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

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

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

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

AVANT: patient demographics Characteristic FOLFOX4 (n=1151) FOLFOX4 + Bev (n=1155) XELOX + Bev (n=1145) Disease stage, n (%) II (high risk) III N1 III N2 192 (17) 585 (51) 370 (32) 194 (17) 590 (51) 370 (32) 187 (16) 572 (50) 380 (33) Male, % Median age, years58 ECOG PS, % All patients randomised

AVANT: duration of chemotherapy and bevacizumab treatment 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 Time (months) Proportion of patients Time (months) Proportion of patients Median Bev duration (months) Arm B: 10.6 Arm C: 10.4 Arm A: FOLFOX4 Arm B: FOLFOX4 + Bev Arm C: XELOX + Bev Arm B: FOLFOX4 + Bev Arm C: XELOX + Bev ChemotherapyBevacizumab

AVANT: mortality Death rate a, N (%) FOLFOX4 (n=1126) FOLFOX4 + Bev (n=1145) XELOX + Bev (n=1135) 60 day 2 (0.18) 4 (0.35) 5 (0.44) 6 month 9 (0.80) 5 (0.44)11 (0.97) 18 month15 (1.33)11 (0.96)17 (1.50) a Excludes death after relapse

AVANT: adverse-event summary Patients with event, % a FOLFOX4 (n=1126) FOLFOX4 + Bev (n=1145) XELOX + Bev (n=1135) Any AE SAE Grade 3–5 AE Discontinuation due to AE (any treatment) AE resulting in death, n (%)9 (0.8)6 (0.5)12 (1.1) a AEs within 28 days of last treatment. Planned treatment duration was 6 months for FOLFOX4 and 12 months for FOLFOX4 + Bev/XELOX + Bev

FOLFOX4 (n=1126) FOLFOX4 + Bev (n=1145) XELOX + Bev (n=1135) Category, % Grade 3–5 Neurosensory toxicity Vomiting / nausea Diarrhoea Neutropenia / granulocytopenia Stomatitis Hand-foot syndrome AVANT: adverse events of special interest for chemotherapy* *AEs within 28 days of last treatment

AVANT: adverse events of special interest for bevacizumab* FOLFOX4 (n=1126) FOLFOX4 + Bev (n=1145) XELOX + Bev (n=1135) Category, % Grade 3–5 Bleeding / haemorrhage Hypertension Proteinuria Fistula / abscess GI perforation Wound healing compl VTE ATE *AE onset within 183 days after last drug intake VTE = venous thromboembolism; ATE = arterial thromboembolism

FOLFOX4 (n=1126) FOLFOX4 + Bev (n=1145) XELOX + Bev (n=1135) Category, % Grade 3–5 Bleeding / haemorrhage Hypertension Proteinuria Fistula / abscess GI perforation000.1 Wound healing compl VTE ATE *AEs with onset >28 days after last chemotherapy VTE = venous thromboembolism; ATE = arterial thromboembolism AVANT: adverse events of special interest for bevacizumab during mono / obs*

AVANT: grade 3–5 AEs of special interest for chemotherapy by age* FOLFOX4FOLFOX4 + BevXELOX + Bev Category, % <70 y n=973 ≥70 y n=153 <70 y n=1009 ≥70 y n=136 <70 y n=988 ≥70 y n=147 Neurosensory Vomiting / nausea Diarrhoea Neutropenia / granulocytopenia Stomatitis Hand-foot syndrome *AEs within 28 days of last treatment

AVANT: grade 3–5 AEs of special interest for bevacizumab by age FOLFOX4FOLFOX4 + BevXELOX + Bev Category, % a <70 y n=973 ≥70 y n=153 <70 y n=1009 ≥70 y n=136 <70 y n=988 ≥70 y n=147 Bleeding / haemorrhage Hypertension Proteinuria Fistula / abscess GI perforation Wound healing compl VTE ATE a AEs within 28 days of last treatment VTE = venous thromboembolism; ATE = arterial thromboembolism

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

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