Dominik Paul Modest1,2,3, Ludwig Fischer von Weikersthal4, Thomas Decker5, Ursula Vehling-Kaiser6, Jens Uhlig7, Michael Schenk8, Jens Freiberg-Richter9, Bettina Peuser10, Claudio Denzlinger11, Christina Peveling Genannt Reddemann12, Ullrich Graeven13, Gunter Schuch14, Ingo Schwaner15, Arndt Stahler1, Andreas Jung2,3,16, Thomas Kirchner2,3,16, Swantje Held17, Sebastian Stintzing1,2,3, Clemens Giessen-Jung1, Volker Heinemann1,2,3. 1. 1 University Hospital Grosshadern, Munich, Germany. 2. 2 German Cancer Consortium, Heidelberg, Germany. 3. 3 German Cancer Research Centre, Heidelberg, Germany. 4. 4 Gesundheitszentrum St Marien, Amberg, Germany. 5. 5 Private Oncological Practice, Ravensburg, Germany. 6. 6 Private Oncological Practice, Landshut, Germany. 7. 7 Private Oncological Practice, Naunhof, Germany. 8. 8 Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany. 9. 9 Private Oncological Practice, Dresden, Germany. 10. 10 Onkologische Praxis am Diakonissenhaus, Leipzig, Germany. 11. 11 Marienhospital, Stuttgart, Germany. 12. 12 MVZ RNR Leverkusen am Gesundheitspark, Leverkusen, Germany. 13. 13 Kliniken Maria Hilf GmbH, Mönchengladbach, Germany. 14. 14 Hämatologisch-Onkologische Praxis Altona, Hamburg, Germany. 15. 15 Onkologische Schwerpunktpraxis Kurfürstendamm, Berlin, Germany. 16. 16 Ludwig Maximilians-Universität, Munich, Germany. 17. 17 ClinAssess GmbH, Leverkusen, Germany.
Abstract
PURPOSE: The XELAVIRI trial investigated the optimal treatment strategy for patients with untreated metastatic colorectal cancer. We tested the noninferiority of initial treatment with a fluoropyrimidine plus bevacizumab, followed by the addition of irinotecan at first progression (arm A) versus upfront use of fluoropyrimidine plus irinotecan plus bevacizumab (arm B) in a 1:1 randomized, controlled phase III trial. METHODS: The primary efficacy end point was time to failure of the strategy (TFS). Given a 90% CI, a power of 70%, and a one-sided α of .05, the margin for noninferiority was set at 0.8. In the case of demonstrated noninferiority of TFS, an analysis of symptomatic toxicities during TFS would define the superior strategy. Secondary end points included the effect of molecular subgroups on efficacy parameters. RESULTS: A total of 421 randomly assigned patients (arm A: n = 212; arm B: n = 209) formed the full analysis set. Median age was 71 and 69 years, respectively. Noninferiority of TFS was not shown (hazard ratio [HR], 0.86; 90% CI, 0.73 to 1.02). In detail, patients with RAS/BRAF wild-type tumors benefitted from combination chemotherapy (HR, 0.61; 90% CI, 0.46 to 0.82; P = .005), whereas patients with RAS mutant tumors (HR, 1.09; 90% CI, 0.81 to 1.46; P = .58) did not (Cox model for interaction of study arm and RAS status: P = .03). Comparable results were obtained for overall survival. CONCLUSION: Noninferiority of sequential escalation therapy compared with initial combination chemotherapy could not be demonstrated for TFS. RAS status may be important to guide therapy as treatment of patients with upfront combination therapy was clearly superior in RAS/BRAF wild-type tumors, whereas sequential escalation chemotherapy seems to provide comparable results in patients with RAS mutant tumors.
RCT Entities:
PURPOSE: The XELAVIRI trial investigated the optimal treatment strategy for patients with untreated metastatic colorectal cancer. We tested the noninferiority of initial treatment with a fluoropyrimidine plus bevacizumab, followed by the addition of irinotecan at first progression (arm A) versus upfront use of fluoropyrimidine plus irinotecan plus bevacizumab (arm B) in a 1:1 randomized, controlled phase III trial. METHODS: The primary efficacy end point was time to failure of the strategy (TFS). Given a 90% CI, a power of 70%, and a one-sided α of .05, the margin for noninferiority was set at 0.8. In the case of demonstrated noninferiority of TFS, an analysis of symptomatic toxicities during TFS would define the superior strategy. Secondary end points included the effect of molecular subgroups on efficacy parameters. RESULTS: A total of 421 randomly assigned patients (arm A: n = 212; arm B: n = 209) formed the full analysis set. Median age was 71 and 69 years, respectively. Noninferiority of TFS was not shown (hazard ratio [HR], 0.86; 90% CI, 0.73 to 1.02). In detail, patients with RAS/BRAF wild-type tumors benefitted from combination chemotherapy (HR, 0.61; 90% CI, 0.46 to 0.82; P = .005), whereas patients with RAS mutant tumors (HR, 1.09; 90% CI, 0.81 to 1.46; P = .58) did not (Cox model for interaction of study arm and RAS status: P = .03). Comparable results were obtained for overall survival. CONCLUSION: Noninferiority of sequential escalation therapy compared with initial combination chemotherapy could not be demonstrated for TFS. RAS status may be important to guide therapy as treatment of patients with upfront combination therapy was clearly superior in RAS/BRAF wild-type tumors, whereas sequential escalation chemotherapy seems to provide comparable results in patients with RAS mutant tumors.
Authors: Arndt Stahler; Volker Heinemann; Ingrid Ricard; Jobst C von Einem; Clemens Giessen-Jung; Christoph Benedikt Westphalen; Marlies Michl; Kathrin Heinrich; Lisa Miller-Phillips; Ivan Jelas; Sebastian Stintzing; Dominik Paul Modest Journal: J Cancer Res Clin Oncol Date: 2020-06-19 Impact factor: 4.553
Authors: Annabel H S Alig; Volker Heinemann; Michael Geissler; Ludwig Fischer von Weikersthal; Thomas Decker; Kathrin Heinrich; Swantje Held; Lena Weiss; Laura E Fischer; Nicolas Moosmann; Arndt Stahler; Ivan Jelas; Annika Kurreck; Jobst C von Einem; Anke C Reinacher-Schick; Andrea Tannapfel; Clemens Giessen-Jung; Sebastian Stintzing; Dominik P Modest Journal: Cancers (Basel) Date: 2022-01-21 Impact factor: 6.639
Authors: Annika Kurreck; Volker Heinemann; Ludwig Fischer von Weikersthal; Thomas Decker; Florian Kaiser; Jens Uhlig; Michael Schenk; Jens Freiberg-Richter; Bettina Peuser; Claudio Denzlinger; Ullrich Graeven; Kathrin Heinrich; Swantje Held; Arndt Stahler; Annabel Helga Sophie Alig; Ivan Jelas; Jobst C von Einem; Sebastian Stintzing; Clemens Giessen-Jung; Dominik P Modest Journal: Front Oncol Date: 2022-02-18 Impact factor: 6.244