TY - JOUR
T1 - 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
AU - Peters, Solange
AU - Danson, Sarah
AU - Hasan, Baktiar
AU - Dafni, Urania
AU - Reinmuth, Niels
AU - Majem, Margarita
AU - Tournoy, Kurt G
AU - Mark, Michael T
AU - Pless, Miklos
AU - Cobo, Manuel
AU - Rodriguez-Abreu, Delvys
AU - Falchero, Lionel
AU - Moran, Teresa
AU - Ortega Granados, Ana Laura
AU - Monnet, Isabelle
AU - Mohorcic, Katja
AU - Sureda, Bartomeu Massutí
AU - Betticher, Daniel
AU - Demedts, Ingel
AU - Macias, Jose Antionio
AU - Cuffe, Sinead
AU - Luciani, Andrea
AU - Sanchez, Jose Garcia
AU - Curioni-Fontecedro, Alessandra
AU - Gautschi, Oliver
AU - Price, Gillian
AU - Coate, Linda
AU - von Moos, Roger
AU - Zielinski, Christoph
AU - Provencio, Mariano
AU - Menis, Jessica
AU - Ruepp, Barbara
AU - Pochesci, Alessia
AU - Roschitzki-Voser, Heidi
AU - Besse, Benjamin
AU - Rabaglio, Manuela
AU - O'Brien, Mary E R
AU - Stahel, Rolf A
N1 - Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
PY - 2020/10
Y1 - 2020/10
N2 - 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.
AB - 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.
KW - Aged
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Carcinoma, Non-Small-Cell Lung/drug therapy
KW - Denosumab/therapeutic use
KW - Female
KW - Humans
KW - Lung Neoplasms/drug therapy
KW - Male
KW - Reference Standards
KW - Retrospective Studies
U2 - 10.1016/j.jtho.2020.06.011
DO - 10.1016/j.jtho.2020.06.011
M3 - Article
C2 - 32565388
VL - 15
SP - 1647
EP - 1656
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
SN - 1556-0864
IS - 10
ER -