1. Neoplasie del Colon-retto

31. The therapeutic spectrum in adjuvant colon cancer and neoadjuvant rectal cancer: Chair’s welcome Alberto Sobrero Ospedale San Martino Genoa, Italy

32. Adjuvant chemotherapy of colon cancer: steps ahead 199019912004199219931994199519961997199819992000200120022003 5-FU/LEV 5-FU/LV 6 monthsElderly as well Stage II XelodaFOLFOX

33. Neoadjuvant chemoradiation: treating early to optimize outcomes  Neoadjuvant chemoradiation improves 1 –downstaging –surgical resection –sphincter-sparing surgery 1 Bosset JF et al. J Clin Oncol 2005;23:5620–7

34. “It’s time we pay more, not less, attention to the concept of cure and give our patients the benefit of the doubt” De Vita, Nature Clin Pract, Feb 2006 New treatments, new hope

35. Evolving choices in adjuvant colon cancer Joe McKendrick Box Hill Hospital, Box Hill, Victoria, Australia

36. Adjuvant chemotherapy for colon cancer  Colon cancer –common –increasing –costly  Adjuvant therapy reduces burden of disease

37. Advances in the adjuvant treatment of stage III CRC 3-year overall survival (%) 100 80 60 40 198019851990199520002005 Surgery alone

38. Efficacy of adjuvant chemotherapy in colon cancer widely accepted  1990 Intergroup study 1 –5-FU/levamisole improves survival in surgically resected stage III colon cancer –16% absolute reduction in risk of death  Efficacy of adjuvant chemotherapy in stage III colon cancer widely accepted by early 1990s  Adoption of adjuvant therapy slow and not universal  Toxicity a significant issue  Conflicting opinion about stage II disease 1 Moertel CG et al. N Engl J Med 1990;322:352–8

39. 5-FU-based adjuvant chemotherapy: early modifications and improvements  NSABP C-03, 1 IMPACT, 2 INT0089, 3 NSABP C-04, 4 QUASAR 5 –no advantage gained by adding levamisole to 5-FU/LV –low dose leucovorin (LV) is adequate –6 months’ therapy as good as 12 months’ therapy –weekly therapy equivalent to monthly 1 Wolmark N et al. J Clin Oncol 1993;11:1879–87; 2 IMPACT investigators. Lancet 1995;345:939–44 3 Haller DG et al. J Clin Oncol 2005;23:8671–8; 4 Wolmark N et al. J Clin Oncol 1999;17:3553–9 5 QUASAR Collaborative Group. Lancet 2000;355:1588–96

40. Roswell Park regimen: equivalent efficacy with distinct safety profiles  No improvement in DFS or OS with Roswell Park versus Mayo Clinic regimen 1  For Mayo Clinic, major toxicity is myelosuppression 2  For Roswell Park, major toxicity is diarrhea 3  Need to improve safety of 5-FU-based therapy 1 Haller DG et al. J Clin Oncol 2005;23:8671–8 2 Haydon A. Intern Med J 2003;33:119–24 3 Schmoll H-J et al. Eur J Cancer Suppl 2005;3:173 (Abst 617)

41. Similar efficacy with infused 5-FU/LV versus bolus Disease-free survival: stage III 00.51.01.52.02.52.8 Hazard ratio = 1.27 95% CI (0.87–1.86) Log-rank p=0.21 1.0 0.8 0.6 0.4 Probability Years Hazard ratio = 1.025 95% CI (0.78–1.35) Log-rank p=0.86 Overall survival: stage III Years André T et al. J Clin Oncol 2003;21:2896–903 00.51.01.52.02.52.8 Mayo (n=256) LV5FU2 (n=257)

42. Better toxicity profile with LV5FU2 versus Mayo *Not significant André T et al. J Clin Oncol 2003;21:2896–903

43. Issues with central venous catheters  Additional costs  Inconvenient for patients  Need for invasive surgical procedure –possible complications include infections, bleeding, pneumothorax, deep-vein thrombosis and pulmonary embolism 1,2 –varying level of risk (7–20%) but base rate of complications unavoidable regardless of center/experience 3 1 Kuter DJ. Oncologist 2004;9:207–16 2 Verso M et al. J Clin Oncol 2003;21:3665–75 3 Sobrero A and Sciallero S. Ann Oncol 2005;16:521–2

44. Xeloda is established in MCRC and should simplify complex adjuvant treatments  Xeloda is effective and well tolerated in MCRC –can replace 5-FU as monotherapy and in combination regimens –convenient home-based oral therapy  Potential to translate these advantages into adjuvant setting

45. Benefit of adjuvant therapy for stage II patients not always clear  Relatively few stage II patients have been randomized  Lower risk of recurrence  Contradictory meta-analyses –IMPACT meta-analysis concluded no advantage in 1 025 patients 1 –NSABP pooled data analysis showed improved event-free and overall survival in 1 565 patients 2 1 IMPACT. J Clin Oncol 1999;17:1356–63 2 Mamounas E et al. J Clin Oncol 1999;17:1349–55

46. QUASAR: adjuvant chemotherapy significantly reduces recurrence in stage II Chemotherapy78.0 Observation 73.8 Hazard ratio = 0.78 (95% CI: 0.67–0.91) p=0.001 5-year RFS (%) Gray RG et al. J Clin Oncol 2004;23:245s (Abst 3501) 100 80 60 40 20 0 012345678910 Years Relapse-free survival (%)

47. QUASAR: adjuvant chemotherapy improves overall survival in stage II Years Gray RG et al. J Clin Oncol 2004;23:245s (Abst 3501) Chemotherapy Observation p=0.04 100 80 60 40 20 0 012345678910 Survival (%)

48. Dutch trial of 5-FU/LEV suggested improved OS for stage II Taal B et al. Br J Cancer 2001;85:1437–43 100 80 60 40 20 0 01234560123456 5-FU/LEV (n=233) Control (n=235) Years Overall survival (%)

49. Should high-risk stage II patients be offered adjuvant chemotherapy?  Some high-risk patients may benefit from adjuvant chemotherapy 1 –obstruction or perforation –venous or lymphatic invasion –perineural invasion –tumor adherence  Better prognostic factors could aid in patient selection –Biomarker data collection incorporated in most ongoing studies 1 NCCN Clinical Practice Guidelines in Oncology v.2.2004

50. Patients who could benefit are still denied adjuvant therapy  Indication of benefit of adjuvant therapy in stage II 1–5 –small but significant benefit of chemotherapy  High-risk stage II patients may benefit as much as some stage III patients  Older patients and some minorities less likely to receive chemotherapy 6,7 –toxicity concerns 1 Gray RG et al. J Clin Oncol 2004;22:245s (Abst 3501) 2 Taal BG et al. Br J Cancer 2001;85:1437–43; 3 IMPACT. J Clin Oncol 1999;17:1356–63 4 Gill S et al. J Clin Oncol 2004;22:1797–806; 5 Figueredo A et al. J Clin Oncol 2004;22:3395–407 6 Sargent DJ et al. N Engl J Med 2001;345:1091–7 7 Grothey A et al. Proc Am Soc Clin Oncol 2002;21:129a (Abst 512)

51. Factors that may influence treatment decisions with adjuvant chemotherapy Benefit to risk ratio Healthcare providers Treatment costs Resource use Patients Impact on lifestyle Convenience Treatment outcomes Efficacy Toxicity Patient characteristics Age Disease stage Preference Comorbidities e.g. diabetes, impaired cardiac function Biomarkers

52. Redefining adjuvant therapies  Improve efficacy with new agents  Reduce toxicity  Prospective identification of high-risk stage II patients  Tailor to ensure all patients can benefit –effective, well-tolerated, convenient therapy  With Xeloda’s approval, the need for an effective, well- tolerated, convenient and cost-effective therapy may be addressed

53. The next level in adjuvant treatment: new chemotherapy combinations Alberto Sobrero Ospedale San Martino Genoa, Italy

54. Combinations in adjuvant chemotherapy: recent evidence 1 de Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501) 2 Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500); 3 Saltz LB et al. J Clin Oncol 2004;22:245S (Abst 3500) 4 Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8); 5 Ychou M et al. Proc ASCO 2005 (Abst 3502) NR = not reported DFS hazard ratio p value OS hazard ratio p value MOSAIC0.77 <0.0010.91 NR NSABP C-07 2 0.79 <0.004 NR Oxaliplatin combinations Irinotecan combinations 3 CALGB89803NR 0.80 NR 0.81 PETACC-3 4 0.89 0.091 NR ACCORD2 5 1.19 0.22 NR 1

55. MOSAIC: superior DFS with FOLFOX versus LV5FU2 in stage III Months FOLFOX4 (n=672)72.2% LV5FU2 (n=675) 65.3% 3-year DFS Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 061218243036 42485460 André T et al. N Engl J Med 2004;350:2343–51 Hazard ratio (95% CI) 0.76 (0.62–0.92)

56. NSABP C-07: superior DFS with FLOX versus 5-FU/LV in stage III Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500) Estimated probability 1.0 0.9 0.8 0.7 0.6 0.5 0123401234 Years FLOX (n=272) 76.5% 5-FU/LV (n=332) 71.6% Hazard ratio (95% CI) 0.79 (0.67–0.93) p<0.004 3-year DFS

57. The strength of MOSAIC: clinically relevant absolute benefit is increasing 4-year DFS (%) 1 3-year DFS (%) 2 II and III6.8*5.1* III N17.0– III N212– III8.7*6.3* II3.82.7 High-risk stage II5.45.1 1 de Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501) 2 André T et al. N Engl J Med 2004;350:2343–51 *p<0.05

58. FLOX vs FOLFOX: no difference in DFS NSABP C-07MOSAIC 3-year DFS (%)76.578.2 Hazard ratio0.790.77 Difference4.95.1

59. FOLFOX versus LV5FU2: grade 3/4 adverse events † *12% grade 4 † Not reported Neutropenia Thrombo- cytopenia Diarrhea Vomiting Neuropathy (sensory) Nausea Allergic reaction Febrile neutropenia FOLFOX4 (n=1 108) LV5FU2 (n=1 111) Patients (%) * André T et al. N Engl J Med 2004;350:2343–51 45 40 15 10 5 0

60. Irinotecan has significant benefits in MCRC RegimenNPRPFSOSAuthor Douillard/AIO + Irinotecan 33823% 35% 4.4 6.7 14.1 17.4 Douillard Lancet 2000 FL (Saltz) + Irinotecan 44021% 39% 4.3 7.0 12.6 14.8 Saltz NEJM 2000 AIO + Irinotecan 43034% 62% 6.4 8.5 16.9 20.1 Köhne JCO 2005

61. CALGB89803: DFS not improved with IFL in stage III colon cancer 1.0 0.8 0.6 0.4 0.2 0.0 Proportion disease free 01224364860 Months p=0.80 5-FU/LV (Roswell Park regimen) IFL Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500)

62. PETACC-3: DFS not significantly improved with FOLFIRI in stage III Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8) 1.0 0.9 0.8 0.7 0.6 0.5 0.0 Estimated probability 036912151821242730333639424548 Months FOLFIRI (n=1 044)63.3 5-FU/LV (n=1 050)60.3 Hazard ratio (95% CI) 0.89 (0.77–1.11) p=0.091 3-year DFS

63. ACCORD2: DFS not improved with FOLFIRI in high-risk colon cancer Ychou M et al. J Clin Oncol 2005;23 (Abst 3502) Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 01234560123456 LV5FU2 60% FOLFIRI 51% Hazard ratio (95% CI) 1.19 (0.90–1.59) p=0.22 3-year DFS Years

64. Xeloda has the potential to replace 5-FU in adjuvant combinations  Xeloda is at least as effective as 5-FU/LV with –significantly superior relapse-free survival –trends to improved disease-free and overall survival –consistent benefits in all efficacy endpoints  XELOX has similar high efficacy and favorable safety profile compared with FOLFOX in metastatic CRC  Xeloda is the optimal fluoropyrimidine partner to simplify complex combination regimens

65. XELOXA: adjuvant Xeloda + oxaliplatin (XELOX) versus 5-FU / LV  1º endpoint: DFS – XELOX >5-FU/LV –minimal absolute difference targeted: 6%  2º endpoints: survival, tolerability, convenience, pharmacoeconomics  Recruitment completed: September 2004 XELOX 24 weeks Bolus 5-FU/LV Mayo Clinic or Roswell Park 24 or 32 weeks Chemotherapy-naïve, stage III colon cancer n=1 886

66. XELOX is an ideal combination in the adjuvant setting 1 Schmoll H-J et al. Proc ASCO GI 2006 (Abst 278) XELOXA 1 Grade 3/4 toxicities XELOX 5-FU/LV Diarrhea 19 20 Stomatitis <1 8 Nausea 5 4 Vomiting 6 3 Neurosensory 11 0 HFS 5 <1 Neutropenia 8 15 Febrile neutropenia <1 4

67. XELOX is an ideal combination in the adjuvant setting 1 Schmoll H-J et al. Proc ASCO GI 2006 (Abst 278) 2 André T et al. N Engl J Med 2004;350:2343–51 3 Smith R et al. Proc Am Soc Clin Oncol 2003;22:294 (Abst 1181; poster update) XELOXA 1 MOSAIC 2 NSABP C-07 3 Grade 3/4 toxicities 5-FU/LVFOLFOX FLOX Diarrhea 20 12 36 8 3 NR Nausea 4 5 15 Vomiting 3 6 12 Neurosensory 0 12 8 HFS <1 2 NR Neutropenia 15 41 5 Febrile neutropenia 4 2 NR XELOX 19 <1 5 6 11 5 8 <1 Stomatitis

68. UK QUASAR2: adjuvant Xeloda ± Avastin  1º endpoint: DFS –minimal absolute difference targeted: 6%  2º endpoints: 5-year overall survival, safety, health economics  Recruitment opened 2005 Xeloda 8 cycles (24 weeks) Xeloda 8 cycles (24 weeks) Avastin 7.5mg/kg 16 cycles (48 weeks) Stage II / III colon cancer n=3 510

69. AVANT: adjuvant FOLFOX vs XELOX ± Avastin  1º endpoint: DFS –minimal absolute difference targeted: 5.3%  2º endpoints include: overall survival and tolerability  Started Q4 2004 XELOX plus Avastin FOLFOX Chemotherapy-naïve, stage II / III colon cancer n=3 450 FOLFOX plus Avastin

70. Xeloda provides added advantages in adjuvant combination regimens  Xeloda should be preferred to i.v. 5-FU/LV –consistent efficacy benefits in stage III colon cancer –more convenient for patient and physician –reduces hospitalizations for adverse events –cost-saving for most healthcare systems  Adjuvant XELOX has a favorable safety profile with less neutropenia than FOLFOX  Xeloda is an ideal backbone for future development

71. Landmark trials: adjuvant Xeloda-based combinations 20042005200620072008200920102011 XELOXA final safety XELOXA 1° efficacy XELOXA survival follow-up QUASAR2 last follow-up planned AVANT 1° efficacy AVANT survival follow-up

82. Avastin ® therapy: the essential basis of first-line treatment regimens Bruce Giantonio Abramson Cancer Center, The University of Pennsylvania, Philadelphia, USA

83. Mode of action suggests Avastin can be combined with all first-line chemotherapy Avastin’s unique mechanism of action is potentially exploited best when used with chemotherapy, but –it shouldn’t be dependent upon any particular chemotherapy regimen Efficacy data indicate that the magnitude of benefit achieved with Avastin is greatest when used with first-line chemotherapy Clinically and statistically significant survival benefit is seen despite modest improvements in response rates

84. Treatment of metastatic CRC CRC = colorectal cancer; IFL = irinotecan, 5-fluorouracil (5-FU)/leucovorin (LV); FOLFIRI = 5-FU/LV + irinotecan; XELIRI = Xeloda ® + irinotecan; FOLFOX = 5-FU/LV + oxaliplatin; XELOX = Xeloda + oxaliplatin; BSC = best supportive care Metastatic CRC IFL/FOLFIRI/ XELIRI 5-FU or XelodaFOLFOX or XELOX Irinotecan + cetuximab FOLFOXBSC/FOLFOX/ FOLFIRI FOLFIRI5-FU/LV First-line Second-line

85. 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 Time (months) IFL + Avastin IFL + placebo 15.6 20.3 Hurwitz H, et al. N Engl J Med 2004;350:2335–42CI = confidence interval; HR = hazard ratio

86. Phase III trial of IFL ± Avastin: 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

87. Use of Avastin with FOLFIRI-based therapy Avastin has proven efficacy in combination with IFL Studies of IFL and FOLFIRI regimens suggest improved safety and comparable, if not superior, efficacy of FOLFIRI Based on what we know, it is expected that Avastin will enhance efficacy when combined with FOLFIRI

88. Phase II trial of Avastin plus FOLFIRI: preliminary efficacy and safety results Avastin plus FOLFIRI appears to be well tolerated with comparable efficacy 1 It is expected that progression-free survival will surpass the 8.5 month median progression-free survival reported for FOLFIRI alone 2 and be at least equivalent to the 10.6 months reported for IFL plus Avastin 3 Incidence of adverse events is lower than that reported with IFL plus Avastin –no grade 3/4 diarrhoea versus 32% 1 1 Hoff PM, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 252. Available at http://www.asco.org. Accessed 28 February 2006 2 Tournigand C, et al. J Clin Oncol 2004;22:229–37 3 Hurwitz H, et al. N Engl J Med 2004;350:2335–42

89. Phase IV trial of Avastin plus irinotecan (AVIRI): study design Primary endpoint: progression-free survival Secondary endpoints: overall survival, overall response rate, duration of response and safety Data available: 2006 Patients with previously untreated metastatic CRC (n=202) Avastin 5mg/kg every 2 weeks + FOLFIRI

90. Planned trial of Avastin plus FOLFIRI/ XELIRI: ACCORD 13 (MEXICO) Primary endpoint: progression-free survival Secondary endpoints: overall survival, overall response rate, duration of response and safety Patients with untreated metastatic CRC (n=140) Avastin 5mg/kg every 2 weeks + FOLFIRI Avastin 7.5mg/kg every 3 weeks + XELIRI Duration of treatment 24 weeks Avastin 7.5mg/kg every 3 weeks PD PD = progression of disease

91. Avastin can be combined with IFL/FOLFIRI/XELIRI-based therapy Metastatic CRC IFL/FOLFIRI/ XELIRI 5-FU or XelodaFOLFOX or XELOX Irinotecan + cetuximab FOLFOXBSC/FOLFOX/ FOLFIRI FOLFIRI5-FU/LV First-line Second-line

92. Combined analysis of Avastin plus 5-FU-based regimens: overall survival Survival (%) 100 80 60 40 20 0 010203040 Time (months) 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

93. Combined analysis of Avastin plus 5-FU-based regimens: progression-free survival Progression-free survival (%) 100 80 60 40 20 0 0102030 Time (months) 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

94. Xeloda in metastatic CRC: significantly superior response rate versus bolus 5-FU/LV Van Cutsem E, et al. Br J Cancer 2004;90:1190–7 The efficacy of Xeloda versus bolus 5-FU/LV was similar to infusional 5-FU/LV versus bolus 5-FU/LV

95. Preclinical evidence for the use of Avastin with Xeloda-based therapy Shen BQ, et al. Proc Am Assoc Cancer Res 2004;45 (Abstract 2203) *Sub-maximum effective doses Combining Avastin and Xeloda resulted in a greater duration of tumour inhibition than with either agent alone Mean tumour volume (mm 3 ) 2,000 1,750 1,500 1,250 1,000 750 500 250 0 Control Avastin* Xeloda* Avastin* + Xeloda* 071421283542495663 Day

96. Ongoing/planned trials of Xeloda plus Avastin in first-line metastatic CRC MAX (ML18513); randomised phase II/III trial (n=333) –patients with previously untreated metastatic CRC will be randomised to receive one of three regimens until disease progression Xeloda Avastin 7.5mg/kg every 3 weeks plus Xeloda Avastin 7.5mg/kg every 3 weeks plus Xeloda plus mitomycin C Several other trials of Avastin plus Xeloda are planned, including –ML18524, open label study comparing the effect of three chemotherapy regimens (n=300) –ML18799, phase II trial (n=80) –ML19823, phase II trial in elderly patients (n=60)

97. Avastin can be combined with 5-FU/LV- or Xeloda-based therapy Metastatic CRC IFL/FOLFIRI/ XELIRI 5-FU or XelodaFOLFOX or XELOX Irinotecan + cetuximab FOLFOXBSC/FOLFOX/ FOLFIRI FOLFIRI5-FU/LV First-line Second-line

98. Phase III trial of Avastin plus FOLFOX in second line (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 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2) 10.212.9 10.8 0369121518212427303336

99. Phase III trial of Avastin plus FOLFOX in second line (E3200): progression-free survival Probability of being progression-free 1.0 0.8 0.6 0.4 0.2 0 Progression-free survival (months) 02468101214161820 CensFailMedianTotal 273228457.2 273241324.8 229215142.7 A: FOLFOX4 + Avastin B: FOLFOX4 C: Avastin HR=0.64 A vs B: p<0.0001 B vs C: p<0.0001 2.77.24.8 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)

100. Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine (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. Available at http://www.asco.org. Accessed 28 February 2006 mFOLFOX = modified FOLFOX bFOL = bolus 5-FU/LV + oxaliplatin

101. Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine: overall response rate TREE-1 (without Avastin) 1 TREE-2 (with Avastin) 2 Response rate (%) mFOLFOX6bFOLXELOX 46.9 32.0 37.5 52.1 34.3 45.8 Regimen* *Avastin is added to each of the regimens in TREE-2 1 Hochster HS, et al. J Clin Oncol 2005;23(June 1 Suppl.):249s (Abstract 3515) 2 Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006

102. Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine: time to tumour progression Probability of being progression-free XELOX + Avastin FOLFOX + Avastin bFOL + Avastin 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. Available at http://www.asco.org. Accessed 28 February 2006

103. Phase II trial of Avastin with oxaliplatin/fluoropyrimidine: toxicity 40 30 20 10 0 NeutropeniaFebrileVomitingDehydrationDiarrhoea Grade 3BleedingThrombo- neutropenianeurotoxicity embolic event mFOLFOX6 + Avastin bFOL + Avastin XELOX + Avastin Overall incidence of grade 3/4 toxicities Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006

104. Phase II trial of Avastin with three oxaliplatin/ fluoropyrimidine regimens: conclusion Avastin given in combination with each of three oxaliplatin-fluoropyrimidine regimens is effective and well tolerated Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006

105. Phase II trial of XELOX plus Avastin (XELOX-A): study design Primary endpoint: response rate Secondary endpoints: safety and tolerability, time to progression, disease-free and overall survival Exclusion criteria include: unstable or poorly controlled hypertension, arterial or venous thrombosis within the last 3 months, coagulopathy and anticoagulation therapy Xeloda 1,000mg/m 2 b.i.d. days 1–5 and days 8–12, every 2 weeks oxaliplatin 85mg/m 2 every 2 weeks Avastin 10mg/kg every 2 weeks PD Previously untreated metastatic CRC (n=50) Fernando N, et al. J Clin Oncol 2005;23(June 1 Suppl.):260s (Abstract 3556)

106. Phase II trial of XELOX plus Avastin (XELOX-A): response rate *Overall response rate = complete response plus partial response RECIST = Response Evaluation Criteria in Solid Tumors Fernando N, et al. J Clin Oncol 2005;23(June 1 Suppl.):260s (Abstract 3556)

107. Ongoing phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (NO16966C) 2 x 2 factorial, randomised phase III trial Primary objectives –at least equivalent time to progression with XELOX (± Avastin) versus FOLFOX4 (± Avastin) –superior time to progression with Avastin + XELOX/FOLFOX4 versus XELOX/FOLFOX4 Previously untreated patients with metastatic CRC (n=1,920) Avastin 5mg/kg every 2 weeks (n=330) Placebo (n=330) Avastin 7.5mg/kg every 3 weeks (n=330) Placebo (n=330) FOLFOX4 (n=300) XELOX (n=300)

108. DREAM study mFOLFOX7 x6 XELOX4 x6 mFOLFOX7 x6 XELOX4 x6 Avastin Previously untreated patients with metastatic CRC (n=640) Primary endpoint: progression-free survival Secondary endpoints include: overall survival, response rate, duration of disease control, tolerance and quality of life mFOLFOX7 or XELOX4: Avastin 5mg/kg every 2 weeks ± Tarceva 100mg/day During chemotherapy pause: Avastin 7.5mg/kg every 3 weeks ± Tarceva 150mg/day Avastin Avastin + Tarceva ® Avastin Avastin + Tarceva

109. Ongoing phase IV optimisation trial (CONcePT) in first-line metastatic CRC Primary endpoint: time to treatment failure mFOLFOX7 + Avastin CONTINUOUS oxaliplatin ‘treat-to-failure’ ± intravenous Ca/Mg mFOLFOX7 + Avastin INTERMITTENT oxaliplatin Patients with metastatic CRC (n=532) 2x2 randomised, multicentre study

110. CONcePT: intermittent oxaliplatin Stage 1 Avastin 5mg/kg CI 5-FU/LV Oxaliplatin 85mg/m 2 Stage 2 Avastin 5mg/kg CI 5-FU/LV Stage 3 Avastin 5mg/kg CI 5-FU/LV Oxaliplatin 85mg/m 2 CI = continuous infusion *Cumulative dose x8 cycles, months 5–8 x8 cycles, months 1–4 Oxaliplatin 680mg/m 2 * x8 cycles, months 9–12 Oxaliplatin 1,360mg/m 2 *

111. Avastin therapy: the essential basis of first-line treatment regimens Metastatic CRC Avastin + IFL/FOLFIRI/ XELIRI Avastin + 5-FU or Xeloda Avastin + FOLFOX or XELOX Irinotecan + cetuximab FOLFOXBSC/FOLFOX/ FOLFIRI FOLFIRI5-FU/LV First-line Second-line

112. Large observational study of Avastin plus first-line chemotherapy for metastatic CRC (BRiTE) Median progression-free survival is at least as good as that reported in trial conditions despite the fact that this is a clinical practice population treated with many different chemotherapy regimens Proportion of patients without disease progression 1.0 0.8 0.6 0.4 0.2 0 02468101214161820 Time (months) 11.3 Kozloff M, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 247. Available at http://www.asco.org. Accessed 28 February 2006

113. Ongoing and planned trials of Avastin in CRC Data from ongoing and planned trials are expected to support and investigate –optimisation of Avastin use with chemotherapy –optimisation of chemotherapy use with Avastin –incorporation of targeted agents with Avastin –activity of Avastin across multiple lines of therapy first-line use is currently recommended to maximise benefit Studies are ongoing to examine continued efficacy after progression

114. Avastin in first-line treatment of metastatic CRC Avastin has shown consistent efficacy improvements in metastatic CRC, regardless of the regimen with which it is combined Metastatic CRC Avastin + IFL/FOLFIRI/ XELIRI Avastin + 5-FU or Xeloda Avastin + FOLFOX or XELOX Irinotecan + cetuximab FOLFOXBSC/FOLFOX/ FOLFIRI FOLFIRI5-FU/LV First-line Second-line