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Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Dirk Arnold 1, Axel Hinke 2, Anke Reinacher-Schick 3, Wolff Schmiegel 3, Ullrich Graeven.

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Presentation on theme: "Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Dirk Arnold 1, Axel Hinke 2, Anke Reinacher-Schick 3, Wolff Schmiegel 3, Ullrich Graeven."— Presentation transcript:

1 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Dirk Arnold 1, Axel Hinke 2, Anke Reinacher-Schick 3, Wolff Schmiegel 3, Ullrich Graeven 4, Stefan Kubicka 5, Ludwig Fischer von Weikersthal 6, Nicolas Moosmann 7, Hans-Joachim Schmoll 1, Volker Heinemann 7 1 Martin Luther University, Halle; 2 WiSP, Langenfeld; 3 Ruhr University, Bochum; 4 Maria Hilf Hospital, Mönchengladbach, 5 Medizinische Hochschule, Hannover; 6 Klinikum St. Marien, Amberg; 7 Ludwig Maximilian University, München; all: Germany Working Group for Medical Oncology from the German Cancer Society Gastrointestinal Tumor Study Group Waterfall plot analysis of XELOX or XELIRI with cetuximab or bevacizumab in pts with advanced colorectal cancer (ACRC). Combined analysis of two randomized 1st line phase II trials if the AIO CRC study group.

2 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Introduction The Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria can be used to assess the treatment response rate (RR) in patients with advanced colorectal cancer (ACRC). Owing to the methodology used, RR measures the percentage of patients with relevant tumor shrinkage rather than the magnitude of response or the time until maximal response. Both of these parameters could be relevant for ACRC treatment strategies. Waterfall plots have commonly been used to capture the anti-tumor efficacy of biologic agents that mainly exhibit a cytostatic effect. Thus far, only one waterfall analysis has been conducted to investigate the use of conventional chemotherapy in patients with ACRC. 1 In order to assess the activity of different compounds used in the treatment of ACRC, waterfall plot analyses were performed on two similarly designed, randomized, first-line, phase II trials: AIO KRK 0104: XELOX-cetuximab vs. XELIRI-cetuximab) (Fischer von Weikersthal et al., ESMO 2006 2 ; update ASCO 2008: #4033 ) AIO KRK 0604: XELOX-bevacizumab vs. XELIRI-bevacizumab (Schmiegel et al., ASCO 2007 3 ; Reinacher-Schick et al., update ASCO 2008: #4030)

3 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Method of the analysis bevacizumab (B) vs. cetuximab (C) (independent from chemotherapy backbone). XELOX vs. XELIRI (independent from biologic agent) Using RECIST, the percentage change from baseline in tumor volume was evaluated when “best response” to treatment was obtained. A time window of assessment from 6 to 21 weeks (wks) was thereby used throughout the analysis. Average reduction in tumor burden (ARTB) was calculated as difference in waterfall area under curve (AUC) divided by the number of pts., capturing the average reduction in tumor burden. Median reduction in tumor burden (MRTB) captures median tumor size regression from baseline. From the 4 treatment arms, pooled 2x2 analysis was performed to compare

4 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Patient population Pts. (total)Pts. herein% of all pts. AIO KRK 0104: XELOX-cetuximab vs. XELIRI-cetuximab 185 92 93 122 56 66 69 AIO KRK 0604: XELOX-bevacizumab vs. XELIRI-bevacizumab 255 127 128 199 100 99 78 total44032173 Data were available from eligible patients with measurable disease and at least one restaging (taken at “best response”):

5 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Combined analysis - I Best response (compared with baseline) XELOX arms N=156 XELIRI arms N=165 Bevacizumab arms N=199 Cetuximab arms N=122 Tumor growth (% of pts) No Change (% of pts) Tumor shrinkage (% of pts) 5 90 6 7 87 6 7 87 6 5 89 MRTB (%) 33313035 ARTB (%) 34.731.229.238.9 p (Wilcoxon Mann Whitney Test) 0.290.009 MRTB = median reduction in tumor burden ARTB = avarage reduction in tumor burden

6 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Combined analysis - II 0 10 20 30 40 50 60 70 80 90 100 XELOXXELIRIwith Bevacizumabwith Cetuximab Tm GrowthNo ChangeTm ShrinkageARTB % of pts. (at best response) / % from baseline (ARTB) Wilcoxon Mann Whitney Test p=0.29p=0.009

7 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Waterfall plot analysis of the treatment arms CIOX / XELOX + Cetuximab: Best Response -150 -100 -50 0 50 100 % change n = 56 AIO 0104: XELOX- cetuximab

8 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Waterfall plot analysis of the treatment arms AIO 0104: XELIRI- cetuximab CIOX / XELIRI + Cetuximab: Best Response -150 -100 -50 0 50 100 % change n = 66

9 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Waterfall plot analysis of the treatment arms AIO 0604: XELOX- bevacizumab KRK 0604 / XELOX + Bevacizumab: Best Response -150 -100 -50 0 50 100 % change n = 100

10 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Waterfall plot analysis of the treatment arms AIO 0604: XELIRI- bevacizumab KRK 0604 / XELIRI + Bevacizumab: Best Response -150 -100 -50 0 50 100 % change n = 99

11 Arnold et al., ASCO 2008 abstr. 4067AIO GI Cancer Study Group Conclusion Waterfall plot analysis was successfully used to evaluate the results of the AIO KRK 0104 and the AIO KRK 0604 clinical trials. Waterfall analyses could be used to examine the results of other CRC trials using chemotherapy and targeted agents. Additional information on the rates of tumor reduction may be obtained by ARTB and MRTB. Our analysis suggests a larger degree of benefit for cetuximab containing combinations. However, the results should be interpreted with caution due to the limited sample sizes and the retrospective and unpreplanned character of the analysis. ARTB and MRTB should be validated in future trials and in relation to parameters like secondary metastasis resection, but also to clinically proven time-to-event-endpoints, like progression free survival and overall survival.


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