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
Por:
Peters, S, Danson, S, Hasan, B, Dafni, U, Reinmuth, N, Majem, M, Tournoy, K, Mark, M, Pless, M, Cobo, M, Rodriguez-Abreu, D, Falchero, L, Moran, T, Granados, A, Monnet, I, Mohorcic, K, Sureda, B, Betticher, D, Demedts, I, Macias, J, Cuffe, S, Luciani, A, Sanchez, J, Curioni-Fontecedro, A, Gautschi, O, Price, G, Coate, L, von Moos, R, Zielinski, C, Provencio, M, Menis, J, Ruepp, B, Pochesci, A, Roschitzki-Voser, H, Besse, B, Rabaglio, M, O'Brien, M and Stahel, R
Publicada:
1 oct 2020
Ahead of Print:
18 jun 2020
Resumen:
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. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Filiaciones:
Peters, S:
Ctr Hosp Univ Vaudois CHUV, Dept Oncol, CH-1011 Lausanne, Switzerland
Danson, S:
Univ Sheffield, Dept Oncol & Metab, Weston Pk Hosp, Sheffield, S Yorkshire, England
Univ Sheffield, Sheffield Expt Canc Med Ctr, Weston Pk Hosp, Sheffield, S Yorkshire, England
Hasan, B:
European Org Res & Treatment Canc EORTC, Brussels, Belgium
Dafni, U:
Natl & Kapodistrian Univ Athens, Sch Hlth Sci, Athens, Greece
Frontier Sci Fdn Hellas, Athens, Greece
Reinmuth, N:
Asklepios Kliniken GmbH, Asklepios Fachkliniken Muenchen, Gauting, Germany
Majem, M:
Hosp De La Santa Creu & St Pau, Dept Med Oncol, Barcelona, Spain
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Tournoy, K:
Univ Ghent, Fac Med & Life Sci, Aalst, Belgium
Onze Lieve Vrouwziekenhuis OLV, Aalst, Belgium
Mark, M:
Swiss Grp Clin Canc Res SAKK, Bern, Switzerland
Cantonal Hosp Graubuenden, Dept Med Oncol, Chur, Switzerland
Pless, M:
Swiss Grp Clin Canc Res SAKK, Bern, Switzerland
Cantonal Hosp Winterthur, Dept Med Oncol & Hematol, Winterthur, Switzerland
Cobo, M:
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Reg & Virgen de la Victoria Univ Hosp IBIMA, Unidad Gest Interctr Med Oncol, Malaga, Spain
Rodriguez-Abreu, D:
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Univ Las Palmas Gran Canaria, Complejo Hosp Univ Insular Maternoinfantil Gran C, Las Palmas Gran Canaria, Spain
Falchero, L:
Hop Nord Ouest, Dept Pneumol & Thorac Oncol, Villefranche, France
Moran, T:
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Univ Autonoma Barcelona UAB, Hosp Germans Trias & Pujol, Inst Catald Oncol ICO Badalona, Dept Med Oncol,Badalona Appl Res Grp Oncol B ARGO, Barcelona, Spain
Granados, A:
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Hosp Univ Jaen, Dept Med Oncol, Jaen, Spain
Monnet, I:
Ctr Hop Intercommunal Creteil, Dept Pneumol, Creteil, France
Mohorcic, K:
Univ Clin Golnik, Dept Med Oncol, Golnik, Slovenia
:
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Hosp Univ Alicante, Inst Invest Sanitaria & Biomed Alicante SABIAL, Alicante, Spain
Betticher, D:
Swiss Grp Clin Canc Res SAKK, Bern, Switzerland
Fribourg Cantonal Hosp HFR, Dept Med Oncol, Fribourg, Switzerland
Demedts, I:
AZ Delta, Dept Pulm Dis, Roeselare, Belgium
Macias, J:
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Hosp Gen Univ Morales Meseguer, Dept Hematol & Oncol, Murcia, Spain
Cuffe, S:
Canc Trials Ireland, Dublin, Ireland
St James Hosp, Dept Med Oncol, Dublin, Ireland
Luciani, A:
Osped San Paolo, Dept Med Oncol, Milan, Italy
Sanchez, J:
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Univ Hosp Arnau de Vilanova, Dept Med Oncol, Valencia, Spain
Curioni-Fontecedro, A:
Swiss Grp Clin Canc Res SAKK, Bern, Switzerland
Univ Hosp Zurich, Dept Med Oncol & Hematol, Zurich, Switzerland
Gautschi, O:
Swiss Grp Clin Canc Res SAKK, Bern, Switzerland
Cantonal Hosp Lucerne, Lucern, Switzerland
Price, G:
Aberdeen Royal Infirm NHS Grampian, Dept Med Oncol, Aberdeen, Scotland
Coate, L:
Canc Trials Ireland, Dublin, Ireland
Univ Hosp Limerick, Midwestern Canc Ctr, Limerick, Ireland
von Moos, R:
Swiss Grp Clin Canc Res SAKK, Bern, Switzerland
Cantonal Hosp Graubuenden, Dept Med Oncol, Chur, Switzerland
Zielinski, C:
Med Univ Vienna, Clin Div Oncol, Vienna, Austria
Cent European Cooperat Oncol Grp, Vienna, Austria
Provencio, M:
Spanish Lung Canc Grp, Grp Espanol Canc Pulm GECP, Barcelona, Spain
Hosp Puerta Hierro Majadahonda, Dept Med Oncol, Madrid, Spain
Menis, J:
European Org Res & Treatment Canc EORTC, Brussels, Belgium
Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy
Ist Ricovero & Cura Carattere Sci IRCCS, Ist Oncol Veneto, Med Oncol Dept, Padua, Italy
Ruepp, B:
European Thorac Oncol Platform ETOP, Bern, Switzerland
Pochesci, A:
European Org Res & Treatment Canc EORTC, Brussels, Belgium
Roschitzki-Voser, H:
European Thorac Oncol Platform ETOP, Bern, Switzerland
Besse, B:
European Org Res & Treatment Canc EORTC, Brussels, Belgium
Paris Saclay Univ, Gustave Roussy Canc Ctr Villejuif, Orsay, France
Rabaglio, M:
European Thorac Oncol Platform ETOP, Bern, Switzerland
O'Brien, M:
Royal Marsden Hosp, Dept Med Oncol, Sutton, Surrey, England
Stahel, R:
Univ Hosp Zurich, Dept Med Oncol & Hematol, Zurich, Switzerland
Green Accepted, Bronze
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