1. The Combination of Bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) is highly active in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal Study Group (AIO trial 0604) A. Reinacher-Schick 1, S. Kubicka 2, W. Freier 3, D. Arnold 4, G. Dietrich 5, M. Geißler 6, S. Hegewisch-Becker 7, U. Graeven 8, H.-J. Schmoll 4 and W. Schmiegel 1, Ruhr University Bochum 1, University Hannover 2, Center of Oncology Hildesheim 3, Martin-Luther- University Halle-Wittenberg 4, Hospital Bietigheim, Bietigheim-Bissingen 5, Community Hospital Esslingen 6, Center of Oncology Eppendorf, Hamburg 7, Maria Hilf Hospital Mönchengladbach 8, Germany

2. Addition of Bevacizumab to 5FU/FA/irinotecan 1 and 5FU/FA/oxaliplatin 2,3 improves progression free survival (PFS) in advanced CRC (aCRC) Efficacy of Capecitabine/Oxaliplatin (CapOx) is similar to 5-FU/FA/Oxaliplatin Data on Capecitabine/Irinotecan (CapIri) combinations remains controversial, due to toxicity 4-7 1 Hurwitz, N Engl J Med 2004; 2 Giantonio, JCO 2007; 3 Saltz, JCO 2008; 4 Fuchs, JCO 2007; 5 Köhne, Ann Oncol 2008; 6 Grothey, ASCO 2003; 7 Koopman, Lancet 2007 Background

3. Aim To investigate whether bevacizumab in combination with CapOx or CapIri is effective for patients with aCRC

4. Study Design Open-label, multicenter, randomized phase II study Primary endpoint: Rate of pts. without disease progression at 6 months: Exclude insufficient activity (defined as rate < 60%) Secondary endpoints: Overall survival, toxicity, resectability of liver/lung mets.

5. Main eligibility criteria - written informed consent - histologically proven aCRC, measurable lesion (RECIST) - Age > 18 years - ECOG performance status < 2 - Adequate haematological, renal and hepatic function - no previous systemic immunotherapy or chemotherapy (except (neo)adjuvant therapy for non-metastatic disease > 6 months) - history of thrombosis or severe bleeding < 6 months, bleeding diathesis, therapeutic anticoagulation - proteinuria < +1 by dipstick urin analysis

6. Treatment protocol Arm A: d 1 d 15 Oxaliplatin 130mg/m 2, 120min i.v. Bevacizumab 7,5 mg/kg i.v. Capecitabine 1000mg/m 2 p.o., 2x daily Arm B: (*) Irinotecan 200mg/m 2, 30min i.v. Bevacizumab 7,5 mg/kg i.v. Capecitabine 800mg/m 2 p.o., 2x daily q 3wks note dose reduction of CapIri compared to previous trials for safety reasons

7. Patient accrual observed expected

8. Baseline characteristics (n=247) No. Patients Arm A 127 Arm B 120 Median age (range), years64 (27-83)64.5 (30-82) Distribution of age, % < 40 years42 40-49 years87 50-59 years23 60-69 years3542 70-79 years2922 > 80 years22 Male, female %66 / 3467 / 33 ECOG Performance status, % 052 14546 232 Prior adjuvant therapy, % No7779 Yes2321

9. Treatment characteristics (n=247) Number of pats. Arm A 127 Arm B 120 Total 247 Number of cycles (evaluable pats.) 115812692427 Mean no. of cycles (+/- SD) 9.1 (+/- 6.7)10.6 (+/-7.1)9.9 (+/-6.9) Range1-371-38 Median899

10. Reasons for end of treatment, EOT (n=222) Reason for EOT n Arm A 116 Arm B 108 Total 222 Disease Progression46 (40%)35 (32%)81 (36%) Progression free70 (60%)73 (68%)143 (64%) - toxicity27 (39%)12 (16%)39 (27%) - SAE5 (7%)8 (11%)13 (9%) - death, not tumor related 4 (6%)-4 (3%) - protocol violation2 (3%)5 (7%)7 (5%) - consent withdrawn11 (16%)14 (19%)25 (17%) - lost to follow-up1 (1%)2 (3%)3 (2%) - Resection/Ablation4 (6%)6 (8%)10 (7%) - Other16 (23%)26 (36%)42 (29%) *end of treatment information available for n=222 pts.

11. CTC V. 3.0 Grade 3 and 4 Toxicities (n=247) Related toxicities Arm A (127) 3°/4° [%] Arm B (120) 3°/4° [%] Diarrhoea21/016/0 Sensory neuropathy24/10 Hand-Foot-Syndrome11/08/0 Neutropenia 2/08/2 Thrombocytopenia6/00 Fatigue2/13/0 Ileus2/12/0 Nausea3/0 Vomiting4/05/0

12. AEs of special interest (n=247) AEs of special interest (Bev) Arm A (127) 3°/4° [%] Arm B (120) 3°/4° [%] Thrombosis/Embolism - venous access thrombosis - other (incl. pulmonary emb.) 3/2 1/0 2/2 4/1 1/0 3/1 Hypertension4/03/0 Cardiac ischemia/infarction00/1 Hemorrhage/bleeding (GI)1/00

13. Best overall response* (n=247) Arm A % of patients (n =127) Arm B % of patients (n =120) CR 56 PR 4849 SD 2928 PD 56 NE/NA** 1311 *ITT, RECIST criteria, investigator‘s assessment; **not evaluated/not available

14. PFS rate after 6 months: Primary endpoint Arm A % of patients (n =127) Arm B % of patients (n =120) PFS rate/6 mo.7684

15. Progression free survival (PFS) - ITT analysis months rate without progression

16. months Survival rate Overall survival (OS) - ITT analysis

17. Conclusion Both regimens, CapOx/Bev and CapIri/Bev, are highly active in aCRC. The dose reduction of CapIri/Bev may lead to a favourable toxicity profile compared to previous capecitabine/irinotecan trials seemingly without compromising efficacy The CapIri/Bev arm - compared to the CapOx/Bev arm - seems to be associated with higher cycle numbers and a tendency towards longer PFS

18. Acknowledgements We would like to thank - the patients and their families - the co-investigators - the study nurses and data monitors - Roche Pharma AG and Sanofi-Aventis for financial support