Margitta Retz1, Jens Bedke2, Martin Bögemann3, Marc-Oliver Grimm4, Uwe Zimmermann5, Lothar Müller6, Christian Leiber7, Dogu Teber8, Manfred Wirth9, Christian Bolenz10, Robbert van Alphen11, Maria De Santis12, Aart Beeker13, Jan Lehmann14, Martin Indorf15, Melanie Frank16, Carsten Bokemeyer17, Jürgen E Gschwend18. 1. Dept. of Urology, Rechts der Isar Medical Center, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; AUO Study Group, Germany. Electronic address: margitta.retz@tum.de. 2. Dept. of Urology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany. Electronic address: jens.bedke@med.uni-tuebingen.de. 3. Dept. of Urology, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany. Electronic address: martin.boegemann@ukmuenster.de. 4. Dept. of Urology, Universitätsklinikum Jena, Lessingstr. 1, 07743 Jena, Germany. Electronic address: marc-oliver.grimm@med.uni-jena.de. 5. Dept. of Urology, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany. Electronic address: ziuro@uni-greifswald.de. 6. Medical Oncology, Onkologie Leer-Emden-Papenburg, Annenestr. 11, 26789 Leer, Germany. Electronic address: lothar.mueller@onkologie-leer.de. 7. Dept. of Urology, Universitätsklinikum Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. Electronic address: christian.leiber@uniklinik-freiburg.de. 8. Dept. of Urology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Electronic address: dogu.teber@med.uni-heidelberg.de. 9. Dept. of Urology, Universitätsklinikum Dresden, Fetscherstr. 74, 01307 Dresden, Germany. Electronic address: manfred.wirth@uniklinikum-dresden.de. 10. Dept. of Urology, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany. Electronic address: christian.bolenz@uniklinik-ulm.de. 11. Dept. of Oncology, Elisabeth Tweesteden Ziekenhuis, Dr. Deelenlaan 5, 5042 AD Tilburg, Netherlands. Electronic address: r.vanalphen@etz.nl. 12. Dept. of Oncology, Kaiser-Franz-Josef-Spital and Department of Urology, Medical University of Vienna, Kundratstr. 3, 1100 Vienna, Austria. Electronic address: maria@desantis.cc. 13. Dept. of Oncology, Spaarne Ziekenhuis, Spaarnepoort 1, 2134 TM Hoofddorp, Netherlands. Electronic address: abeeker@spaarneziekenhuis.nl. 14. Dept. of Urology, Städtisches Krankenhaus Kiel, Chemnitzstr. 33, 24116 Kiel, Germany; AUO Study Group, Germany. Electronic address: jan.lehmann@krankenhaus-kiel.de. 15. IOMEDICO AG, Hanferstr. 28, 79108 Freiburg, Germany. Electronic address: martin.indorf@iomedico.com. 16. IOMEDICO AG, Hanferstr. 28, 79108 Freiburg, Germany. Electronic address: Melif@gmx.de. 17. Center for Oncology, II. Medical Clinic and Polyclinic, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: c.bokemeyer@uke.de. 18. Dept. of Urology, Rechts der Isar Medical Center, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; AUO Study Group, Germany. Electronic address: juergen.gschwend@tum.de.
Abstract
PURPOSE: This trial compared the sequential therapy with the multikinase inhibitor sorafenib (So) followed by pazopanib (Pa) or vice versain advanced/metastatic renal cell carcinoma (mRCC) patients. METHODS: This multicenter, randomized phase 3 study assessed the sequential use of So-Pa versus Pa-So in patients with mRCC without prior systemic therapy. Pts were randomized to So 2 × 400 mg/day followed by Pa 1 × 800 mg/day in case of progression or intolerable toxicity or vice versa. Primary endpoint was total PFS (tPFS), defined as time from randomization to progression, or death during second-line therapy. Key secondary endpoints included overall survival (OS), first-line PFS, disease control rate (DCR) and safety. RESULTS:A total of 377 pts were randomized (So-Pa, n = 189; Pa-So, n = 188). Recruitment of a total 544 pts was calculated, but actual accrual rate turned out to be lower than expected. The primary endpoint median tPFS was 8.6 mo (95% CI 7.7-10.2) for So-Pa and 12.9 mo (95% CI 10.8-15.2) for Pa-So with a hazard ratio (HR) of 1.36 (upper limit of one-sided 95% CI 1.68), which exceeded a predefined HR <1.225 as a one-sided 95% confidence interval. Non-inferiority of So-Pa regarding tPFS was not met. Secondary endpoints displayed marked statistical differences in favor of Pa-So in first-line PFS and DCR but not for OS and 2nd-line PFS. Side effect profiles were consistent with known toxicities of the respective multikinase-inhibitor including diarrhea, fatigue, hand-foot skin reaction and hypertension. CONCLUSIONS: Non-inferiority of the primary endpoint tPFS could not be demonstrated for So-Pa. The results for first-line PFS and DCR favored the Pa-So sequence. TRIAL REGISTRATION: NCT01613846, www.clinicaltrials.gov.
RCT Entities:
PURPOSE: This trial compared the sequential therapy with the multikinase inhibitor sorafenib (So) followed by pazopanib (Pa) or vice versa in advanced/metastatic renal cell carcinoma (mRCC) patients. METHODS: This multicenter, randomized phase 3 study assessed the sequential use of So-Pa versus Pa-So in patients with mRCC without prior systemic therapy. Pts were randomized to So 2 × 400 mg/day followed by Pa 1 × 800 mg/day in case of progression or intolerable toxicity or vice versa. Primary endpoint was total PFS (tPFS), defined as time from randomization to progression, or death during second-line therapy. Key secondary endpoints included overall survival (OS), first-line PFS, disease control rate (DCR) and safety. RESULTS: A total of 377 pts were randomized (So-Pa, n = 189; Pa-So, n = 188). Recruitment of a total 544 pts was calculated, but actual accrual rate turned out to be lower than expected. The primary endpoint median tPFS was 8.6 mo (95% CI 7.7-10.2) for So-Pa and 12.9 mo (95% CI 10.8-15.2) for Pa-So with a hazard ratio (HR) of 1.36 (upper limit of one-sided 95% CI 1.68), which exceeded a predefined HR <1.225 as a one-sided 95% confidence interval. Non-inferiority of So-Pa regarding tPFS was not met. Secondary endpoints displayed marked statistical differences in favor of Pa-So in first-line PFS and DCR but not for OS and 2nd-line PFS. Side effect profiles were consistent with known toxicities of the respective multikinase-inhibitor including diarrhea, fatigue, hand-foot skin reaction and hypertension. CONCLUSIONS: Non-inferiority of the primary endpoint tPFS could not be demonstrated for So-Pa. The results for first-line PFS and DCR favored the Pa-So sequence. TRIAL REGISTRATION: NCT01613846, www.clinicaltrials.gov.
Authors: Fabian Hofmann; Eu Chang Hwang; Thomas Bl Lam; Axel Bex; Yuhong Yuan; Lorenzo So Marconi; Börje Ljungberg Journal: Cochrane Database Syst Rev Date: 2020-10-14
Authors: Kirsi M Manz; Klaus Fenchel; Andreas Eilers; Jonathan Morgan; Kirsten Wittling; Wolfram C M Dempke Journal: Adv Ther Date: 2019-12-14 Impact factor: 3.845