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

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

This trial will test whether starting with trastuzumab rezetecan and then switching to a CDK4/6 inhibitor plus endocrine therapy helps women with HR-positive, HER2-low or ultra-low advanced breast cancer live longer without disease progression.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 45 (estimated)
• Ages: 18 Years and up
• Sex: Female
• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University (Academic / other)
• Drugs / interventions: chemotherapy, Trastuzumab
• Locations: 1 site (Guangzhou, Guangdong)
• Trial ID: NCT07037199 on ClinicalTrials.gov

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.

Who should consider this trial

Good fit: Ideal candidates are adult women with HR-positive, HER2-low or ultra-low unresectable or metastatic breast cancer who have measurable disease, an ECOG performance status of 0–1, and prior progression after endocrine therapy plus a CDK4/6 inhibitor within the allowed prior therapy limits.

Not a fit: Patients who are not HR-positive, have HER2-negative disease outside the low/ultra-low definitions, have poor performance status (ECOG >1), inadequate organ function, or who have received extensive prior lines of therapy are unlikely to benefit.

Why it matters

Potential benefit: If successful, this approach could extend progression-free survival and offer a new sequential treatment option for women with HR+/HER2-low advanced breast cancer.

How similar studies have performed: Antibody–drug conjugates targeting HER2 have shown meaningful benefit in HER2-low breast cancer and CDK4/6 inhibitors with endocrine therapy are established in HR-positive disease, but the exact sequential use tested here is relatively novel with limited direct data.

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.

Where this trial is running

Guangzhou, Guangdong

• 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

Conditions Advanced Breast Cancer; endocrine therapy; breast cancer; Trastuzumab rezetecan; CDK4/6 inhibitors