1. Avastin ® : setting the standard in treatment for metastatic colorectal cancer (CRC) Fairooz Kabbinavar David Geffen School of Medicine at UCLA Los Angeles, USA

2. Treating cancer with Avastin Avastin has positive survival data in large trials in metastatic CRC, in combination with irinotecan-based regimens in first line 1 oxaliplatin-based regimens in second line 2 5-FU/LV in first line 3 1 Hurwitz H, et al. N Engl J Med 2004;350:2335–42 2 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2) 3 Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12 CRC = colorectal cancer 5-FU = 5-fluorouracil LV = leucovorin

3. Hurwitz H, et al. N Engl J Med 2004;350:2335–42 Phase III trial of IFL ± Avastin (AVF2107g): study design May receive Avastin beyond disease progression No Avastin beyond disease progression May receive Avastin beyond disease progression Previously untreated metastatic CRC (n=923) IFL* + placebo (n=411) IFL* + Avastin (5mg/kg, every 2 weeks) (n=402) 5-FU/LV † + Avastin (5mg/kg, every 2 weeks) (n=110) Arm closed to enrolment Primary endpoint: duration of survival IFL = irinotecan, 5-FU/LV * Bolus 5-FU/LV † Roswell Park regimen

4. Phase III trial of IFL ± Avastin (AVF2107g): progression-free survival Median progression-free survival IFL + placebo: 6.2 (95% CI: 5.6–7.7) IFL + Avastin: 10.6 (95% CI: 9.0–11.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001 Probability of being progression-free 1.0 0.8 0.6 0.4 0.2 0 0102030 Progression-free survival (months) 6.2 10.6 IFL + Avastin IFL + placebo Hurwitz H, et al. N Engl J Med 2004;350:2335–42

5. Phase III trial of IFL ± Avastin (AVF2107g): survival Median survival IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs IFL + Avastin: 20.3 (95% CI: 18.5–24.2) HR=0.66 (95% CI: 0.54–0.81) p<0.001 Probability of survival 1.0 0.8 0.6 0.4 0.2 0 010203040 Survival (months) IFL + Avastin IFL + placebo 15.6 20.3 Hurwitz H, et al. N Engl J Med 2004;350:2335–42

6. Treatment schema for metastatic CRC First line FOLFOX (XELOX) Avastin + IFL 5-FU/LV (Xeloda) IFL = irinotecan, 5-FU/LV FOLFOX = 5-FU/LV + oxaliplatin XELOX = Xeloda + oxaliplatin

7. Combined analysis of Avastin plus 5-FU-based regimens: methodology Analysis of results from phase II and III studies of IFL or 5-FU/LV ± Avastin in metastatic CRC (trials AVF2107, AVF0780 and AVF2192) combined control group: those randomised to 5-FU/LV or IFL comparator arm: patients randomised to 5-FU/LV plus Avastin 5mg/kg every 2 weeks Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12

8. Combined analysis of Avastin plus 5-FU-based regimens: overall survival Survival (%) 100 80 60 40 20 0 010203040 Months since treatment initiation Median survival: 14.6 vs 17.9 months HR=0.74, p=0.0081 5-FU/LV/Avastin 5mg/kg 5-FU/LV or IFL 14.6 17.9 Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12

9. Combined analysis of Avastin plus 5-FU-based regimens: progression-free survival Progression-free survival (%) 100 80 60 40 20 0 0102030 Months since treatment initiation Median progression-free survival: 5.6 vs 8.8 months HR=0.63, p=0.0001 5-FU/LV/Avastin 5mg/kg 5-FU/LV or IFL 5.6 8.8 Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12

10. Treatment schema for metastatic CRC First line FOLFOX (XELOX) Avastin + IFL Avastin + 5-FU/LV (Xeloda)

11. Avastin plus FOLFOX in second line metastatic CRC (E3200): study design FOLFOX4 + Avastin (10mg/kg, every 2 weeks) (n=289) FOLFOX4 (n=290) Avastin (10mg/kg, every 2 weeks) (n=243) Metastatic CRC patients previously treated with an irinotecan-based regimen (n=822) PD Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2) PD = progression of disease Primary endpoint: duration of survival

12. E3200: overall survival Probability of survival 1.0 0.8 0.6 0.4 0.2 0 Time (months) AliveDeadMedianTotal A: FOLFOX4 + Avastin2892464312.9 B: FOLFOX42902573310.8 C: Avastin2432162710.2 HR=0.76 A vs B: p=0.0018 B vs C: p=0.95 HR = hazard ratioGiantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2) 10.212.9 10.8 0369121518212427303336 A: FOLFOX4 + Avastin C: Avastin B: FOLFOX4

13. First-line trial with various oxaliplatin-based regimens (TREE-2): study design First-line metastatic CRC (n=223) mFOLFOX6 + Avastin 5mg/kg every 2 weeks (n=75) XELOX + Avastin 7.5mg/kg every 3 weeks (n=74) bFOL + Avastin 5mg/kg every 2 weeks (n=74) PD Primary endpoint: grade 3/4 toxicity Secondary endpoints include overall response rate, time to progression and overall survival Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244

14. TREE-2: overall response rate Response rate (%) mFOLFOX6 + Avastin bFOL + Avastin XELOX + Avastin 52.1 34.3 45.8 Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244

15. TREE-2: time to tumour progression Probability of being progression-free 1.0 0.8 0.6 0.4 0.2 0 05101520 Time (months) CapeOx + Avastin FOLFOX + Avastin bFOL + Avastin Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244

16. TREE-2: time to treatment failure Probability of treatment failure 1.0 0.8 0.6 0.4 0.2 0 Time (months) 05101520 Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244 CapeOx + Avastin FOLFOX + Avastin bFOL + Avastin

17. Treatment schema for metastatic CRC First line Avastin + IFL Avastin + 5-FU/LV (Xeloda) Avastin + FOLFOX (XELOX)

18. When to use Avastin? 1 Hurwitz H, et al. N Engl J Med 2004;350:2335–42; 2 Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12; 3 Hurwitz HI, et al. J Clin Oncol 2005;23:3502–8; 4 Hochster HS, et al. J Clin Oncol 2005;23(June 1 Suppl.): (Abstract 3515); 5 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl):1s (Abstract 2); 6 Saltz L, et al. J Clin Oncol 2005;23 (June 1 Suppl.): (Abstract 3508); 7 Chen H, et al. J Clin Oncol 2004;22 (July 15 Suppl.): (Abstract 3515) *OS benefit observed with 5-FU/LV is a result of a combined analysis 2

19. Why is Avastin not used in the second line? Superior efficacy with Avastin when it is used early in disease progression Immature vasculature is more reliant on VEGF for survival Despite the efficacy benefits observed in the second-line, first-line use of Avastin provides better patient outcomes Avastin has suboptimal efficacy in terms of patient survival and response rates in the second-line setting

20. Who to treat with Avastin Subgroup analyses have shown that adding Avastin to IFL improves overall survival and progression-free survival independent of baseline patient risk factors, including age gender performance status location of primary tumour number of metastatic sites duration of metastatic disease biomarker status (k-ras, b-raf or p53 mutation status, P53 expression or VEGF expression) Hurwitz H, et al. N Engl J Med 2004;350:2335–42 Hurwitz H, et al. Presented at ASCO GI 2006 Koeppen H, et al. Eur J Cancer Suppl 2004;2:48 (Abstract 150)

21. How long should Avastin treatment be continued? Avastin should be used until disease progression, the treatment strategy in all clinical trials of Avastin to date The toxicity of oxaliplatin/irinotecan-based combinations often leads to regimen modification prior to progression it is important not to stop Avastin treatment in these patients Avastin plus 5-FU/LV appears to be as active as FOLFOX/FOLFIRI in this population, and therefore a suitable treatment strategy if toxicity leads to oxaliplatin/irinotecan withdrawal Avastin also has some activity as monotherapy

22. Do patients who do not respond derive benefit from Avastin therapy? Due to the disparity between progression-free survival/overall survival and response in the IFL ± Avastin trial, 1 Mass et al. 2 performed an exploratory analysis to examine clinical outcome in patients who responded to treatment versus those who did not Patients were grouped by best response achieved complete/partial responses stable/progressive disease or non-evaluable (designation of stable disease required at least two post-baseline tumour assessments as per RECIST) Results of this exploratory analysis provide further rationale for treatment until progression with Avastin 1 Hurwitz H, et al. N Engl J Med 2004;350:2335–42 2 Mass RD, et al. J Clin Oncol 2005;23(June 1 Suppl.):249s (Abstract 3514) RECIST = Response Evaluation Criteria in Solid Tumours

23. Clinical benefit of Avastin in responding and non-responding patients with metastatic CRC : overall survival Mass RD, et al. J Clin Oncol 2005;23(June 1 Suppl.):249s (Abstract 3514) 1.0 0.8 0.6 0.4 0.2 0 010203040 Probability of survival Time (months) IFL/Avastin (responders, n=180) IFL/placebo (responders, n=143) IFL/Avastin (non-responders, n=222) IFL/placebo (non-responders, n=268)

24. Clinical benefit of Avastin in responding and non-responding patients with metastatic CRC: progression-free survival 1.0 0.8 0.6 0.4 0.2 0 0102030 Probability of being Progression free Time (months) IFL/Avastin (responders, n=180) IFL/placebo (responders, n=143) Mass RD, et al. J Clin Oncol 2005;23(June 1 Suppl.):249s (Abstract 3514)

25. Safety profile of Avastin

26. Effect of adding Avastin to chemotherapy Avastin does not significantly increase the incidence of chemotherapy-related adverse events such as diarrhoea and leucopenia 1–3 The addition of Avastin to chemotherapy 1 did not increase significantly the incidence of adverse events leading to death within 60-days death hospitalisation discontinuation 1 Hurwitz H, et al. N Engl J Med 2004;350:2235–42 2 Kabbinavar F, et al. J Clin Oncol 2003;21:60–5 3 Kabbinavar FF, et al. J Clin Oncol 2005;23:3697–705 4 Roche. Data on file

27. Avastin-related events in CRC trials to date: overview Phase II/III CRC trials have identified a number of side effects associated with Avastin therapy Many side effects are mild to moderate in severity and manageable using standard therapies, including hypertension (most common) proteinuria bleeding Relatively uncommon adverse events associated with Avastin therapy include arterial thrombosis effects on wound healing GI perforation Kabbinavar F, et al. J Clin Oncol 2003;21:60–5 Hurwitz H, et al. N Engl J Med 2004;350:2335–42 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2) Kabbinavar FF, et al. J Clin Oncol 2005;23:3697–705

28. Hypertension: incidence 1 Giantonio BJ, et al. J Clin Oncol 2005:23(June 1 Suppl.):1s (Abstract 2) 2 Kabbinavar F, et al. J Clin Oncol 2003;21:60–5 3 Hurwitz H, et al. N Engl J Med 2004;350:2235–42 4 Kabbinavar FF, et al. J Clin Oncol 2005;23:3697–705

29. Hypertension An increased incidence of hypertension is observed in patients treated with Avastin Effectively managed using oral antihypertensives angiotensin-converting enzyme inhibitors calcium channel blockers Hypertensive crisis is rare but requires discontinuation of treatment Recommendations blood pressure monitored while on therapy in patients with severe hypertension requiring medical therapy, Avastin therapy should be temporarily interrupted until adequate control is achieved if hypertension cannot be controlled with medical therapy, Avastin should be permanently discontinued Avastin Summary of Product Characteristics

30. ATEs * : results of a pooled analysis of five studies Higher risk observed in patients with history of ATEs and aged ≥65 years, hypertension and proteinuria *Pooled analysis of five randomised trials ATE = arterial thromboembolic event Skillings JR, et al. J Clin Oncol 2005;23(June 1 Suppl.):196s (Abstract 3019) † p=0.076; ‡ p=0.03 CI = confidence interval Chemotherapy alone (n=782) Avastin + chemotherapy (n=963) ATEs, n (%) 13 (1.7) 37 (3.8) Person-years of observation419673 Rate/100 person-years (95% CI)3.1 (1.7–5.3)5.5 † (3.9–7.6) Hazard ratio (95% CI)1.99 ‡ (1.05–3.75)

31. Management of thromboembolic events In the Hurwitz trial 1 patients who were treated with full-dose anticoagulation for thrombotic events, while continuing study medication, showed no increase in the risk of haemorrhagic complications 2 53 of 392 (14%) patients in the IFL plus Avastin arm had a thrombotic event treated with full-dose anticoagulation therapy (warfarin) 2 median time of treatment with full-dose warfarin on study for these patients was 218 days 1 Hurwitz H, et al. N Engl J Med 2004;350:2335–42 2 Hambleton J, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3528 Therapy Patients receiving full dose warfarin (n) Grade 3/4 bleeding incidence (%) Avastin + IFL532 (3.8) Placebo + IFL302 (6.7)

32. Thromboembolic events: summary Adding Avastin to 5-FU-based chemotherapy does not increase the incidence of venous thromboembolism 1 ATEs are increased, but remain relatively uncommon 1 Patients with a history of ATEs or aged >65 years are at an increased risk of developing ATEs during therapy caution should be taken when treating these patients with Avastin 2 Recommendation patients who develop ATEs should discontinue Avastin 2 1 Novotny WF, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3529 2 Avastin Summary of Product Characteristics

33. Wound healing/bleeding in metastatic CRC patients who undergo surgery prior to and during treatment with Avastin Wound healing/bleeding complicationsIFL + placeboIFL + Avastin Surgery 28–60 days prior to therapy 1 1/1553/150 Surgery on therapy 2 0/254/40 1 Scappaticci F, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3530 2 Hurwitz H, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3702

34. Wound healing Avastin therapy may adversely affect the wound healing process Major surgical procedures in CRC patients treated with Avastin may uncommonly lead to wound healing complications 1,2 No evidence that Avastin increases the risk of complications in patients who have undergone surgery >28 days prior to Avastin therapy 2 Avastin therapy should be discontinued 3 in patients who experience wound healing complications during therapy until the wound is fully healed for at least 28 days following major surgery or until the surgical wound is fully healed prior to elective surgery 1 Hurwitz H, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3702 2 Scappaticci F, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3530 3 Avastin Summary of Product Characteristics

35. Bleeding: incidence *Epistaxis + GI haemorrhage 1 Giantonio BJ, et al. J Clin Oncol 2005:23(June 1 Suppl.):1s (Abstract 2) 2 Kabbinavar F, et al. J Clin Oncol 2003;21:60–5; 3 Hurwitz H, et al. N Engl J Med 2004;350:2235–42 4 Kabbinavar FF, et al. J Clin Oncol 2005;23:3697–705

36. Bleeding in patients taking aspirin at baseline n=1,203 for grade 3/4 bleeding n=615 for grade 1/2 bleeding Hambleton J, et al. J Clin Oncol 2005;23(June 1 Suppl.):259s (Abstract 3554) *Adjustment for time on therapy resulted in a numerically increased incidence of grade 3/4 bleeding with Avastin, but the difference was not statistically significant

37. Bleeding Patients treated with Avastin may have an increased risk of developing tumour-associated haemorrhage Epistaxis is the most common bleeding event associated with Avastin in patients with metastatic CRC easily managed using standard first-aid techniques Avastin is contraindicated in patients with untreated CNS metastases Recommendations Avastin should be permanently discontinued in patients who experience grade 3 or 4 bleeding during therapy Avastin Summary of Product CharacteristicsCNS = central nervous system

38. GI perforation: incidence and mortality rate 1 Kabbinavar FF, et al. J Clin Oncol 2005;23:3697 – 705 2 Giantonio BJ, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3017 3 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2) 4 Hurwitz H, et al. N Engl J Med 2004;350:2335–42 (Roche data on file) 5 Hurwitz HI, et al. J Clin Oncol 2005;23:3502–8 6 Hochster HS, et al. J Clin Oncol 2005;23(June 1 Suppl.):249s (Abstract 3515) NR = not reported; bFOL = bolus 5-FU/LV + oxaliplatin

39. GI perforation Patients with metastatic carcinoma of the colon or rectum and an intra ‑ abdominal inflammatory process may be at increased risk of developing GI perforation when treated with Avastin and chemotherapy Uncommon but life-threatening event 1.4–2.0% of patients with metastatic CRC treated with Avastin 1–4 more than 50% of patients experiencing GI perforation have one or more identified potential risk factor 5 Recommendations 4 caution should be exercised when treating patients with metastatic carcinoma of the colon or rectum Avastin therapy should be permanently discontinued in patients who develop GI perforation 1 Kabbinavar FF, et al. J Clin Oncol 2005;23:3697–705; 2 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2); 3 Hurwitz H, et al. N Engl J Med 2004;350:2235–42; 4 Avastin Summary of Product Characteristics; 5 Kozloff M, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 247

40. BRiTE: US observation study First-BEAT: Roche Expanded Access Programme Updated results

41. BRiTE: first-line chemotherapy regimens used on study 60 50 40 30 20 10 0 Patients (%) Infusional 5-FU/LV Bolus 5-FU/LV Capecitabine FOLFIRI IFL XELIRI IROX FOLFOX FLOX XELOX Other FOLFIRI = 5-FU/LV + irinotecan; CapeIRI = capecitabine (Xeloda) + irinotecan; IROX = irinotecan + oxaliplatin; CapeOx = capecitabine + oxaliplatin Kozloff M, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26– 28 January 2006; San Francisco, Ca. Abstract 247 6.7 14.1 9.7 55.8

42. BRiTE: Avastin-related serious adverse events Kozloff M, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 247 SAEs possibly related to AvastinNo. of patients (%) (n=1,968) Any237 (12.0) GI perforation 34 (1.7) Postoperative bleeding or wound healing complication 24 (1.2) ATE 41 (2.1) Grade 3/4 bleeding 38 (1.9) Other 60 (3.0) ATE = arterial thromboembolic event; GI = gastrointestinal; SAE = serious adverse event

43. First-BEAT: most commonly used chemotherapy regimens 30 25 20 15 10 5 0 MonotherapyOxaliplatinIrinotecanOther/missing (16%)(47%)(33%)(4%) 5-FU bolus 8% 5-FU infusion 58% Capecitabine 29% Other 5% Percentage (%) Van Cutsem E, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 250

44. First-BEAT: serious adverse events Type Any SAE n (%) Related* SAE n (%) Any SAE: patients, n (%) events, n 394 (25) 638 132 (8) 161 Febrile neutropenia14 (0.9)1 (0.1) Deep vein thrombosis19 (1.2)16 (1.0) Pulmonary embolism18 (1.1)16 (1.0) Arterial thromboembolic events11 (0.7)9 (0.6) Bleeding19 (1.2)13 (0.8) GI perforation20 (1.2)11 (0.7) Hypertension8 (0.5) Wound healing5 (0.3) *Avastin related, Investigator assessment Van Cutsem E, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 250

45. BRiTE and First-BEAT: summary These ongoing observational studies are evaluating Avastin in combination with different chemotherapy regimens in a large population of patients with metastatic CRC Avastin plus standard first-line chemotherapy is generally well tolerated, with a safety profile that is consistent with that observed in clinical trials Data show that there are no new safety concerns for Avastin therapy in the clinical setting

46. Conclusions Avastin improves survival in metastatic CRC when used first-line in combination with all standard chemotherapy regimens Avastin should be considered as the critical first-line component to which chemotherapy is added Avastin therapy should be continued until disease progression, irrespective of any modification to the concomitant chemotherapy regimen Patients receiving Avastin experience progression-free and overall survival benefit even if they do not achieve an objective response to treatment, further supporting the use of Avastin until disease progression Combination of Avastin with standard first-line chemotherapy is generally well tolerated Addition of Avastin does not exacerbate toxicities associated with chemotherapy