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

NCT06837792 | Recruiting Phase 2

• 1 other identifier: 4-2023-1363
• Study Type: interventional
• Target: 141
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Keywords

low HER2, advanced breast cancer, T-DXd

Outcome Measures

Primary Outcomes (1)

• PFS according to RECIST 1.1 in the ITT population.

  Progression-free survival (PFS) is defined as the time from day 1 of the randomization to the first evidence of disease progression or death, whichever is earlier.

  from date of randomization until the date of first evidence of disease progression or date of death from any cause, whichever came first, assessed up to 36 months

Secondary Outcomes (6)

• OS

  On treatment: Every 3-4 weeks from date of randomization until the date of of death from any cause, assessed up to 36 months

• ORR

  From screening and every 9 weeks for 54 weeks from randomization and every 12 weeks after 54 weeks from randomization to objective (RECIST 1.1 defined) disease progression, withdrawal of subject consent, or unacceptable toxicity, up to 36 months

• Progression-free survival (PFS2)

  from date of randomization until the date of first evidence of second disease progression or date of death from any cause, whichever came first, assessed up to 36 months

• safety

  From administration of the first dose of study treatment and every 3-4 weeks on treatment and until 90 days after the last administration of the investigational drug or the initiation of new antitumor therapy, up to 36 months

• Quality of life (QoL) by EORTC-QLQ-C30

  From administration of the first dose of study treatment and every 9 weeks (±3 days) until 2 years (even after disease progression))

Study Arms (2)

Experimental treatment arm(T-DXd arm)

EXPERIMENTAL

Trastuzumab deruxtecan (T-DXd)

Drug: Experimental treatment arm

Control treatment arm

ACTIVE COMPARATOR

Endocrine therapy of physician's choice\[TPC\]

Drug: Control treatment arm

Interventions

Experimental treatment arm DRUG

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

Also known as: T-DXd arm

Experimental treatment arm(T-DXd arm)

Control treatment arm DRUG

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

Also known as: Endocrine therapy of physician's choice[TPC]

Control treatment arm

Eligibility Criteria

• Age: 19 Years+
• Gender Eligibility Details: Female patients
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed hormone receptor-positive advanced breast cancer patients
• Have recurrent, metastatic, or unresectable disease
• Have HER2-low expression status, defined as IHC 2+/ISH- or IHC 1+,with a validated assay by ASCO/CAP guidelines
• Have no previous history of HER2-positive breast cancer (IHC 3+ or ISH+) by ASCO/CAP guidelines
• The hormone receptor (HR) status is defined by ER/PR IHC nuclear staining, and ER or PgR ≥1% is defined as hormone receptor-positive status
• Patients who progressed on 1st line endocrine + CDK4/6 inhibitor therapy for advanced breast cancer and received no other systemic therapy for advanced breast cancer. The all FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib, and Abemaciclib) are allowed, and combination with aromatase inhibitors or fulvestrant are both allowed.
• Patients who have received chemotherapy or adjuvant endocrine therapy in the neo-adjuvant or adjuvant setting are eligible.
• Female patients with ≥19 years of age
• Radiologic or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment
• Patients must have at least one measurable lesion by RECIST 1.1 criteria, which was not previously irradiated or showed objective progression after irradiation to that lesion
• Patients must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory and other exploratory biomarker analyses
• Patients with ECOG performance status 0 or 1
• Both pre- and post-menopausal patients are eligible, and pre-menopausal patients should receive ovarian function suppression treatment (GnRH agonist injection or surgical bilateral oophorectomy) while receiving fulvestrant or aromatase inhibitor treatment in the control arm.
• Adequate organ function for treatment Adequate organ and bone marrow function within 14 days before randomization/enrolment as described below:"
• a) Haemoglobin: ≥ 9.0 g/dL NOTE: Participants requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥9.0 g/dL are not eligible. (Red blood cell transfusion is not allowed within 1 week prior to C1D1) b) Serum albumin: ≥ 2.5 g/dL c) International normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time: ≤ 1.5 × ULN d) Absolute neutrophil count (ANC) ≥1500 cells/mm3

You may not qualify if:

• Previous history of T-DXd or Dato-Dxd treatment for advanced breast cancer
• Severe Cardiac disease (e.g., uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within the past year, Left Ventricular Ejection Fraction (LVEF) \> grade 2)
• Patients with a medical history of myocardial infarction (MI) within 6 months before randomization/enrolment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI.
• Current active hepatic or biliary disease (except for Gilbert syndrome, asymptomatic gallstones, liver metastasis or stable chronic liver disease per investigator assessment)
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of T-DXd.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
• Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to \>Grade 2 for at least 3 months prior to \[randomization/enrollment/Cycle 1 Day 1\] and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, such as:
• Chemotherapy-induced neuropathy
• Fatigue
• Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies which may include:
• Hypothyroidism/hyperthyroidism
• Type 1 diabetes
• Hyperglycaemia
• Adrenal insufficiency

Sponsors & Collaborators

• Yonsei University: lead

Study Sites (1)

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

Seoul, South Korea

RECRUITING

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2024
• First Posted: February 20, 2025
• Study Start: October 1, 2023
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: April 29, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)