@article{3103821,
    title = "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",
    author = "Peters, S. and Danson, S. and Hasan, B. and Dafni, U. and Reinmuth, N. and Majem, M. and Tournoy, K.G. and Mark, M.T. and Pless, M. and Cobo, M. and Rodriguez-Abreu, D. and Falchero, L. and Moran, T. and Ortega Granados, A.L. and Monnet, I. and Mohorcic, K. and Sureda, B.M. and Betticher, D. and Demedts, I. and Macias, J.A. and Cuffe, S. and Luciani, A. and Sanchez, J.G. and Curioni-Fontecedro, A. and Gautschi, O. and Price, G. and Coate, L. and von Moos, R. and Zielinski, C. and Provencio, M. and Menis, J. and Ruepp, B. and Pochesci, A. and Roschitzki-Voser, H. and Besse, B. and Rabaglio, M. and O'Brien, M.E.R. and Stahel, R.A.",
    journal = "Journal of Thoracic Oncology",
    year = "2020",
    volume = "15",
    number = "10",
    pages = "1647-1656",
    publisher = "HANLEY & BELFUS-ELSEVIER INC",
    issn = "1556-0864, 1556-1380",
    doi = "10.1016/j.jtho.2020.06.011",
    keywords = "denosumab;  erlotinib;  gemcitabine;  pemetrexed;  zoledronic acid;  antineoplastic agent;  denosumab, adult;  aged;  Article;  bone metastasis;  cancer chemotherapy;  cancer immunotherapy;  cancer staging;  cohort analysis;  controlled study;  drug safety;  drug tolerance;  dyspnea;  Europe;  ex-smoker;  fatigue;  febrile neutropenia;  female;  histology;  human;  human tissue;  hypertension;  lung infection;  major clinical study;  male;  multicenter study;  multiple cycle treatment;  nausea;  non small cell lung cancer;  oncology;  overall survival;  phase 3 clinical trial;  primary health care;  priority journal;  randomized controlled trial;  sepsis;  clinical trial;  lung tumor;  retrospective study;  standard, Aged;  Antineoplastic Combined Chemotherapy Protocols;  Carcinoma, Non-Small-Cell Lung;  Denosumab;  Female;  Humans;  Lung Neoplasms;  Male;  Reference Standards;  Retrospective Studies",
    abstract = "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. © 2020 International Association for the Study of Lung Cancer"
}