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Axel Grothey Professor of Oncology Mayo Clinic, Rochester, Minnesota, USA

Axel Grothey Professor of Oncology Mayo Clinic, Rochester, Minnesota, USA. Vice Chair and Director of Cancer Treatment of the North Central Cancer Treatment Group (NCCTG) Co-chair of the gastrointestinal program of NCCTG

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Axel Grothey Professor of Oncology Mayo Clinic, Rochester, Minnesota, USA

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  1. Axel GrotheyProfessor of OncologyMayo Clinic, Rochester, Minnesota, USA • Vice Chair and Director of Cancer Treatment of the North Central Cancer Treatment Group (NCCTG) • Co-chair of the gastrointestinal program of NCCTG • Former Senior Consultant and Head of the Oncological Research Laboratory at the Martin-Luther-University in Halle, Germany • Prior posts at the MD Anderson Cancer Center, Houston, USA and the University of Essen and University of Bochum, Germany • Author of many papers in English and German Mayo Clinic, Rochester

  2. Mounting evidence in early CRC Axel Grothey Mayo Clinic, Rochester, Minnesota, USA

  3. Adjuvant chemotherapy of colon cancer: steps ahead 5-FU/LV 1-year superior to surgery alone 6- and 12-month equivalent Elderly benefitas well Stage II 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Capecitabine Bolus 5-FU/LV superior to surgery alone FOLFOX better than LV5FU2 LV5FU2 equivalent to bolus 5-FU/LV 5-FU = 5-fluorouracilLV = leucovorin

  4. Stage II colon cancer:a heterogeneous population • In 2007, approximately 80,000 patients will be diagnosed with either stage II or III colon cancer in the USA • 28% of diagnosed colon cancer patients • Wide spectrum of disease1 • IIa: T3, N0, M0 • IIb: T4, N0, M0 • 5-year disease-free survival2 • IIa: 65–73% • IIb: 51–60% • 25–30% of stage II patients will relapse within 5 years 1AJCC Cancer Staging Handbook, 6th ed2Gill S, et al. J Clin Oncol 2004;22:1797–806

  5. Who should be offered adjuvant therapy of colon cancer? • All patients with stage III tumours • Patients with ‘high-risk’ stage II tumours according to • clinico-pathological parameters • T4 tumours • obstruction/perforation • lymphatic or vascular invasion • undifferentiated histology • <10 (12) lymph nodes examined • molecular parameters? (in trials)

  6. Adjuvant therapy for stage II colon cancer • The role of adjuvant therapy for patients with stage II disease is controversial • studies have confirmed the benefits of treatment in stage III disease1,2 • A number of factors may influence adjuvant treatment decisions • treatment outcomes, patient characteristics, comorbidities, convenience, costs, etc. • The evidence for adjuvant treatment of stage II colon cancer comes from >13,500 patients • relative risk reduction between 14% and 31% 1Jessup JM, et al. JAMA 2005;294:2758–602de Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007)

  7. 5-FU-based adjuvant therapyfor colon cancer

  8. 5-FU: historical standardin the adjuvant setting Observation1 5-FU/high-dose LV (Mayo)2 6 months 5-FU/LV (Mayo)1 5-FU/low-dose LV (Mayo)3 LV5FU24 55 60 65 70 75 3-year disease-free survival (%) 1IMPACT Investigators, Lancet 1995;345:939–442Wolmark N, et al. J Clin Oncol 1993;11:1879–87 3QUASAR Group. Lancet 2000;355:1588–964André T, et al. J Clin Oncol 2003;21:2896–903 Stage II and III colon cancer patients

  9. PETACC-3: DFS not significantly improved with FOLFIRI in stage III n 3-year DFS (%) FOLFIRI 1,044 63.3 5-FU/LV 1,050 60.3 1.0 0.9 0.8 0.7 0.6 0.5 0 Estimated probability HR=0.89 (95% CI: 0.77–1.11)p=0.091 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Months DFS = disease free survivalHR = hazard ratio; CI = confidence interval Van Cutsem E, et al. J Clin Oncol 2005;23:(Suppl. 16):3s (Abstract LBA8)

  10. ACCORD2: DFS not improved with FOLFIRI in high-risk colon cancer 3-year DFS (%) FOLFIRI 51 LV5FU2 60 1.0 0.8 0.6 0.4 0.2 0 Estimated probability HR=1.19(95% CI: 0.90–1.59)p=0.22 0 1 2 3 4 5 6 Years Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502)

  11. CALGB 89803: DFS and OS not improvedwith IFL in stage III colon cancer 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Proportion surviving Proportion disease-free FU/LV IFL FU/LV IFL 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Years n Events FU/LV 629 227IFL 635 248 p (stratified) = 0.85 (1-sided) n Events FU/LV 629 171IFL 635 181 p (stratified) = 0.74 (1-sided) OS = overall survival; IFL = irinotecan, 5-FU plus leucovorin Saltz L, et al. J Clin Oncol 2007;25:3456–61

  12. MOSAIC: superior DFSwith FOLFOX4 in stage III n 3-year DFS (%) FOLFOX4 1,123 72.2 LV5FU2 1,123 65.3 1.0 0.8 0.6 0.4 0.2 0 Estimated probability HR=0.76 (95% CI: 0.62–0.92)p=0.002 0 6 12 18 24 30 36 42 48 54 60 Months André T, et al. N Engl J Med 2004;350:2343–51

  13. MOSAIC: consistent benefitin DFS with FOLFOX4 versus LV5FU2 *p<0.05 1de Gramont A, et al. J Clin Oncol 2005;23(Suppl. 16)246s (Abstract 3501) 2André T, et al. N Engl J Med 2004;350:2343–51

  14. MOSAIC: OS for stage II and stage III patients 1.0 0.8 0.6 0.4 0.2 0 p=0.996 0.1% p=0.029 4.4% Probability FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR (95% CI) Stage II 1.00 (0.71–1.42) Stage III 0.80 (0.66–0.98) 0 12 24 36 48 60 72 84 96 Overall survival (months) De Gramont A, et al. J Clin Oncol 2007;25(Suppl. 18)165s (Abstract 4007) Data cut-off: January 2007

  15. NSABP C-07: superior DFSwith FLOX in stage II/III combined n 3-year DFS (%) FLOX 1,200 76.5 5-FU/LV 1,207 71.6 1.0 0.9 0.8 0.7 0.6 0.5 Estimated probability HR=0.79 (95% CI: 0.67–0.93)p<0.004 0 1 2 3 4 Years Kuebler JP, et al. J Clin Oncol 2007;25:2156–8

  16. Adjuvant combination therapy: summary • Data from MOSAIC and NSABP C-07 suggest that • oxaliplatin plus 5-FU/LV significantly improves DFS in patients with stage II and III colon cancer • oxaliplatin plus 5-FU/LV significantly improves OS in patients with stage III colon cancer • Data from PETACC-3, ACCORD and CALGB 89803 suggest that • addition of irinotecan to LV5FU2 may reduce riskof recurrence in patients with stage III colon cancer • there is no clear significant benefit for irinotecan in the adjuvant setting

  17. Capecitabine: the potential agent of choice for adjuvant therapy

  18. Capecitabine mode of action:TP-activation – proof of concept at last? Intestine Liver Capecitabine Tumour >> healthy tissue Capecitabine CE 5'-DFCR 5'-DFCR CyD CyD 5'-DFUR 5'-DFUR Thymidine phosphorylase (TP) 5-FU 5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase

  19. X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer RANDO MIS ATION Capecitabine 1,250mg/m2 b.i.d. days 1–14 q3w n=1,004 Chemonaïve stage IIIresection 8 weeks Bolus5-FU/LV 5-FU 425mg/m2 + LV 20mg/m2days 1–5 q4w n=983 • Primary endpoint: non-inferiority in DFS • Secondary endpoint: OS Data cut-off: January 2007 b.i.d. = twice daily Twelves C, et al. Eur J Cancer Suppl2007;5:1 (Abstract 1LB)

  20. X-ACT: 5-year DFS (median follow-up 6.8 years) 5-year DFS (%) Capecitabine 1,004 60.8 5-FU/LV 983 56.7 1.0 0.8 0.6 0.4 0.2 0 n Estimated probability HR=0.88 (95% CI: 0.77–1.01) NI margin 1.20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Months Test of non-inferiority p<0.0001 Test of superiority p=0.0682 ITT population Twelves C, et al. Eur J Cancer Suppl2007;5:1 (Abstract 1LB) ITT (intent-to-treat) population; NI = non-inferiority

  21. X-ACT: 5-year OS (median follow-up 6.8 years) 5-year OS (%) Capecitabine 1,004 71.4 5-FU/LV 983 68.4 n 1.0 0.8 0.6 0.4 0.2 0 Estimated probability HR=0.86 (95% CI: 0.74–1.01) NI margin 1.14 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Months Test of non-inferiority p=0.000116 Test of superiority p=0.06 Twelves C, et al. Eur J Cancer Suppl2007;5:1 (Abstract 1LB) ITT population

  22. Favours capecitabine Favours 5-FU 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 HR (95% CI) X-ACT: improved efficacy with capecitabine(5-year OS subgroup analysis) n ITT population Male Female <40 40–69 years old 70 pN1 pN2 Baseline CEA <ULN Baseline CEA >ULN 1,987 1,074 912 76 1,513 396 1,389 593 1,672 155 CEA = carcinoembryonic antigen ULN = upper limit of normal Twelves C, et al. Eur J Cancer Suppl2007;5:1 (Abstract 1LB)

  23. Multivariate analysis of OS Twelves C, et al. N Engl J Med 2005;352:2696–704

  24. Treatment duration and intensity Twelves C, et al. N Engl J Med 2005;352:2696–704

  25. X-ACT: improved safety with capecitabine Grade 3/4 adverse events 50 40 30 20 10 0 Capecitabine (n=993) 5-FU/LV (n=974) Patients (%) * * * * HFS Nausea/vomiting Diarrhoea Stomatitis Febrileneutropenia Neutropenia *p<0.001HFS = hand foot syndrome Scheithauer W, et al. Ann Oncol 2003;14:1735–43

  26. Capecitabine (n=1,004) FOLFOX (n=672) Bolus 5-FU/LV (n=983) LV5FU2 (n=675) X-ACT and MOSAIC: projection of OS in stage III patients X-ACT1 MOSAIC2 1.0 0.8 0.6 0.4 1.0 0.8 0.6 0.4 Estimated probability Estimated probability 0 2 4 6 8 0 2 4 6 8 Years Years 1Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB) 2De Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007) ITT population

  27. X-ACT: 5-year survival update –conclusions • Update shows that capecitabine is at least equivalent to bolus 5-FU/LV with a trend to superiority (p=0.06) in terms of 5-year OS • First indication in the adjuvant setting from a cross-trial comparison showing that capecitabine is equivalent to infusional 5-FU Capecitabine is known to be an effective/better tolerated alternative to bolus 5-FU/LV (Mayo Clinic) in the adjuvant treatment of stage III colon cancer

  28. CAPOX: a new optionin the adjuvant setting • Primary endpoint: disease-free survival RANDO MIS ATION CAPOX Capecitabine 1,000mg/m2 b.i.d. days 1–15 Oxaliplatin 130mg/m2 day 1 q3w n=944 Chemo/radiotherapy-naïve stage III colon cancer Bolus 5-FU/LVMayo Clinic or Roswell Park n=942 Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23

  29. Adjuvant CAPOX: favourable toxicity compared with FOLFOX and FLOX 50 40 30 20 10 0 Grade 3/4 adverse events CAPOX1 (n=938) FOLFOX42 (n=1,108) FLOX3 (n=1,200) Patients (%) * * * HFS Nausea Vomiting Febrileneutropenia Diarrhoea Stomatitis Neutropenia Neurosensory 1Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034)2André T, et al. N Engl J Med 2004;350:2343–51 3Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500) Cross-trial comparison *Not reported

  30. Active patient management minimises adverse events: before and after dose modification 20 15 10 5 0 Grade 2 Grade 3 Grade 4 Cycles (%) Before After Before After Before After HFS Diarrhoea Stomatitis Cassidy J, et al. J Clin Oncol 2004;22(Suppl. 14):14s (Abstract 3509)

  31. Role of adjuvant anti-VEGF therapy

  32. Rationale for anti-VEGF therapy in the adjuvant setting • The roles of angiogenesis and VEGF in colorectal tumour growth are well established1 • Using anti-VEGF therapy such as bevacizumab when micrometastases are dormant and potentially reliant on VEGF may prevent the angiogenic switch,2 thereby improving outcomes • In preclinical studies, bevacizumab causes regression of human tumour xenografts,3–5 and a reduction in the number and size of liver metastases6 • Bevacizumab may have a greater impact in earlier disease stages 1Bergers G, et al. Nat Rev Cancer 2003;3:401–10; 2Poon RT, et al. J Clin Oncol 2001;19:1207–25; 3Gerber HP, et al. Cancer Res 2000;60:6253–8; 4Wildiers H, et al. Br J Cancer 2003;88:1979–86; 5Shen B-Q, et al. Proc Amer Assoc Cancer Res 2004;45 (Abstract 2203); 6Warren RS, et al. J Clin Invest 1995;95:1789–97 VEGF = vascularendothelial growth factor

  33. Anti-VEGF therapy regresses some existing tumour microvasculature • Reduction in tumour vessel blood flow after 1 day of anti-VEGF therapy • Control Anti-VEGF therapy* Inai T, et al. Am J Pathol 2004;165:35–52 Rugo HS, et al. J Clin Oncol 2005;23:5474–83 *AG013736 (VEGF tyrosine kinase inhibitor)

  34. Abnormal vasculature normalised following VEGF inhibition* Inai T, et al. Am J Pathol 2004;165:35–52 Rugo HS, et al. J Clin Oncol 2005;23:5474–83 *AG013736 (VEGF tyrosine kinase inhibitor)

  35. Normalisation of tumour vasculature improves delivery of chemotherapy • 46% increase in intratumoral availability of irinotecan after pretreatment with an anti-VEGF antibody* 15.98 20 15 10 5 0 10.93 Tumour irinotecan concentration (mg/g) Placebo A4.6.1 Wildiers H, et al. Br J Cancer 2003;88:1979–86 *In a preclinical model

  36. Withdrawal of anti-VEGF therapyresults in vessel regrowth CD31 Untreated AG-013736, 7d Withdrawal, 2d Withdrawal, 7d RIP-Tag2 Continue anti-angiogenic therapy to avoid vessel regrowth Mancuso MR, et al. J Clin Invest 2006;116:2610–21

  37. Linking the MoA of bevacizumab with clinical benefit in adjuvant CRC EARLY EFFECTS CONTINUED EFFECTS Regression Normalisation Inhibition 1 2 3 Prevent growth of small, unresected tumours Improve delivery of chemotherapy Suppress the ‘angiogenic switch’ in dormant cells Eliminate residual cancer cells following surgery Improve DFS

  38. Primary endpoint: DFS Secondary endpoints include survival and tolerability Recruitment started September 2006 306 patients enrolled (March 2007) QUASAR-2 (phase III): study design Bevacizumab (7.5mg/kg) + capecitabine every 3 weeks (bevacizumab 16 cycles and capecitabine 8 cycles over24 weeks) Colon cancer (stage II/III) (n=2,240) Capecitabine (8 cycles over 24 weeks)

  39. Phase III trial BO17920 (AVANT):study design Randomised, open-label study Observation FOLFOX4 Surgery for high-risk stage II + stage III colon cancer (n=3,450) FOLFOX4 + bevacizumab (5mg/kg every 2 weeks) Bevacizumab alone (7.5mg/kg every 3 weeks) CAPOX + bevacizumab (7.5mg/kg every 3 weeks) Bevacizumab alone (7.5mg/kg every 3 weeks) Duration of treatment phases 24 weeks 24 weeks • Primary endpoint: DFS at 3 years for stage III • Secondary endpoints: OS and safety • Accrual completed Q2 2007

  40. NSABP C-08: study design • Primary endpoint: DFS at 3 years • Secondary endpoints include survival and tolerability • Trial design • 90% power for 25% reduction in risk of progression after 3 years • 82% power for 25% reduction in risk of death after 7 years • Patient recruitment is complete, efficacy results expected for ASCO 2009 Observation mFOLFOX6 Dukes’ C colon cancer (n=2,714) mFOLFOX6 + bevacizumab 5mg/kg every 2 weeks Bevacizumab 5mg/kg every2 weeks 24 weeks 24 weeks

  41. Trials of bevacizumab/capecitabinein the adjuvant setting

  42. Important adjuvant capecitabine/bevacizumab-based combination trials AVANT 1° efficacy NSABP C-08 1° efficacy QUASAR-2 1° efficacy XELOXA survival follow-up XELOXA 1° efficacy XELOXA final safety 2004 2005 2006 2007 2008 2009 2010 2011

  43. Conclusions • Adjuvant capecitabine is as effective as bolus 5-FU/LV, with fewer grade 3/4 toxicities • Capecitabine in combination with oxaliplatin is a promising option in the adjuvant setting • There is a strong rationale for the use of bevacizumab in the adjuvant setting • Adjuvant bevacizumab and capecitabine clinical development programme is ongoing, results expected soon

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