and the NSABP Investigators Initial Safety Report of NSABP C-08, A Randomized Phase III Study of Modified FOLFOX 6 With or Without Bevacizumab in the Adjuvant Treatment of Patients With Stage II/III Colon Cancer Carmen Allegra, Greg Yothers, Saima Sharif, Michael O’Connell, Norman Wolmark and the NSABP Investigators

I have no relevant industry relationships to disclose. Disclosure Statement I have no relevant industry relationships to disclose.

Stage II or III Colon Cancer Number of Positive Lymph Nodes NSABP C-08 Schema Stage II or III Colon Cancer Stratification Number of Positive Lymph Nodes Randomization mFOLFOX6 mFOLFOX6 + Bevacizumab Disease-free survival: primary endpoint

mFOLFOX6 Regimen Leucovorin 400 mg/m2 IV 5-FU 400 mg/m2 IV 5-FU 2400 mg/m2 over 46 hrs Oxaliplatin 85 mg/m2 IV Bevacizumab (Arm 2) 5mg/kg Repeat every 2 wks X 12 doses (chemo) 26 doses (bev)

C-08 Patient Recruitment Timeline Opened: Sept ’04 Closed: Oct ’06 Total Accrual: 2710 Pts Average monthly accrual: 110 Pts

C-08 Patient Demographics 31 March 2008 FOLFOX FOLFOX + Bev Randomized 1356 1354 Mean time on study (mo) Age < 60 (%) 58.3 58.2 Male (%) 49.8 49.9 Stage II (%) 24.9 Stage III (1-3) (%) 45.4 45.5 Stage III (4+) (%) 29.7 29.6 28.5

C-08 Selected Inclusion/Exclusion Criteria Stage II or III colon adenocarcinoma Randomization between day 29 & 50 post-op ECOG PS 0 or 1 Exclusion Any history of CVA or TIA Any symptomatic PVD History of ATE within 12 months

Doses of Therapy Administered Restricted to Pts without DFS Event mFOLFOX6 mFOLFOX6+Bev p Oxali ≥ 10 of 12 73% 78% <0.01 5-FU ≥ 10 of 12 80% 85% <0.01 Bev ≥ 21 of 26 61%

Cumulative Dose Oxali (mg/m2) Restricted to Pts without DFS Event Median Dose Delivered mFF6= 850 mg/m2 mFF6+Bev= 880 mg/m2 p = 0.0002 Median Dose Intensity mFF6= 40.6 mg/m2/wk mFF6+Bev= 41.6 mg/m2/wk p = 0.13 Percent of Patients

Duration of Bev (5 mg/kg q2wks) Restricted to Pts without DFS Event Percent of Bev Patients Median Duration 11.5 months Months

Duration of Bev and 5-FU Restricted to Pts without DFS Event Bev Duration 5-FU Duration (both arms) Percent of Patients Months

Treatment Associated Mortality (%) Excluding death after relapse or second primary within 6 months of randomization mFOLFOX6 0.96 mFOLFOX6 + bev 0.90 p=1.0 within 18 months of randomization mFOLFOX6 1.33 mFOLFOX6 + bev 1.35 p=1.0

Maximum Grade of AE by Treatment First 18 months after Randomization p = 0.0006 Percent of Patients

Chemotherapy Associated Toxicities (Grade 3+) (%) mFOLFOX6 mFOLFOX6+bev Venous Thrombosis 8 9 Neutropenia 33 30 Febrile neutropenia 1 Fatigue 7 Diarrhea 10 11 Dehydration 4 5 Sensory Neuropathy 14 16 (33 Gr 2) p<0.01;Gr2+ (29 Gr 2)

Toxicities Associated with Bevacizumab in Advanced Disease Studies Not Significantly Different in C-08 (%) mFOLFOX6 mFOLFOX6+bev Cardiac Ischemia 0.76 1.51 CNS Ischemia 0.38 0.45 Peripheral Arterial Ischemia 0.23 GI Perforation 0.15 0.3 Hemorrhage 1.9

Toxicities (Grade 3+) Significantly Reduced with Bevacizumab (%) mFOLFOX6 mFOLFOX6 + Bev p-value Thrombocytopenia 3.4 1.4 <0.001 Allergic Reaction 4.7 3.1 0.03

Toxicities (Grade 3+) Significantly Increased with Bevacizumab (%) mFOLFOX6 + Bev p-value Hypertension 1.8 12 (5 pts Gr 4) <0.0001 Any Pain 6.3 11.1 Proteinuria 0.8 2.7 <0.001 Wound Complications 0.3 1.7 (all Gr 3)

Bevacizumab Arm -Wound Complications- 23 cases (1.7%) on bevacizumab arm All Grade 3 All but one resulted in surgical intervention Half resulted in bevacizumab discontinuation 14 pts had symptomatic abdominal inc. hernias 1 dehiscence/abscess Median time to occurrence – 5 mos 9 pts had inf port dehiscence and/or infect/inflam Median time to occurrence – 2 mos

Pain (Grade 3+) Chest Pain 1 2.3 <0.01 Joint Pain 2.1 0.04 mFOLFOX6 (%) + Bev (%) p-value Chest Pain 1 2.3 <0.01 Joint Pain 2.1 0.04 Muscle Pain 1.2 2.4 0.03

Significantly Different Toxicities (Grade 3+) After Chemotherapy Completion mFOLFOX6 (%) + Bev (%) p-value Wound Complication 0.3 1.1 0.01 Hypertension 0.7 5.9 <0.0001 Sensory Neuropathy (Grade 2+) 26.1 32.4 <0.001 Depression 1.3 2.9 <0.01 Dizziness 1.6 0.04 Proteinuria 0.2 Pain - Any 2.1 4.7

Maximum Grade of AE by Age Decade (All Patients) Percent of Patients

C-08 Summary The overall safety of adding bevacizumab to mFOLFOX6 in the colon cancer adjuvant setting is acceptable in the selected population of patients eligible for C-08 with a mean time on study of 28.5 mos; however, the use of bevacizumab in the colon adjuvant setting cannot currently be recommended in the absence of efficacy data The cumulative dose & dose-intensity of mFOLFOX6 was not decreased by the addition of bevacizumab No increase in ATE, hemorrhage, GI perforations or death from any cause as a result of the addition of bevacizumab to mFOLFOX6

C-08 Summary Other complications seen at increased frequency (HTN, wound complications, proteinuria & pain) are important but manageable Sensory neuropathy grade 2+ was increased with bev but may be secondary to an increased cumulative dose of oxaliplatin Long term follow-up to detect any potential increase in delayed side effects associated with bevacizumab continues

Special Thanks to our NSABP Investigators and to All of the Patients Who Participated in the Conduct of C-08