1. BOPA 2009 Clinical Update: Colorectal Cancer Dr Nick Maisey

2. Treatment Intent AdjuvantPalliative

3. ADJUVANT CHEMOTHERAPY

4. Moertel et al, 1990 / 1995

5. CALGB 89803. Saltz et al ASCO 2004 ACCORD-2 Trial, Ychou et al ASCO 2005 PETACC-3, Van Cutsem, ASCO 2005 Irinotecan in Adjuvant Therapy ACCORD-2: Ychou et al, ASCO 2005 PETACC 3: Van Cutsem et al, ASCO 2005 CALGB 89803: Saltz et al, ASCO 2004

6. Andre, T. et al. J Clin Oncol; 27:3109-3116 2009 Overall survival (A) by treatment arm and (B) by treatment arm and by stage Oxaliplatin: MOSAIC Trial FU/LVFOLFOX 5Y DFS (III)58.9%66.4%7.5%p=0.005 5Y DFS (II)79.9%83.7%3.8%p=NS 5Y DFS (HRII)74.6%82.3%7.7%p=NS 6Y OS (III)76%78.5%2.5%p=0.045 6Y OS (II)86.8%86.9%0.1%p=NS

7. Adjuvant Biologics Bevacizumab Cetuximab NSABP C-08 AVANT QUASAR-2 PETACC-8 Intergroup 0147

8. NSABP C-08 R Stage II / III CRC (n=2714) FOLFOX 6/12 AVASTIN 12/12 Wolmark et al, JCO 2009

9. NSABP-C08 3Y DFS1.01.52.02.53.0 FOLFOX75.5% (n=1338) 0.60.740.810.850.87 0.00040.0040.020.050.08 FOLFOX-B77.4% (n=1334)

10. Adjuvant Summary Most patients benefit from a FP Irinotecan does not work Oxaliplatin has small but significant OS effect Data supports use of oral FP No data to support Biologics

11. PALLIATIVE CHEMOTHERAPY

12. Patient outcomes have improved with the evolution of mCRC treatment options Median OS Months BSC 5-FU 30 25 20 15 10 5 0 1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004 3. Rothenberg, et al. JCO 2003; 4. Hurwitz, et al. NEJM 2004 5. Karapetis, et al. NEJM 2008 Irinotecan 1 Capecitabine 2 Oxaliplatin 3 Cetuximab 5 Bevacizumab 4 1980s1990s2000s2009 BSC = best supportive care

13. What order to give the drugs? Tournigand et al, JCO 2004

14. Survival and Access to 3 Drugs Grothey et al, JCO 2004

15. Avastin: mechanism of action EARLY BENEFIT CONTINUED BENEFIT Regressio n of existing microvasculature Normalisati on of surviving microvasculature Inhibition of vessel regrowth and neovascularisation

16. First-Line Avastin and Irinotecan Adapted from 1. Hurwitz H et al. N Engl J Med 2004;350(23):2335-42. 2. Hurwitz H et al. J Clin Oncol 2005;23(15):3502-8. * p<0.001 Avastin + IFL vs IFL alone 453539 IFL + placebo 1 (n=411) Overall response rate (%) Duration of response (months) Median overall survival (months)* Median progression-free survival (months)* IFL + Avastin 1 (n=402) 5-FU/FA + Avastin 2 (n=110) 10.47.18.5 20.315.618.3 10.66.28.8

17. NO16966: XELOX ± Avastin vs FOLFOX ± Avastin in first-line mCRC Initial two- arm open-label study (n=1 000) Protocol amended to 2x2 placebo- controlled design after Avastin Phase III data became available (n=1 400) Recruitment June 2003 – May 2004 XELOX + placebo n=350 FOLFOX4 + placebo n=351 XELOX + Avastin n=350 FOLFOX4 + Avastin n=349 XELOX n=317 FOLFOX4 n=317 Recruitment February 2004 – February 2005 Cassidy, et al. J Clin Oncol 2008 Cassidy, et al. ASCO GI 2008

18. Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 2008

19. Second Line FOLFOX-B OS (months) Estimated probability FOLFOX4 + bevacizumab FOLFOX4 1.0 0.8 0.6 0.4 0.2 0 Second-line 2 Median OS 10.8 vs 12.9 months (HR=0.75; p=0.0011) 010203040 12.910.8 Giantonio et al, JCO 2007 829pts pretreated with 5FU + Irinotecan R FOLFOX (RR=8.6 %) FOLFOX- B (RR=22.7 %) B (RR=3.3 %)

20. Duration of Treatment? BevNo Bev Hurwitz40.4 wks27.6 wks Saltz27.1 wks*25.1 wks *discontinuations for chemo tox

21. BRiTE:* continuation of bevacizumab post- first progression significantly increases OS ‡ Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008 *Non-randomised, observational trial ‡ Time from initiation of first-line treatment to death OS (months) 12.619.931.8 Post-progression bevacizumab HR=0.48 (95% CI: 0.41–0.57) 05101520253035 1.0 0.8 0.6 0.4 0.2 0 Estimated probability p<0.00 1 Post-progression therapy Bevacizumab post-PD (n=642) No bevacizumab post-PD (n=531) No treatment (n=253)

22. The EGFr Antibodies

23. Cetuximab In Irinotecan Refractory mCRC CETUXIMAB + IRINOTECANCETUXIMAB ALONE Saltz 2001Saltz 2004Cunningham 2003 22.5%22.9%10.8% 8.8% (1)Saltz et al, ASCO 2001 (2)Cunningham et al, NEJM 2004 (3)Saltz et al, JCO 2004

25. The role of KRAS

26. KRAS wild-type and EGFR inhibitor efficacy in chemorefractory CRC: Response 10 (31) Reference Treatment No. of patients (wild-type: mutant) Objective response n (%) Wild-typeMutant Lièvre A, et al. J Clin Oncol 2008CETUXIMAB ± CT114 (78:36) 34 (44) 0 (0) Benvenuti S, et al. Cancer Res 2007 Panitumumab or CETUXIMAB or CETUXIMAB + CT 48 (32:16)1 (6) DeRoock W, et al. Ann Oncol 2008CETUXIMAB or CETUXIMAB + irinotecan 113 (67:46) 27 (41) 0 (0) Capuzzo F, et al. Br J Cancer 2008CETUXIMAB ± CT81 (49:32) 13 (26) 2 (6) Di Fiore F, et al. Br J Cancer 2007CETUXIMAB + CT59 (43:16) 12 (28) 0 (0) Khambata-Ford S, et al. J Clin Oncol 2007CETUXIMAB80 (50:30) 5 (10) 0 (0) Amado RG, et al. J Clin Oncol 2008Panitumumab208 (124:84) 21 (17) (0) Karapetis CS, et al. NEJM 2008CETUXIMAB + BSC or BSC 287 (117:81) 15 (12.8) 1 (1.2)

27. Wild type ras Mutant ras KRAS mutation on PFS with panitumumab v BSC: a predictive marker Amado et al, JCO 2008

28. NCIC CTG C0.17: Overall survival in K-ras Wild-Type patients HR 0.55 95% CI (0.41,0.74) Log rank p-value: <0.0001 Study arm MS (months) 95% CI Cetuximab + BSC 9.5 7.7 – 10.3 BSC alone 4.8 4.2 – 5.5 Karapetis CS, et al. NEJM 2008; 359:17, 1757 -1765 Log rank p<0.001

29. Cetuximab used First-Line in KRAS w/t mCRC CRYSTAL 1 OPUS 2 FOLFI RI FOLFIR I-C FOLFO X FOLFOX -C N=1217 / 540N=337 / 233 med PFS8.79.97.27.7 ORR43%59%37%61% med OS21.024.9-- (1)Van Cutsem et al, NEJM 2009 (2)Bokemeyer et al, JCO 2009

30. Palliative Chemotherapy: Summary Survival continues to improve Avastin appears to improve overall survival if used ‘optimally’ Patients with mutated KRAS do not benefit from cetuximab Cetuximab confers survival advantage in chemo- resistant disease First line cetuximab improves PFS and RR

31. Neoadjuvant Chemotherapy

32. Rationale ‘In-Vivo’ test of sensitivity Kill off microscopic disease Down-size to allow operability

33. Curing Metastatic Disease

34. Who is considered for curative liver resection? No Bilobar Disease No more than 3 mets No extra-hepatic disease Marathon runner fitness Untreatable primary Insufficient remant liver Unresectable extra- hepatic disease Progression through chemo

36. Resection rate of metastases and tumour response Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001) Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96; p=0.002) Phase III studies including nonselected patients with mCRC (dashed line) (r=0.67; p=0.024) Response rate 0.90.80.70.60.50.40.3 Resection rate 0.6 0.5 0.4 0.3 0.2 0.1 0 Folprecht G, et al. Ann Oncol 2005;16:1311–1319

37. Survival after ‘down-sizing’ in initially unresectable disease Bismuth et al, Ann Surg 1996

38. Effect of Cetuximab in KRAS w/t tumours Response rate (%) 0 10 20 30 40 50 60 70 CRYSTALOPUS n=176n=73n=172n=61 59 37 43 61 Chemotherapy alone CETUXIMAB + chemotherapy 1. Van Cutsem E, et al.: NEJM 360(14): 1408-17 (2009); 2. Bokemeyer C, et al.: J Clin Oncol 27(5): 663-671 (2009) RO resection FOLFIRI vs FOLFIRI-C 1.7% vs 4.8% Odds ratio 3.02 (p=0.002)

39. EMR 604-CELIM study Adjuvant therapy for 6 cycles (same schedule as pre-operatively) R Patients with technically unresectable/ ≥5 liver metastases without extrahepatic disease ERBIT UX + FOLF OX (n=56) 8 cycles (~4 months) Technicall y resectable Primary endpoint: Response rate 4 further treatme nt cycles RESECTI ON ERBIT UX + FOLFI RI (n=55) Technicall y unresecta ble Folprecht et al. ASCO GI 2009 Abstract no. 296

40. Response rates FOLFOX6 +FOLFIRI +KRAS All ERBITUX wild-typemutantpatients n=53 n=67N=28n=106* CR/PR 68%57%70%43%62% (36 pts)(30 pts)(47 pts)(12 pts)(66 pts) 95% CI54-80%42-70%58-81%24-63%52-72% SD28%30%21%46%29% (15 pts)(16 pts)(14 pts)(13 pts)(31 pts) PD4%13%9%11%8% (2 pts)(7 pts)(6 pts)(3 pts)(9 pts) * 106 pts evaluable for efficacy These are confirmed response rates Folprecht et al. ASCO GI 2009 Abstract no. 296

41. Resection rates FOLFOX6 +FOLFIRI +KRASAll ERBITUX wtpatients n=53 N=67n=106* R0/R1 resect. /RFA49%43%NR46% R0 resections38%30%33%34% (20 pts)(16 pts)(22 pts)(36 pts) * 106 pts evaluable for efficacy Folprecht et al. ASCO GI 2009 Abstract no. 296

42. Bevacizumab: significant pathological response when combined with FOLFOX 1,2 100 80 60 40 20 0 Pathological response (%) 1–8 cycles≥9 cycles1–8 cycles≥9 cycles FOLFOXFOLFOX + bevacizumab Major response Complete response p=0.007 p=0.011 Pathological response predicts for survival 2 Complete response: no residual cells Major response: 1–49% residual cells Minor response: ≥50% residual cells 1. Zorzi, et al. ASCO GI 2009; 2. Blazer, et al. JCO 2008

43. NO16966: surgery with curative intent Patients (%) 6.1 8.4 12.9 19.2 (n=701)(n=699)(n=178)(n=177) 10 5 0 20 15 10 5 0 Patients (%)PlaceboAvastin ITT populationPatients with liver metastases only XELOX/FOLFOX4 + AvastinXELOX/FOLFOX4 + placebo Saltz, et al. WCGC 2007

44. Neoadjuvant Therapy: Summary Metastatic disease can be cured Higher response rates lead to higher resection rates Cure depends on successful resection Cetuximab increases reponse rate and R0 resections Bevacizumab may augment neoadjuvant chemo