1. Mario Scartozzi Clinica di Oncologia Medica Ancona HIGHLIGHTS IN COLORECTAL CANCER MANAGEMENT TREATMENT OF METASTATIC DISEASE

2. Bittoni, Giampieri et al, CROH 2012

3. – Chemotherapy has determined a relevant improvement in survival in the last 15 years: from 6 to 18 months – Probably FOLFOX = FOLFIRI and XELOX=FOLFOX (XELIRI has PHYLOSOPHICAL problems with toxicity) – Concept of all three drugs – Some patients with stage IV disease can be cured by an interdisciplinary approach Colon Cancer: what we already know

4. – Chemotherapy has determined a relevant improvement in survival in the last 15 years: from 6 to 18 months – Probably FOLFOX = FOLFIRI and XELOX=FOLFOX (XELIRI has PHYLOSOPHICAL problems with toxicity) – Concept of all three drugs – Some patients with stage IV disease can be cured by an interdisciplinary approach Colon Cancer: what we already know

5. Not all liver metastases are created equal

7. Bittoni, Giampieri et al, CROH 2012

8. Multimodality Management of CRC Liver Metastases – Neoadjuvant chemotherapy Resectable liver metastases: – Facilitate surgery – Obtain predictive and prognostic information – Early systemic therapy for poor-prognosis pts – Conversion chemotherapy Unresectable liver metastases: – Allow R0 resection via downsizing – Postoperative (adjuvant) chemotherapy Hepatic arterial infusion (HAI) Systemic treatment

9. BIOLOGICALLY CHALLANGING Colon Cancer: NOT all liver metastases are created equal PFS/OS

10. – Neoadjuvant chemotherapy Resectable liver metastases: – Facilitate surgery – Obtain predictive and prognostic information – Early systemic therapy for poor-prognosis pts – Conversion chemotherapy Unresectable liver metastases: – Allow R0 resection via downsizing – Postoperative (adjuvant) chemotherapy Colon Cancer: MULTIMODALITY management

11. – Neoadjuvant chemotherapy Resectable liver metastases: – Facilitate surgery – Obtain predictive and prognostic information – Early systemic therapy for poor-prognosis pts – Conversion chemotherapy Unresectable liver metastases: – Allow R0 resection via downsizing – Postoperative (adjuvant) chemotherapy Colon Cancer: MULTIMODALITY management

12. 364 patients randomized Potentially resectable (≤ 4 liver metastases) Goal: Improve PFS Interim objective: Evaluate tumor response to perioperative CT Perioperative CT (n = 182) – 159 (87.3%) underwent surgery – 151 (83.0%) resected Surgery (n=182) – 170 (93.4%) underwent surgery – 152 (83.0%) resected R Nordlinger B, et al. Lancet 2008 FOLFOX4 for 6 cycles (12 wks) (n = 182) Surgery FOLFOX4 for 6 cycles (12 wks) Surgery (n = 182) Colon Cancer: EORTC 40983 (the EPOC trial)

13. Efficacy Results No. pts CT No. pts Surgery % absolute difference in 3-year PFS Hazard ratio (confidence interval)p Value All patients182 +7.2% (28.1% to 35.4%) 0.79 (0.62-1.02) 0.058 All eligible patients 171 +8.1% (28.1% to 36.2%) 0.77 (0.60-1.00) 0.041 All resected patients 151152 +9.2% (33.2% to 42.4%) 0.73 (0.55-0.97) 0.025 MOSAIC: 3-yr DFS for stage III: +7.2% Adapted from Nordlinger B, et al. Lancet 2008;371(9617):1007-16.

14. 2012 Nordlinger et al

15. Biologicals Surgery Chemotherapy Biologicals: How Do They Fit Into This Strategy?

16. Colon Cancer: PFS in BEVACIZUMAB trials Wagner et al. Cochrane Review ‘09

17. Loupakis, Bria E et al. Cancer 2011 Colon Cancer: PFS in anti-EGFR trials

18. BEVACIZUMAB: PFS on TREATMENT! Saltz, et al. ASCO GI 2007

19. TECHNICALLY CHALLANGING Colon Cancer: NOT all liver metastases are created equal RR/R0/OS

20. – Neoadjuvant chemotherapy Resectable liver metastases: – Facilitate surgery – Obtain predictive and prognostic information – Early systemic therapy for poor-prognosis pts – Conversion chemotherapy Unresectable liver metastases: – Allow R0 resection via downsizing – Postoperative (adjuvant) chemotherapy Colon Cancer: MULTIMODALITY management

21. – Neoadjuvant chemotherapy Resectable liver metastases: – Facilitate surgery – Obtain predictive and prognostic information – Early systemic therapy for poor-prognosis pts – Conversion chemotherapy Unresectable liver metastases: – Allow R0 resection via downsizing – Postoperative (adjuvant) chemotherapy Colon Cancer: MULTIMODALITY management

22. High (anatomical) response rate – RR = goal of therapy in stage IV CRC only for Conversion therapy Patients with significant tumor-related symptoms Good toxicity profile – No hepatotoxicity – No interference with surgery – No interference with liver regeneration What Do We Expect from Ideal Conversion Chemo?

23. – 5-FU: hepatic steatosis, associated with increased postoperative morbidity - yellow liver – Irinotecan: non-alcoholic steatohepatitis (especially in obese patients), can affect hepatic reserve and increase morbidity and mortality after hepatectomy - orange liver – Oxaliplatin: hepatic sinusoidal obstruction syndrome, does not appear to be associated with increased risk of perioperative death - blue liver – Both response rate and toxicity should be considered when selecting preoperative CT in patients with colorectal liver metastases Adapted from Zorzi D, et al. Br J Surg 2007;94:274-86. Conversion Therapy: Liver Toxicities REMEMBER: AS SOON AS….

24. Folprecht et al. Ann Oncol ‘05 Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line Selected pts (liver mets) Not selected pts Colon Cancer: Rate of Liver Resections/RR

25. FOLFIRI 122 pts FOLFOXIRI 122 pts P value Confirmed RR 34%60% <0.0001 R0 surgery (all pts) 6%15% 0.033 R0 surgery (liver only) 12%36% 0.017 mPFS (months) 6.89.8 <0.001 mOS (months) 16.723.4 0.026 Falcone A, JCO ‘07 & Masi JNCI’10 FOLFIRI vs FOLFOXIRI: RESULTS

26. Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010

27. Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010

28. Folprecht et al. Ann Oncol ‘05 Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line K-RAS wt Not selected pts Colon Cancer: Rate of Liver Resections/RR

29. Folprecht et al. Ann Oncol ‘05 Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line Selected pts (liver mets) Not selected pts Colon Cancer: Rate of Liver Resections/RR K-RAS wt K-RAS mt

30. Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010

31. Folprecht et al. Ann Oncol ‘05 Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line Selected pts (liver mets) Not selected pts Colon Cancer: Rate of Liver Resections/RR K-RAS wt K-RAS mt

32. Loupakis F, Bria E et al. Cancer 2011 Response Rate in anti-EGFR trials

33. Response Rate in BEVACIZUMAB trials Wagner et al. Cochrane Review ‘09

34. A - PretreatmentB - Posttreatment C - Pretreatment D - Posttreatment CT Morphology vs RECIST

35. CT Morphology vs RECIST to Determine Response on BEV Computer Tomographic Tumor Characteristics Morphology group Overall AttenuationTumor-Liver InterfacePheripheral Rim of Enhancement 3HeterogeneousIII definedMay be present 2MixedVariableIf initially present, partially resolved 1 Homogeneous and hypoattenuating SharpIf initially present, completely resolved Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44. 234 pts with CRC liver mets treated with chemo + BEV −50 pts underwent hepatic resection Three blinded radiologists evaluated response of liver mets according to −Standard RECIST criteria −Novel CT morphology criteria

36. 0.0 Proportion surviving 1.0 0.4 0.2 0.0 Proportion surviving 1.0 0.4 0.2 60 0.6 Morphologic response criteriaRECIST Log-rank p=0.009Log-rank p=0.45 Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44. 0.8 504030201006050403020100 Patients with unresectable tumor Months No. at risk Responders30 261662 Ronresponder5249251441 3534251430 4745261673 Response Evaluation: Morphology vs. RECIST

37. Colon Cancer: NEVER (NEVER!) resectable Bad, Bad luck….. PFS/OS/QoL

38. Phase III randomized trials: gains in activity and efficacy in 1st line therapy N° of patientsRRPFSOS Bevacizumab Hurwitz40245 vs 3510.6 vs 6.220.3 vs 15.6 No1696670038 vs 389.4 vs 8nr Cetuximab Crystal59958 vs 409.9 vs 8.723.5 vs 20 COIN244564 vs 578.6 vs 8.617 vs 17.9 Nordic56647 vs 467.9 vs 8.719.7 vs 20.3 Panitumumab Prime65655 vs 489.6 vs 8Ne vs 18.8

39. Wagner et al. Cochrane Review ‘09 Overall Survival in BEVACIZUMAB trials

40. Overall Survival in anti-EGFRs trials Loupakis, Bria E et al. Cancer 2011

41. N° of patientsRRPFSOS Bevacizumab Giantonio82922.7 vs 8.67.3 vs 4.712.9 vs 10.8 Cetuximab EPIC129816.4 vs 4.24 vs 2.610.7 vs 10 Panitumumab Peeters59735 vs 155.9 vs 3.914.5 vs 12.5 Phase III randomized trials: gains in activity and efficacy in 2nd line therapy

42. Amado JCO 2008

44. CRYSTAL 5 COIN 3 PRIME 4 NORDIC VII 2 CO.17 9 Amado 8 N0147 1 PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS wild-type patients Hazard ratio 1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011 4. Douillard, et al. ASCO 2011; 5. Van Cutsem, et al. JCO 2011; 6. Langer, et al. ESMO 2008 7. Sobrero, et al. ASCO GI 2012; 8. Amado, et al. JCO 2008; 9. Karapetis, et al. NEJM 2008 First lineSecond line Salvage (single agent) Adjuvant 1.2 1.0 0.8 0.6 0.4 0.2 0 Study 181 7 EPIC 6 Slide Courtesy of A Grothey

45. 2012 Arnold D, et Al

46. 2012 Arnold D, et Al

47. 2012 Arnold D, et Al

48. 2012 Arnold D, et Al

49. AFLIBERCEPT

50. 2012 Allegra C, et Al

51. 2012 Allegra C, et Al the VELOUR trial

52. 2012 Allegra C, et Al

53. GI 2009 Kopetz S et AL

54. 2012 Van Cutsem E, et al

55. 2012 Van Cutsem E, et al

56. 2012 Van Cutsem E, et al

57. 2012 Van Cutsem E, et al

58. 2012 Van Cutsem E, et al

59. Baseline After 2 cycles CT Response on REGORAFENIB

60. Bittoni, Giampieri et al, CROH 2012