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  1. AVANT: A Randomized, Three-Arm Multinational Phase III Study to Investigate Bevacizumab (q3w or q2w) in Combination with either Intermittent Capecitabine plus Oxaliplatin (XELOX) (q3w) or Fluorouracil / Leucovorin with Oxaliplatin (FOLFOX4) Versus FOLFOX4 Regimen Alone as Adjuvant Chemotherapy in Colon Carcinoma de Gramont A, Van Cutsem E, Tabernero J, Moore MJ Cunningham D, Rivera F, Im SA, Makrutzki M, Shang A Hoff PM, On behalf of the AVANT study group

  2. Disclosure Honoraria/consulting • Roche • Sanofi-Aventis For work unrelated to the AVANT study

  3. Rationale for adjuvant Bevacizumab • The roles of angiogenesis and VEGF in colorectal tumour growth are well established • Using anti-VEGF therapy such as Bevacizumab when micrometastases are dormant and potentially reliant on VEGF may prevent the ‘angiogenic switch’ • Preclinical studies show that treatment with Beva. leads to regression of human tumour xenografts,1–3 and a reduction in the number and size of liver metastases in nude mice4 • Clinical studies show that treatment with Beva. increases PFS in metastatic disease5,6 1Gerber HP, et al. Cancer Res 2000;60:6253–58 2Wildiers H, et al. Br J Cancer 2003;88:1979–86 3Shen BQ, et al. Proc Am Assoc Cancer Res 2004;45:508 (Abstract 2203) 4Warren RS, et al. J Clin Invest 1995;95:1789–97 5Hurwitz H. N Eng J Med 2004 6Saltz L. J Clin Oncol 2008 VEGF = vascular endothelial growth factor

  4. NSABP C-08 R mFOLFOX6 Observation Stage II/III colon cancer (n=2700) mFOLFOX6 + Beva. (5mg/kg q 2 weeks) Beva. mono ((5mg/kg q 2 weeks) 24 weeks Duration of treatment 24 weeks Primary endpoint: disease-free survival Wolmark, et al. ASCO 2009 - Allegra JCO 2010

  5. NSABP C-08: DFS 100 80 60 40 20 0 HR=0.89 p=0.15 Estimated probability Treatment Events 3-year DFS mFOLFOX6 312 75.5 mFOLFOX6 + bevacizumab 291 77.4 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 DFS (years) Wolmark, et al. ASCO 2009 - Allegra JCO 2010

  6. NSABP C-08: efficacy at 1 year DFS at 1 year Event-free at 1 year 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Estimated probability Estimated probability Events DFS mFOLFOX6 + bevacizumab 75 94.3 Δ 3.6 mFOLFOX6 122 90.7 Events mFOLFOX6 +bevacizumab 216 mFOLFOX6 190 HR=0.60 p=0.0004 HR=1.07 p=0.48 0 6 12 12 18 24 30 36 42 DFS (months) DFS (months) Time-treatment interaction p=0.001 Wolmark, et al. ASCO 2009 - Allegra JCO 2010

  7. Observation Follow-up FOLFOX4 Surgery for high-risk stage II or stage III colon cancer (N=3451) FOLFOX4 + bevacizumab Bevacizumab monotherapy Follow-up Bev 5 mg/kg q2w Bev 7.5 mg/kg q3w XELOX + bevacizumab Bevacizumab monotherapy Follow-up Bev 7.5 mg/kg q3w AVANT Study Design Bev 7.5 mg/kg q3w 24 weeks 24 weeks

  8. Study Conduct & Endpoints • 330 centers, 34 countries, 8 regions (stratified) • 3451 patients randomized between 20 December 2004 and 08 June 2007 - 2867 patients with Stage III disease Primary endpoints (Stage III patients only): • DFS: FOLFOX4 + bevacizumab vs. FOLFOX4 • DFS: XELOX + bevacizumab vs. FOLFOX4 Secondary endpoints: • OS • Safety • Non-inferiority of DFS and OS for FOLFOX4 + bevacizumab vs. XELOX + bevacizumab (if co-primary endpoints met)

  9. Patient Demographics (ITT Stage III) *Calculated for alive patientsas number of months from randomization to the last date the patients were known to be alive

  10. DFS (ITT Stage III) Data cut-off date: 30 June 2010 (3-year minimum follow-up) Event-free rate FOLFOX4 FOLFOX4 + Bev XELOX + Bev 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 24 0 54 60 30 36 66 72 42 48 6 18 12 Time (months) Number at risk 609 586 580 282 280 268 32 33 28 0 0 0 FOLFOX4 FOLFOX4 + Bev XELOX + Bev 955 960 952 890 921 900 823 868 865 779 791 784 740 728 722 708 695 688 451 436 415 121 123 110 0 1 0

  11. DFS: Cumulative Hazard Ratio (ITT Stage III) Hazard ratio FOLFOX4 + Bev XELOX + Bev 1.4 1.2 1.15 1.13 1.13 1.12 1.11 1.08 1.02 1.00 1.0 0.8 0.63 0.61 0.6 0.4 0.2 0.0 2 3 2.5 1.5 1 Time from randomization (years)

  12. Interim OS (ITT Stage III) Event-free rate FOLFOX4 FOLFOX4 + Bev XELOX + Bev 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 24 0 54 60 30 36 66 72 42 48 6 18 12 Time (months) Number at risk 776 763 765 461 449 445 63 70 64 0 0 0 FOLFOX4 FOLFOX4 + Bev XELOX + Bev 955 960 952 914 942 920 899 925 908 884 900 894 863 869 861 844 835 840 573 573 546 288 269 290 0 1 0

  13. Summary of Results (ITT Stage III) *Due to hypothesis of global test for DFS not being rejected, all subsequent analyses are of exploratory nature only

  14. AEs of Special Interest for Avastin (all Patients) AE onset between time of very first drug intake and 183 days after very last drug intake

  15. Duration of Treatment (All Patients) Chemotherapy stop Bevacizumab stop 1.0 1.0 FOLFOX4 FOLFOX4 + Bev XELOX + Bev FOLFOX4 + Bev XELOX + Bev 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 N at risk N at risk 1097 1029 1049 992 1014 957 957 920 943 891 896 837 858 813 839 792 813 772 781 744 403 230 61 18 7 2 0 0 0 0 FOLFOX4 + Bev XELOX + Bev 1145 1135 419 334 216 72 42 15 1 1 0 FOLFOX4 FOLFOX4 + Bev XELOX + Bev 1126 1145 1135 1100 1111 1071 1070 1074 1017 1041 1050 983 1012 1011 950 970 957 911 11 5 1 0 0 0 0.0 0.0 4 4 0 0 12 9 9 13 5 6 5 6 10 11 10 14 15 7 8 7 8 1 1 3 3 2 2 Median capecitabine/5-FU duration (months) FOLFOX4: 5.6 FOLFOX4 + Bev: 5.4 XELOX + Bev: 5.3 Median bevacizumab duration (months) FOLFOX4 + Bev: 10.6 XELOX + Bev: 10.4 Median oxaliplatin duration (months) FOLFOX4: 5.3 FOLFOX4 + Bev: 5.2 XELOX + Bev: 4.9 Time (months) Time (months)

  16. Site of Recurrence (ITT Stage III) *And without evidence of disease at randomization; percentages based on N

  17. Subsequent Drug Therapy After Recurrence / New Occurrence of CRC (ITT Stage III)

  18. Time from Recurrence / New Occurrence to Death (ITT Stage III patients) Event-free rate FOLFOX4 FOLFOX4 + Bev XELOX + Bev 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Recurrence/new occurrence 24 0 54 60 30 36 66 72 42 48 6 18 12 Time (months) Number at risk 16 16 26 2 1 2 0 0 0 0 0 0 FOLFOX4 FOLFOX4 + Bev XELOX + Bev 222 259 228 178 209 193 135 158 158 111 104 110 65 65 79 34 39 47 7 4 8 0 0 0 0 0 0

  19. Why an active therapy in advanced disease is not active in the adjuvant setting? Is it something new? • Irinotecan and cetuximab also failed in adjuvant therapy • Of note, cetuximab and irinotecan also inhibit VEGF signaling (via HIFα) Is there a rebound effect? • N sites of relapse and survival after relapse are similar in all arms of the trial • Is induction of tumor cell dormancy possible? • Arrested angiogenesis is a component of cell dormancy (Almog, Cancer Letters 2010) and experimental models have shown that dormancy can protect tumor cells from chemotherapy (Naumov et al. Breast Cancer Research and Treatment 82: 199–206, 2003)

  20. AVANT Biomarker Program

  21. Summary and Conclusions The addition of bevacizumab to FOLFOX4 or XELOX did not prolong DFS in the adjuvant treatment of stage III colon cancer The chemotherapy alone arm was favored numerically Immature OS data suggest a potential detriment. Continued follow-up is ongoing. Bevacizumab treatment effect was not constant over time A transient favorable effect can be seen within 1 year, which is in-line with the NSABP C-08 study The treatment effect became unfavorable after 1 year, which is not in-line with the NSABP C-08 study Bevacizumab is the third agent, after irinotecan and cetuximab, with proven efficacy in metastatic CRC and no observed benefit in the adjuvant treatment of colon cancer

  22. Acknowledgments • Patients and their families • Investigators, study coordinators and nurses at 330 centers in 34 countries • AVANT study team at Genentech, Roche & Chugai

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