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

Обзор

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.

Вмешательства

• Препарат 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)

Первичные конечные точки

• Progression-free survival (PFS) [Срок оценки: 2-year PFS]

Вторичные конечные точки (6)

• Objective Response Rate (ORR) [Срок оценки: ORR (CR+PR rate per RECIST 1.1) with ≥30% tumor reduction at 2 years post-enrollment, assessed by investigators]
• Clinical Benefit Rate (CBR) [Срок оценки: CBR (CR+PR+SD≥24 weeks rate per RECIST 1.1) at 2 years post-enrollment, assessed by investigators.]
• Disease Control Rate (DCR) [Срок оценки: DCR (CR+PR+SD rate per RECIST 1.1) at 2 years post-enrollment (investigator-assessed)]
• Overall Survival (OS) [Срок оценки: OS (time from enrollment to death) at 2-year follow-up (primary endpoint)]
• Treatment-Related Adverse Events (TRAEs) [Срок оценки: TRAEs (all AEs from first dose to 30 days post-treatment) graded by CTCAE v5.0, with causality assessment]
• Quality of Life (QoL) [Срок оценки: QoL (EORTC QLQ-C30) evaluated serially from baseline to treatment discontinuation over 2 years]

Критерии участия

Критерии включения

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:

• 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.

3\. 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).

5\. 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.

Критерии исключения

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:

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:

• 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:

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:

• Severe comorbidities interfering with treatment (e.g., active HBV, pulmonary infections requiring therapy).
• Any condition deemed unsuitable by investigators.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Sun Yat-sen Memorial Hospital — Гуанчжоу

Идентификаторы

NCT: NCT07037199 · SDE-BRCA

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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