Journal article
A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial.
- Peters S Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. Electronic address: Solange.Peters@chuv.ch.
- Danson S Department of Oncology and Metabolism & Sheffield Experimental Cancer Medicine Centre, University of Sheffield, Weston Park Hospital, Sheffield, United Kingdom.
- Hasan B European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
- Dafni U School of Health Sciences, National and Kapodistrian University of Athens & Frontier Science Foundation-Hellas, Athens, Greece.
- Reinmuth N Asklepios Kliniken GmbH, Asklepios Fachkliniken Muenchen, Gauting, Germany.
- Majem M Department of Medical Oncology, Hospital De La Santa Creu I Sant Pau, Barcelona, Spain; Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain.
- Tournoy KG Faculty of Medicine and Life Sciences, Ghent University and Onze-Lieve-Vrouwziekenhuis (OLV), Aalst, Belgium.
- Mark MT Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; Department of Medical Oncology, Cantonal Hospital Graubuenden, Chur, Switzerland.
- Pless M Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; Department of Medical Oncology and Hematology, Cantonal Hospital Winterthur, Winterthur, Switzerland.
- Cobo M Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; Unidad Gestion Intercentros of Medical Oncology. Regional and Virgen de la Victoria University Hospitals (IBIMA), Málaga, Spain.
- Rodriguez-Abreu D Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.
- Falchero L Department of Pneumology and Thoracic Oncology, Hopital Nord-Ouest, Villefranche-sur-Saône Cedex, France.
- Moran T Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; Department of Medical Oncology, Institut Català d'Oncologia (ICO) Badalona, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), Badalona Applied Research Group in Oncology (B-ARGO), Barcelona, Spain.
- Ortega Granados AL Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; Department of Medical Oncology, Hospital Universitario de Jaén, Jaén, Spain.
- Monnet I Department of Pneumology, Centre Hopitalier Intercommunal De Créteil, Créteil, France.
- Mohorcic K Department of Medical Oncology, University Clinic Golnik, Golnik, Slovenia.
- Sureda BM Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; El Instituto de Investigación Sanitaria y Biomédica de Alicante (SABIAL), Hospital Universitario Alicante, Alicante, Spain.
- Betticher D Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; Department of Medical Oncology, Fribourg Cantonal Hospital (HFR), Fribourg, Switzerland.
- Demedts I Department of Pulmonary Diseases, AZ Delta, Roeselare, Belgium.
- Macias JA Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; Department of Hematology and Oncology, Hospital General Universitario Morales Meseguer, Murcia, Spain.
- Cuffe S Cancer Trials Ireland, Dublin, Ireland; Department of Medical Oncology, St. James's Hospital, Dublin, Ireland.
- Luciani A Department of Medical Oncology, Ospedale San Paolo, Milano, Italy.
- Sanchez JG Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; Department of Medical Oncology, University Hospital Arnau de Vilanova, Valencia, Spain.
- Curioni-Fontecedro A Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; Department for Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.
- Gautschi O Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; Cantonal Hospital Lucerne, Lucern, Switzerland.
- Price G Department of Medical Oncology, Aberdeen Royal Infirmary NHS Grampian, Aberdeen, United Kingdom.
- Coate L Cancer Trials Ireland, Dublin, Ireland; Mid-Western Cancer Centre, University Hospital Limerick, Limerick, Ireland.
- von Moos R Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; Department of Medical Oncology, Cantonal Hospital Graubuenden, Chur, Switzerland.
- Zielinski C Clinical Division of Oncology, Medical University Vienna, Vienna, Austria; Central European Cooperative Oncology Group, Vienna, Austria.
- Provencio M Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; Department of Medical Oncology, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain.
- Menis J European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology Department, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy.
- Ruepp B European Thoracic Oncology Platform (ETOP), Bern, Switzerland.
- Pochesci A European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
- Roschitzki-Voser H European Thoracic Oncology Platform (ETOP), Bern, Switzerland.
- Besse B European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium; Gustave Roussy Cancer Center Villejuif, Paris Saclay University, Orsay, France.
- Rabaglio M European Thoracic Oncology Platform (ETOP), Bern, Switzerland.
- O'Brien MER Department of Medical Oncology, Royal Marsden Hospital, Sutton, United Kingdom.
- Stahel RA Department for Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.
- 2020-06-23
Published in:
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. - 2020
English
INTRODUCTION
Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC.
METHODS
Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate.
RESULTS
A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%.
CONCLUSIONS
Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.
Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC.
METHODS
Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate.
RESULTS
A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%.
CONCLUSIONS
Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.
- Language
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- English
- Open access status
- closed
- Identifiers
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- DOI 10.1016/j.jtho.2020.06.011
- PMID 32565388
- Persistent URL
- https://sonar.ch/global/documents/135276
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