Trastuzumab rezetecan followed by CDK4/6 inhibitor plus hormone therapy for HR+/HER2‑low/ultra‑low advanced breast cancer

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

What this trial studies

This multicenter, prospective Phase II trial will enroll 45 patients with HR-positive, HER2-low or HER2-ultra-low unresectable or metastatic breast cancer. Participants will receive trastuzumab rezetecan monotherapy for 6–8 cycles and, if they derive clinical benefit, will transition to dalpiciclib combined with endocrine therapy (fulvestrant or an aromatase inhibitor) until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival, and secondary endpoints include objective response rate, overall survival, and treatment-related adverse events. The trial is led by Sun Yat-sen Memorial Hospital with participating centers in the region.

Why it matters

Who can join: the full rules

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.

Where it's running

• Sun Yat-sen Memorial Hospital
  Guangzhou, Guangdong, China Recruiting

Study contacts

• Principal investigator: JianLi Zhao, PhD — Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Study coordinator: JianLi Zhao, PhD
• Email: zhaojianli1988@126.com
• Phone: 008615920589334

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.