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 |
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| Affiliation: | 1. Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland;2. Department of Oncology and Metabolism & Sheffield Experimental Cancer Medicine Centre, University of Sheffield, Weston Park Hospital, Sheffield, United Kingdom;3. European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium;4. School of Health Sciences, National and Kapodistrian University of Athens & Frontier Science Foundation-Hellas, Athens, Greece;5. Asklepios Kliniken GmbH, Asklepios Fachkliniken Muenchen, Gauting, Germany;6. Department of Medical Oncology, Hospital De La Santa Creu I Sant Pau, Barcelona, Spain;7. Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain;8. Faculty of Medicine and Life Sciences, Ghent University and Onze-Lieve-Vrouwziekenhuis (OLV), Aalst, Belgium;9. Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland;10. Department of Medical Oncology, Cantonal Hospital Graubuenden, Chur, Switzerland;11. Department of Medical Oncology and Hematology, Cantonal Hospital Winterthur, Winterthur, Switzerland;12. Unidad Gestion Intercentros of Medical Oncology. Regional and Virgen de la Victoria University Hospitals (IBIMA), Málaga, Spain;13. Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain;14. Department of Pneumology and Thoracic Oncology, Hopital Nord-Ouest, Villefranche-sur-Saône Cedex, France;15. 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;p. Department of Medical Oncology, Hospital Universitario de Jaén, Jaén, Spain;q. Department of Pneumology, Centre Hopitalier Intercommunal De Créteil, Créteil, France;r. Department of Medical Oncology, University Clinic Golnik, Golnik, Slovenia;s. El Instituto de Investigación Sanitaria y Biomédica de Alicante (SABIAL), Hospital Universitario Alicante, Alicante, Spain;t. Department of Medical Oncology, Fribourg Cantonal Hospital (HFR), Fribourg, Switzerland;u. Department of Pulmonary Diseases, AZ Delta, Roeselare, Belgium;v. Department of Hematology and Oncology, Hospital General Universitario Morales Meseguer, Murcia, Spain;w. Cancer Trials Ireland, Dublin, Ireland;x. Department of Medical Oncology, St. James''s Hospital, Dublin, Ireland;y. Department of Medical Oncology, Ospedale San Paolo, Milano, Italy;z. Department of Medical Oncology, University Hospital Arnau de Vilanova, Valencia, Spain;11. Department for Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland;22. Cantonal Hospital Lucerne, Lucern, Switzerland;33. Department of Medical Oncology, Aberdeen Royal Infirmary NHS Grampian, Aberdeen, United Kingdom;44. Mid-Western Cancer Centre, University Hospital Limerick, Limerick, Ireland;55. Clinical Division of Oncology, Medical University Vienna, Vienna, Austria;66. Central European Cooperative Oncology Group, Vienna, Austria;77. Department of Medical Oncology, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain;88. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy;99. Medical Oncology Department, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy;1010. European Thoracic Oncology Platform (ETOP), Bern, Switzerland;1111. Gustave Roussy Cancer Center Villejuif, Paris Saclay University, Orsay, France;1212. Department of Medical Oncology, Royal Marsden Hospital, Sutton, United Kingdom |
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| Abstract: | IntroductionReceptor 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.MethodsPatients 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.ResultsA 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%.ConclusionsDenosumab 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. |
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| Keywords: | NSCLC RANK RANKL Denosumab Bone metastases |
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