Trastuzumab Deruxtecan (T-DXd) in Patients Who Have Hormone Receptor-negative and Hormone Receptor-positive HER2-low or HER2 IHC 0 Metastatic Breast Cancer

Official title

A Phase 3b, Multicenter, Global, Interventional, Open-label Study of Trastuzumab Deruxtecan (T-DXd), an Anti-HER2-Antibody Drug Conjugate (ADC), in Subjects Who Have Unresectable and/or Metastatic HER2-low or HER2 Immunohistochemistry (IHC) 0 Breast Cancer (DESTINY-Breast15)

Overview

This study will evaluate the safety and efficacy of trastuzumab deruxtecan (T-DXd) in participants with human epidermal growth factor receptor 2 (HER2)-low or HER2 immunohistochemistry (IHC) 0 (who are both hormone receptor \[HR\]-negative and HR-positive) unresectable and/or metastatic breast cancer.

Detailed description

The primary endpoint of interest in this study is time to next treatment (TTNT), a measure that will determine how long T-DXd allows patients to derive clinical benefit from the study drug.

Interventions

• Drug Trastuzumab Deruxtecan
  Intravenous administration, 5.4 mg/kg on Day 1 of each 21-day cycle until radiographic disease progression as assessed by the investigator, unacceptable toxicity, other discontinuation criteria are met, or 2 years after first dose of study drug

Primary outcome measures

• Time From the Start of T-DXd to Initiation of Subsequent Anticancer Treatment (TTNT) [Time frame: Until subsequent therapy or death, assessed up to 24 months]

Secondary outcome measures (12)

• Real-World Progression Free Survival (PFS) [Time frame: Until progression or death, assessed up to 24 months]
• Time From Start of T-DXd to Discontinuation of T-DXd or Death (TTD) [Time frame: Until treatment discontinuation or death, up to 24 months]
• Objective Response Rate (ORR) [Time frame: Until progression, assessed up to 24 months]
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) [Time frame: Up to follow up period, up to 24 months]
• Mean Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ)-C30 Score [Time frame: Assessed up to 24 months]
• Mean Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ)-BR45 Score [Time frame: Assessed up to 24 months]
• Time to First and Definitive Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ) Scales [Time frame: Assessed up to 24 months]
• Mean Change from Baseline in EuroQol Questionnaire-5 Dimensions-5 Levels (EQ-5D-5L) [Time frame: Assessed up to 24 months]
• Mean Change From Baseline in EuroQol Questionnaire-5 Dimensions-5 Levels (EQ-5D-5L) Index Score [Time frame: Assessed up to 24 months]
• Mean Change From Baseline in EuroQol Questionnaire-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale (VAS) [Time frame: Assessed up to 24 months]
• Time to First and Definitive Deterioration in EuroQol Questionnaire-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale (VAS) [Time frame: Assessed up to 24 months]
• Patient's Global Impression of Change (PGI-C) Response [Time frame: Assessed up to 24 months]

Eligibility criteria

Inclusion criteria

• Sign and date the main informed consent form
• Must agree to provide a newly obtained or archival baseline biopsy from primary and/or metastatic lesion.
• Pathologically documented Breast Cancer (BC) tumor

• Is unresectable and/or metastatic.
• Is hormone receptor-negative or hormone receptor-positive.

• Must include percentage of positively stained cells to characterize if hormone receptor-positive or -negative.
• Has confirmed HER2 IHC 1+ or IHC 2+/ISH- (HER2-low) status or HER2 IHC 0 status as determined according to ASCO CAP 2018 guidelines1 based on sample collected during Tissue Screening as described above.
• Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per ASCO CAP guidelines).
• Was never previously treated with anti-HER2 therapy in the metastatic setting.
• Has had at least one and up to two prior lines of therapy in the metastatic setting.

• In participants with hormone receptor-positive HER2-low metastatic BC (Cohort 3):

• Has recurrent disease <2 years from the initiation of adjuvant ET OR
• Has disease progression on CDK4/6 inhibitor-based regimen within 12 months of completion of adjuvant therapy with a CDK4/6 inhibitor OR
• Has disease progression within the first 12 months of CDK4/6 in the first line metastatic setting
• Presence of at least one measurable lesion based on computed tomography or magnetic resonance imaging.
• Participants with brain metastases are allowed in the study. The brain lesion(s) should be small (<2 cm), untreated, asymptomatic, not requiring urgent medical intervention, and are asymptomatic and clinically stable.
• Has an Eastern Cooperative Oncology Group performance status of 0 or 1.
• Has a minimum life expectancy of 12 weeks at Screening.
• Has a left ventricular ejection fraction ≥50% within 28 days before enrollment.
• Has adequate organ and bone marrow function within 28 days before enrollment.
• Has adequate treatment washout period before enrollment.
• Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception.

Exclusion criteria

• Prior treatment with an antibody drug conjugate (ADC).
• Uncontrolled or significant cardiovascular disease.
• Has a corrected QT interval prolongation.
• Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
• Has spinal cord compression or clinically active central nervous system metastases.
• Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral BC.
• Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
• Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
• Has an uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
• Active primary immunodeficiency, known uncontrolled active human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.
• Has history of receiving a live, attenuated vaccine (messenger RNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study drug.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline.
• Is pregnant or breastfeeding or planning to become pregnant.
• Lung-specific intercurrent clinically significant illnesses.
• Any autoimmune, connective tissue, or inflammatory disorders.
• Prior complete pneumonectomy.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 15 centers

• Centro de Oncologia - Unidade Brasília - Hospital Sírio Libanês — Brasília
• CIONC-Centro Integrado de Oncologia de Curitiba — Curitiba
• Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer — Curitiba
• CEPON - Centro de Pesquisas Oncológicas de Santa Catarina — Florianópolis
• Oncosite - Centro de Pesquisa Clinica e Oncologia — Ijuí
• Fundação Doutor Amaral Carvalho — Jaú
• Instituto de Cancer de Londrina — Londrina
• Hospital das Clínicas FMRP-USP — Riberão Preto
• … and 7 more centers

China · 14 centers

• Beijing Hospital — Beijing
• 307 Hospital of PLA — Beijing
• Fujian Cancer Hospital — Fujian
• Sun Yat sen University Cancer Center — Guangzhou
• Zhejiang Cancer Hospital — Hangzhou
• Anhui Provincial Cancer Hospital — Hefei
• Shandong Cancer Hospital — Jinan
• Yunnan Cancer Hospital — Kunming
• … and 6 more centers

Spain · 14 centers

• Hospital de la Santa Creu i Sant Pau — Barcelona
• ICO l'Hospitalet - Hospital Duran i Reynals — Barcelona
• Hospital Universitario Donostia — Donostia / San Sebastian
• Hospital Universitario Virgen de las Nieves — Granada
• Complejo Hospitalario Universitario Insular Materno-Infantil — Las Palmas de Gran Canaria
• Hospital Beata Maria Ana — Madrid
• … and 8 more centers

Italy · 11 centers

• Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico Bari — Bari
• Azienda Ospedaliera Universitaria Policlinico Sant Orsola Malpighi IRCCS — Bologna
• Istituto Nazionale per la Ricerca sul Cancro di Genova — Genova
• Ospedale San Raffaele — Milan
• Humanitas Istituto Clinico Catanese — Misterbianco
• Istituto Nazionale Tumori Fondazione G Pascale — Naples
• IOV - Istituto Oncologico Veneto IRCCS — Padova
• Nuovo Ospedale di Prato — Prato
• … and 3 more centers

Netherlands · 8 centers

• Amsterdam UMC, Locatie VUMC — Amsterdam
• Amphia Ziekenhuis Molengracht — Breda
• Medisch Centrum Leeuwarden — Leeuwarden
• Alrijne Ziekenhuis Leiden — Leiden
• Maastricht University Medical Center — Maastricht
• Haga Ziekenhuis — The Hague
• Elisabeth TweeSteden Ziekenhuis — Tilburg
• Bernhoven Uden — Uden

Belgium · 7 centers

• Institut Jules Bordet — Anderlecht
• GZA Ziekenhuizen — Antwerp
• Universitair Ziekenhuis Brussel — Brussels
• Cliniques Universitaires Saint-Luc — Brussels
• UZ Leuven — Leuven
• Centre Hospitalier Universitaire de Liege Sart-Tilman — Liège
• GZA Ziekenhuizen — Wilrijk

United States · 5 centers

• Mount Sinai Medical Center — Miami Beach
• USF College of Medicine — Tampa
• Dana-Farber Cancer Institute — Boston
• Beth Israel Lahey Health — Burlington
• Overlook Medical Center — Summit

Ireland · 5 centers

• Cork University Hospital — Cork
• St Vincent's University Hospital — Dublin
• St James Hospital — Dublin
• Beaumont Hospital — Dublin
• Galway University Hospital — Galway

Portugal · 5 centers

• Hospital de Braga — Braga
• Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE — Lisbon
• Fundação Champalimaud — Lisbon
• Centro Hospitalar de Lisboa Norte E P E Hospital de Santa Maria — Lisbon
• Instituto Português de Oncologia do Porto Francisco Gentil, EPE — Porto

Australia · 4 centers

• Mater Hospital Sydney — North Sydney
• Monash Medical Centre Moorabbin — East Bentleigh
• GenesisCare St Andrews Hospital — Adelaide
• Fiona Stanley Hospital — Murdoch

Publications

• Yaziji H, Hornick JL, Troxell ML. The Suitability of Repurposed, Legacy HER2 Immunohistochemistry Assays for the Detection of HER2 Low and Ultralow Expression: Current Limitations and Potential Considerations. Appl Immunohistochem Mol Morphol. 2026 Jan 1;34(1):1-4. doi: 10.1097/PAI.0000000000001296. Epub 2025 Dec 4. No abstract available. PMID 41342740

Identifiers

NCT: NCT05950945 · DS8201-0001-CIS-MA · 2023-505616-38-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗