A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer

Autor: Seock-Ah Im, Patrick Neven, John Crown, Rosa-Maria Espadero, Noelia Martínez, Yen-Shen Lu, Jonas Bergh, Thomas Bogenrieder, J. Alejandro Pérez-Fidalgo, Peter Schmid, Guy Jerusalem, Laura Schlieker, Serafin Morales, Dennis Chin-Lun Huang, Douglas Adamson, Javier Cortes, Anthony Gonçalves, Keun Seok Lee, Marie-Paule Sablin, Aleix Prat
Přispěvatelé: Queen Mary University of London (QMUL), Institut Curie [Paris], Karolinska University Hospital [Stockholm], Seoul National University Hospital, National Taiwan University Hospital [Taipei], Ramon & Cajal University Hospital, UZ Leuven - campus Gasthuisberg, Hospital of National Cancer Center [Goyang], Hospital Universitario Arnau de Vilanova de Lleida, Biomedical Research Institute [Valencia, Spain] (INCLIVA ), Ninewells Hospital and Medical School [Dundee], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre Hospitalier Universitaire de Liège (CHU-Liège), Boehringer Ingelheim Pharma GmbH & Co. KG, St Vincent's University Hospital, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Institute of Oncology Prof. Dr. Alexandru Trestioreanu (IOB), Institut Català de la Salut, [Schmid P] Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK. [Sablin MP] Department of Drug Development and Innovation, Institut Curie, Paris, France. [Bergh J] Department of Oncology-Pathology, Karolinska Institutet and Breast Cancer Centre, Cancer Theme, Karolinska University Hospital, Stockholm, Sweden. [Im SA] Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. [Lu YS] Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. [Martínez N] Department of Oncology, Ramon y Cajal University Hospital, Madrid, Spain. [Cortés J] Breast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Department of Oncology, IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Oncology
Receptor
ErbB-2
Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES]
chemistry.chemical_compound
0302 clinical medicine
Breast cancer
Exemestane
Antineoplastic Combined Chemotherapy Protocols
terapéutica::farmacoterapia::farmacoterapia combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS
DIAGNÓSTICOS Y TERAPÉUTICOS]
Clinical endpoint
Insulin-like growth factor
Neoplasm Metastasis
Aged
80 and over
neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES]
0303 health sciences
education.field_of_study
Hazard ratio
Therapeutics::Drug Therapy::Drug Therapy
Combination [ANALYTICAL
DIAGNOSTIC AND THERAPEUTIC TECHNIQUES
AND EQUIPMENT]
Disease Management
Middle Aged
Prognosis
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Metastatic breast cancer
Treatment Outcome
Receptors
Estrogen
030220 oncology & carcinogenesis
Female
Receptors
Progesterone
Life Sciences & Biomedicine
Research Article
medicine.drug
Adult
medicine.medical_specialty
Maximum Tolerated Dose
Population
Breast Neoplasms
[SDV.CAN]Life Sciences [q-bio]/Cancer
Antibodies
Monoclonal
Humanized
lcsh:RC254-282
03 medical and health sciences
Internal medicine
Biomarkers
Tumor
medicine
Hormone receptor-positive
Humans
Xentuzumab
Everolimus
education
Adverse effect
Aged
Neoplasm Staging
030304 developmental biology
Science & Technology
business.industry
diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS
DIAGNÓSTICOS Y TERAPÉUTICOS]
Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL
DIAGNOSTIC AND THERAPEUTIC TECHNIQUES
AND EQUIPMENT]
medicine.disease
Androstadienes
chemistry
Mama - Càncer - Tractament
Medicaments - Eficàcia
business
HER2-negative
Zdroj: Breast Cancer Research
Breast Cancer Research, 2021, 23 (1), pp.8. ⟨10.1186/s13058-020-01382-8⟩
Breast Cancer Research, Vol 23, Iss 1, Pp 1-11 (2021)
Breast Cancer Research : BCR
Scientia
ISSN: 1465-5411
1465-542X
DOI: 10.1186/s13058-020-01382-8⟩
Popis: Background Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). Methods Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). Results MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). Conclusions Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). Trial registration ClinicalTrials.gov, NCT02123823. Prospectively registered, 8 March 2013.
Databáze: OpenAIRE
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