RecruitingPhase 2NCT06837792

Trastuzumab Deruxtecan vs Endocrine Therapy in Low-HER2 HR+ Advanced Breast Cancer

The Exploratory Randomized Phase II Study of Trastuzumab Deruxtecan Versus Endocrine Therapy of Physician's Choice in Low-HER2 Expressing Hormone Receptor-positive Advanced Breast Cancer Patients

Sponsor

Yonsei University

Enrollment

141 participants

Start Date

Oct 1, 2023

Study Type

INTERVENTIONAL

Conditions

Hormone Receptor(HR)-Positive, Low HER2 Advanced Breast Cancer Patients (HER2 IHC 1+ or 2+ & ISH Negative)

Summary

"This is a randomized phase II, two-arm, open label, clinical trial to identify LP-WGS ctDNA biomarker to predict T-DXd response in low-HER2 expressing advanced breast cancer patients compared with endocrine therapy. The hormone receptor (HR)-positive low-HER2 advanced breast cancer patients (HER2 IHC 1+ or 2+ \& ISH negative, n=141) who progressed on 1st line endocrine + CDK4/6 inhibitor therapy and received no other systemic therapy for advanced disease are enrolled in this study. Patients are 2:1 randomized to receive T-DXd (5.4mg/kg every 3 weeks, n=94) or endocrine therapy of physician's choice (TPC: fulvestrant, fulvestrant + alpelisib, Fulvestrant + Capivasertib, exemestane, exemestane + everolimus, or tamoxifen, n=47, fulvestrant + alpelisib can be selected in PIK3CA activating mutation positive patients, Fulvestrant + Capivasertib can be selected in 1 or More mutation positive of PIK3CA/AKT1/PTEN). The mandatory baseline archival tissue and ctDNA collection followed by on-treatment ctDNA collection (Cycle 1, Cycle 2, and Cycle 6) and ctDNA collection at progression will be performed in this study. The primary endpoint is PFS after randomization in two treatment arms. The secondary endpoints include overall survival (OS), objective response rate (ORR), progression-free survival (PFS2), adverse events by CTCAE 5.0 criteria, and Quality of life (QoL) measured by EORTC-QLQ-C30 and EORTC-QLQ-BR23 evaluated by questionnaire. The exploratory endpoints are to identify ctDNA biomarkers to predict the TDxd treatment outcome (PFS, OS, ORR) compared to endocrine therapy in HER2-low advanced breast cancer patients and to assess the accordance of genomic profiles between ctDNA and tumor tissues. Predictive biomarkers include copy number aberration (CNA) of gene loci, total ctDNA CNA burden, mutations, ctDNA-based molecular subtype, or HER2 amplicon copy number on LP-WGS ctDNA analysis. The investigator believe this trial will identify crucial circulating biomarkers for T-DXd treatment response in low-HER2 patients, which can guide right patient selection and potential molecular target identification to maximize T-DXd response and to overcome T-DXd resistance.

Eligibility

Sex: FEMALEMin Age: 19 Years

Plain Language Summary

Simplified for easier understanding

This study compares trastuzumab deruxtecan (T-DXd) — an antibody that delivers chemotherapy directly into HER2-expressing cancer cells — to standard hormone therapy in women with hormone receptor-positive, HER2-low advanced breast cancer whose disease progressed after a CDK4/6 inhibitor. **You may be eligible if...** - You are a woman with confirmed hormone receptor-positive advanced breast cancer - Your tumor shows low-level HER2 expression (IHC 1+ or IHC 2+ without gene amplification) - Your cancer progressed after first-line treatment with a CDK4/6 inhibitor (such as palbociclib, ribociclib, or abemaciclib) plus hormone therapy - You have not received any other systemic treatment for advanced disease **You may NOT be eligible if...** - Your cancer is HER2-positive (high expression) - You have had prior T-DXd or similar antibody-drug conjugate treatment - You have severe lung disease, uncontrolled brain metastases, or significant organ dysfunction - You are pregnant or breastfeeding Talk to your doctor to see if this trial is right for you.

This summary was AI-generated to explain the trial in plain language. It is not medical advice. Always discuss eligibility with your doctor before enrolling in a clinical trial.

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Interventions

DRUGExperimental treatment arm

Trastuzumab deruxtecan (T-DXd) 5.4mg/kg intravenous infusion every 3 weeks. (1 cycle = 3 weeks)

DRUGControl treatment arm

1. Fulvestrant intramuscular injection of two 250mg injection every 4 weeks (every 2 weeks for the first cycle, 1 cycle = 4 weeks) 2. Fulvestrant (administered same as above) + alpelisib 300mg oral administration every day (1 cycle = 4 weeks)\* 3. Exemestane 25mg oral administration every day (1 cycle = 4 weeks) 4. Exemestane 25mg + everolimus 10mg oral administration every day (1 cycle = 4 weeks) 5. Tamoxifen 20mg oral administration every day (1 cycle = 4 weeks) 6. Fulvestrant (administered same as above) + Capivasertib 400mg oral administration twice a day(dosed on Days 1 to 4 in each week of a 28-day treatment cycle) * fulvestrant + alpelisib can be selected in PIK3CA activating mutation positive patients * Fulvestrant + Capivasertib can be selected in 1 or More mutation positive of PIK3CA/AKT1/PTEN

Locations(1)

Division of Medical Oncology, Yonsei Cancer Center, Yonsei Univ. College of Medicine

Seoul, South Korea

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NCT06837792