%0 Journal Article
%A Peters, Solange
%A Danson, Sarah
%A Hasan, Baktiar
%A Dafni, Urania
%A Reinmuth, Niels
%A Majem, Margarita
%A Tournoy, Kurt G
%A Mark, Michael T
%A Pless, Miklos
%A Cobo, Manuel
%A Rodriguez-Abreu, Delvys
%A Falchero, Lionel
%A Moran, Teresa
%A Ortega Granados, Ana Laura
%A Monnet, Isabelle
%A Mohorcic, Katja
%A Sureda, Bartomeu Massutí
%A Betticher, Daniel
%A Demedts, Ingel
%A Macias, Jose Antionio
%A Cuffe, Sinead
%A Luciani, Andrea
%A Sanchez, Jose Garcia
%A Curioni-Fontecedro, Alessandra
%A Gautschi, Oliver
%A Price, Gillian
%A Coate, Linda
%A von Moos, Roger
%A Zielinski, Christoph
%A Provencio, Mariano
%A Menis, Jessica
%A Ruepp, Barbara
%A Pochesci, Alessia
%A Roschitzki-Voser, Heidi
%A Besse, Benjamin
%A Rabaglio, Manuela
%A O'Brien, Mary E R
%A Stahel, Rolf A
%T 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.
%D 2020
%U http://hdl.handle.net/10668/15788
%X 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. 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. 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%. 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.
%K Bone metastases
%K Denosumab
%K NSCLC
%K RANK
%K RANKL
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