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

Solange Peters, Sarah Danson, Baktiar Hasan, Urania Dafni, Niels Reinmuth, Margarita Majem, Kurt G Tournoy, Michael T Mark, Miklos Pless, Manuel Cobo, Delvys Rodriguez-Abreu, Lionel Falchero, Teresa Moran, Ana Laura Ortega Granados, Isabelle Monnet, Katja Mohorcic, Bartomeu Massutí Sureda, Daniel Betticher, Ingel Demedts, Jose Antionio MaciasSinead Cuffe, Andrea Luciani, Jose Garcia Sanchez, Alessandra Curioni-Fontecedro, Oliver Gautschi, Gillian Price, Linda Coate, Roger von Moos, Christoph Zielinski, Mariano Provencio, Jessica Menis, Barbara Ruepp, Alessia Pochesci, Heidi Roschitzki-Voser, Benjamin Besse, Manuela Rabaglio, Mary E R O'Brien, Rolf A Stahel

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1647-1656
Number of pages10
JournalJournal of Thoracic Oncology
Volume15
Issue number10
DOIs
Publication statusPublished - Oct 2020

Keywords

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Denosumab/therapeutic use
  • Female
  • Humans
  • Lung Neoplasms/drug therapy
  • Male
  • Reference Standards
  • Retrospective Studies

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