Joachim von Pawel1, Robert Jotte2, David R Spigel2, Mary E R O'Brien2, Mark A Socinski2, Jörg Mezger2, Martin Steins2, Léon Bosquée2, Jeffrey Bubis2, Kristiaan Nackaerts2, José M Trigo2, Philip Clingan2, Wolfgang Schütte2, Paul Lorigan2, Martin Reck2, Manuel Domine2, Frances A Shepherd2, Shaoyi Li2, Markus F Renschler2. 1. Joachim von Pawel, Asklepios Fachkliniken München-Gauting, Gauting; Jörg Mezger, St Vincentius-Kliniken Karlsruhe, Karlsruhe; Martin Steins, Thoraxklinik am Universitätsklinikum, Heidelberg; Wolfgang Schütte, Krankenhaus Martha-Maria Halle-Dölau, Halle; Martin Reck, Krankenhaus Großhansdorf, Großhansdorf, Germany; Robert Jotte, Rocky Mountain Cancer Center, Denver, CO, and US Oncology, Houston, TX; David R. Spigel, Sarah Cannon Research Institute, Nashville, TN; Mary E.R. O'Brien, Royal Marsden National Health Service (NHS) Foundation Trust, Surrey; Paul Lorigan, Christie NHS Foundation Trust, Manchester, United Kingdom; Mark A. Socinski, University of Pittsburgh Medical Center, Pittsburgh, PA; Léon Bosquée, Centre Hospitalier Universitaire Sart-Tilman, Liège; Kristiaan Nackaerts, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; Jeffrey Bubis, Cancer Specialists of North Florida, Jacksonville, FL; José M. Trigo, Hospital Universitario Virgen de la Victoria, Malaga; Manuel Domine, Fundación Jiménez Diaz, Universidad Autónoma de Madrid, Madrid, Spain; Philip Clingan, Southern Medical Day Care Centre, Wollongong, New South Wales, Australia; Frances A. Shepherd, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Shaoyi Li and Markus F. Renschler, Celgene, Summit, NJ. j.pawel@asklepios.com. 2. Joachim von Pawel, Asklepios Fachkliniken München-Gauting, Gauting; Jörg Mezger, St Vincentius-Kliniken Karlsruhe, Karlsruhe; Martin Steins, Thoraxklinik am Universitätsklinikum, Heidelberg; Wolfgang Schütte, Krankenhaus Martha-Maria Halle-Dölau, Halle; Martin Reck, Krankenhaus Großhansdorf, Großhansdorf, Germany; Robert Jotte, Rocky Mountain Cancer Center, Denver, CO, and US Oncology, Houston, TX; David R. Spigel, Sarah Cannon Research Institute, Nashville, TN; Mary E.R. O'Brien, Royal Marsden National Health Service (NHS) Foundation Trust, Surrey; Paul Lorigan, Christie NHS Foundation Trust, Manchester, United Kingdom; Mark A. Socinski, University of Pittsburgh Medical Center, Pittsburgh, PA; Léon Bosquée, Centre Hospitalier Universitaire Sart-Tilman, Liège; Kristiaan Nackaerts, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; Jeffrey Bubis, Cancer Specialists of North Florida, Jacksonville, FL; José M. Trigo, Hospital Universitario Virgen de la Victoria, Malaga; Manuel Domine, Fundación Jiménez Diaz, Universidad Autónoma de Madrid, Madrid, Spain; Philip Clingan, Southern Medical Day Care Centre, Wollongong, New South Wales, Australia; Frances A. Shepherd, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Shaoyi Li and Markus F. Renschler, Celgene, Summit, NJ.
Abstract
PURPOSE: Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC. PATIENTS AND METHODS: A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m(2) intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m(2) IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety. RESULTS:Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes. CONCLUSION: Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin.
RCT Entities:
PURPOSE:Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC. PATIENTS AND METHODS: A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m(2) intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m(2) IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety. RESULTS: Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes. CONCLUSION:Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin.
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