AVANT (BO17920) study design

1. A three-arm randomized phase III trial of FOLFOX4 vs FOLFOX4 + bevacizumab vs XELOX + bevacizumab in the adjuvant treatment of patients with stage III or high-risk stage II colon cancer: results of the interim safety analysis of the AVANT trial P M Hoff, S Clarke, D Cunningham, E Van Cutsem, M Moore, H-J Schmoll, J Tabernero, B Mueller, A de Gramont

2. AVANT (BO17920) study design FOLFOX4 Observation Follow-up Surgery for high- risk stage II or stage III colon cancer (n=3451) FOLFOX4 + bevacizumab Bevacizumab monotherapy Follow-up XELOX + bevacizumab Bevacizumab monotherapy Follow-up Duration of treatment : 24 weeks (5.5 months) 24 weeks (5.5 months) • FOLFOX4 (oxaliplatin 85 mg/m2 day 1, LV 200 mg/m2, 5-FU 400 mg/m2 bolus + 600 mg/m2 continuous infusion, Days 1 + 2) every 2 weeks • FOLFOX4 + bevacizumab 5 mg/kg every 2 weeks • XELOX (oxaliplatin 130 mg/m2 Day 1, capecitabine 2 x 1000 mg/m2 Days 1–14) + bevacizumab 7.5 mg/kg every 3 weeks • Bevacizumabmonotherapy: 7.5 mg/kg every 3 weeks

3. AVANT: study objectives • Primary objectives • Superiority of bevacizumab + FOLFOX4 vs. FOLFOX4 alone in terms of DFS (Stage III disease patients only) • Superiority of bevacizumab + XELOX vs. FOLFOX4 alone in terms of DFS (Stage III disease patients only) • Secondary objectives • Superiority of bevacizumab + FOLFOX4 vs. FOLFOX4 alone in terms of OS (Stage III disease patients only) • Superiority of bevacizumab + XELOX vs. FOLFOX4 alone in terms of OS (Stage III disease patients only) • Safety profiles of the treatment groups and immunogenicity of bevacizumab

4. AVANT: patient recruitment timeline Opened: December 2004 Closed: June 2007 Total accrual: 3451 patients Average monthly accrual: 115 patients Accrual temporarily on hold due to DSMB decision: February–May 2006

5. AVANT: patient demographics All patients randomised

6. AVANT: duration of chemotherapy and bevacizumab treatment Chemotherapy Bevacizumab Arm A: FOLFOX4 Arm B: FOLFOX4 + Bev Arm C: XELOX + Bev Arm B: FOLFOX4 + Bev Arm C: XELOX + Bev 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median oxaliplatin duration (months) Arm A: 5.3 Arm B: 5.2 Arm C: 4.9 Median capecitabine/5-FU duration (months) Arm A: 5.6 Arm B: 5.4 Arm C: 5.3 Proportion of patients Proportion of patients Median Bev duration (months) Arm B: 10.6 Arm C: 10.4 13 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 11 12 14 15 Time (months) Time (months)

7. AVANT: mortality aExcludes death after relapse

8. AVANT: adverse-event summary aAEs within 28 days of last treatment. Planned treatment duration was 6 months for FOLFOX4 and 12 months for FOLFOX4 + Bev/XELOX + Bev

9. AVANT: adverse events of special interest for chemotherapy* *AEs within 28 days of last treatment

10. AVANT: adverse events of special interest for bevacizumab* *AE onset within 183 days after last drug intake VTE = venous thromboembolism; ATE = arterial thromboembolism

11. AVANT: adverse events of special interest for bevacizumab during mono / obs* *AEs with onset >28 days after last chemotherapy VTE = venous thromboembolism; ATE = arterial thromboembolism

12. AVANT: grade 3–5 AEs of special interest for bevacizumab by age aAEs within 28 days of last treatment VTE = venous thromboembolism; ATE = arterial thromboembolism

13. Conclusions • When used in combination with FOLFOX or XELOX, safety profile of Bev was confirmed; no new safety signals emerged • During Bev monotherapy vs observation (months 6–12): • VTE and ATE frequencies were similar • bleeding, hypertension and proteinuria events were mainly of low intensity and medically manageable • Bev plus FOLFOX4 or XELOX for 24 weeks followed by 24 weeks of Bev monotherapy is a well tolerated adjuvant treatment for patients with stage III and high-risk stage II colon cancer • Efficacy results (event driven analysis) expected in 2010

14. Acknowledgements The authors would like to thank: • Patients and their families in 34 countries • Investigators & study personnel at 332 sites