facility Contacts

Jianli Zhao

Role: primary

Other Identifiers

SDE-BRCA

Identifier Type: -

Identifier Source: org_study_id