Disclosure – Thierry André

1. A multinational, randomized phase III study of bevacizumab with FOLFOX4 or XELOX vs. FOLFOX4 alone as adjuvant treatment for colon cancer: Results andsubgroup analyses from the AVANT trial André T, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shmueli E, Bajetta E, Makrutzki M, Shang A, de Gramont A, Hoff PM, on behalf of the AVANT Investigators

2. Disclosure – Thierry André 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’1,2 • Specifically in colorectal cancer, increased VEGF expression correlates with invasiveness, vascular density, metastasis and recurrence2–5 • Clinical studies show that treatment with bevacizumab increases PFS and/or OS in metastatic disease5,6 1. Folkman J. N Engl J Med 1995 2. Carmeliet P. Nature 2000 3. Takahashi Y. Cancer Res 1995 4. Warren RS. J Clin Invest 1995 5. Hurwitz H. N Eng J Med 2004 6. Saltz L. J Clin Oncol 2008 VEGF = vascular endothelial growth factor

4. NSABP C-08 Study Design R mFOLFOX6 Observation mFOLFOX6 + Bev (5mg/kg q 2 weeks) Bev mono (5mg/kg q 2 weeks) Stage II/III colon cancer (n=2700) 24 weeks 24 weeks Duration of treatment Primary endpoint: disease-free survival Wolmark N. ASCO 2009 Allegra C. J Clin Oncol 2010

5. FOLFOX4 Observation Follow-up 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

6. Analysis Plan • Primary endpoint: • DFS in stage III patients* • STEP 1Test global hypothesis:DFS (FOLFOX4) = DFS (FOLFOX4 + Bev) = DFS (XELOX + Bev)If p≤0.05 proceed to • STEP 2Compare FOLFOX4 + Bev vs. FOLFOX4 and XELOX + Bev vs. FOLFOX4 • Secondary endpoints: • OS in stage III patients • Safety • Non-inferiority DFS and OS: FOLFOX4 + Bev vs. XELOX + Bev (if co-primary objectives met) *non-stratified log-rank test (two-sided, at overall 5% -level), power at least 80%

7. Study Conduct • Conducted worldwide: • 330 centres • 34 countries • 8 regions (stratified) • 3451 patients randomized: • between 20 December 2004 and 08 June 2007 • 2867 patients with Stage III disease • Data cut-off date: 30 June 2010 (3-year minimum follow-up) • Median duration of follow-up was 48 months (range 0–66)

8. Patient Demographics (ITT Stage III) *Calculated for alive patientsas no. of months from randomization to last date patients known to be alive

9. AEs of Special Interest for Bevacizumab(All Patients) AE onset between time of very first drug intake and 183 days after very last drug intake

10. AEs of Special Interest for Bevacizumab(All Patients) AE onset between time of very first drug intake and 183 days after very last drug intake

11. Summary of Results For DFS (ITT Stage III)

12. 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

13. 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)

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

15. Interim OS (ITT Stage III)Median duration of follow-up 48 months (range 0–66) 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

16. 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

17. Subgroup analysis

18. Hazard Ratio for DFS by Subgroup(ITT Stage III): FOLFOX4 + Bev vs FOLFOX4 Favours FOLFOX4+Bev Favours FOLFOX4 Category Estimate N Subgroup All All 1.17 1915 <70 1.17 1681 Age category (years) 1.19 ≥70 234 Gender Female 1.32 898 Male 1.07 1017 2.18 1.09 254 1604 Race category* Asian White 1.27 1366 T stage T3 0.95 345 T4 1.23 204 Other 1.26 1.13 <12 No. of lymph nodes analyzed 530 1379 ≥12 1.37 0.99 N1 N stage 1175 740 N2 0.2 0.4 0.6 1 2 3 4 5 6 10 20 *Other races contain very small number of patients (n=55) and therefore not displayed Hazard ratio

19. Hazard Ratio for DFS by Subgroup(ITT Stage III): XELOX + Bev vs FOLFOX4 Favours XELOX+Bev Favours FOLFOX4 Category Estimate N Subgroup All All 1.07 1907 <70 Age category (years) 1.04 1652 ≥70 1.28 255 Gender Female 1.11 1.04 857 1050 Male 262 1586 1.52 1.04 Race category* Asian White T stage T3 1.07 1349 T4 1.11 361 Other 0.84 197 1.06 1.08 <12 No. of lymph nodes analyzed 544 1359 ≥12 1.14 0.99 N1 N stage 1157 750 N2 0.2 0.4 0.6 1 2 3 4 5 6 10 20 *Other races contain very small number of patients (n=55) and therefore not displayed Hazard ratio

20. DFS by N Stage (ITT Stage III) FOLFOX4 (N1) FOLFOX4 (N2) FOLFOX4 + Bev (N1) FOLFOX4 + Bev (N2) XELOX + Bev (N1) XELOX + Bev (N2) Event-free rate 60% N1 1.0 0.9 0.8 0.7 0.6 N2 40% 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 411 198 379 207 376 204 190 92 181 99 177 91 22 10 20 13 17 11 0 0 0 0 0 0 FOLFOX4 III N1 FOLFOX4 III N2 FOLFOX4 + Bev III N1 FOLFOX4 + Bev III N2 XELOX + Bev III N1 XELOX + Bev III N2 585 370 590 370 572 380 550 340 562 359 545 355 528 295 541 327 533 332 506 273 501 290 495 289 487 253 464 264 462 260 475 233 451 244 448 240 305 146 279 157 267 148 78 43 75 48 74 36 0 0 0 1 0 0

21. Summary and Conclusions Addition of bevacizumab to FOLFOX4 or XELOX did not prolong DFS in adjuvant treatment of stage III colon cancer chemotherapy alone arm was favoured numerically Bevacizumab treatment effect was not constant over time transient favourable effect can be seen within 1 year, which is in-line with NSABP C-08 although transient favourable effect is more dominant in N2 subgroup, overall treatment effect is lost Further subgroup analysis results for DFS were consistent with those seen in overall stage III colon cancer population Immature OS data suggest a potential detriment. Follow up will continue until at least June 2012, for 5 years minimum follow up for analysis of OS Biomarker programme might help us to understand results seen with bevacizumab in the adjuvant setting

22. Food for Thought Why is an active therapy in advanced disease not active in the adjuvant setting? • Is it something different? • Is bevacizumab induction of tumour cell dormancy possible? • Is induction of pro-survival pathway and tumour resistance a possibility? • Does bevacizumab show any transient favourable effect in relation to action on undetectable macro-metastases? 1. Goss PE. Nat Rev Cancer 2010 2. Almog N. Cancer Lett 2010 3. Naumov GN. Clin Exp Metastasis 2009 4. Ebos JM. Clin Cancer Res 2009

23. Acknowledgments Thanks to the following: • Patients and their families • Investigators, study coordinators and nurses at 330 centres in 34 countries • AVANT study team at Genentech, Roche & Chugai

24. Thank you for your attention