1. The Very Best, Most Perfect Possible Way to Treat Advanced Colorectal Cancer in 2005: Agent Choice and Ideal Sequencing Charles D. Blanke, M.D. OHSU Cancer Institute

2. FIRE Trial: Abstract #3516 Comparison of infusional 5FU + irinotecan (AI2-IRI) versus irinotecan + oxaliplatin (IROX) Primary end-point: Progression-free survival Secondary end-points: ORR, OS, liver met resectability, toxicity A. Schalhorn et al.

3. FIRE Trial: Abstract #3516 Comparison of infusional 5FU + irinotecan (AI2-IRI) versus irinotecan + oxaliplatin (IROX) Primary end-point: Progression-free survival Secondary end-points: ORR, OS, liver met resectability, toxicity

4. FIRE Trial: Abstract #3516 Comparison of infusional 5FU + irinotecan (AI2-IRI) versus irinotecan + oxaliplatin (IROX) Primary end-point: Progression-free survival Secondary end-points: ORR, OS, liver met resectability, toxicity

5. FIRE Results and Conclusions Infus 5FU-I IROXp Objective responses (%)4548NS PFS (months)8.27.00.17 Overall survival21.919.30.427 60-day mortality (%)6.34.2 Authors: Regimens are comparable in regard to ORR, PFS, OS, and toxicity

6. FIRE Results and Conclusions Infus 5FU-I IROXp Objective responses (%)4548NS PFS (months)8.27.00.17 Overall survival21.919.30.427 60-day mortality (%)6.34.2 Authors: Regimens are comparable in regard to ORR, PFS, OS, and toxicity

7. FIRE Results and Conclusions Infus 5FU-I IROXp Objective responses (%)4548NS PFS (months)8.27.00.17 Overall survival21.919.30.427 60-day mortality (%)6.34.2 Authors: Regimens are comparable in regard to ORR, PFS, OS, and toxicity

8. FIRE Results and Conclusions Infus 5FU-I IROXp Objective responses (%)4548NS PFS (months)8.27.00.17 Overall survival21.919.30.427 60-day mortality (%)6.34.2 Authors: Regimens are comparable in regard to ORR, PFS, OS, and toxicity

9. FIRE Results and Conclusions Infus 5FU-I IROXp Objective responses (%)4548NS PFS (months)8.27.00.17 Overall survival21.919.30.427 60-day mortality (%)6.34.2 Authors: Regimens are comparable in regard to ORR, PFS, OS, and toxicity

10. FIRE: Commentary Infusional 5FU-irinotecan and IROX results for both arms are similar to those from previous phase III studies IROX was previously shown to offer similar PFS and improved overall survival vs. bolus IFL There may be a hint that IROX is not quite as good as regimens (irinotecan or oxaliplatin-based) that include infusional 5FU IROX would not be my first choice –IROX remains a perfectly reasonable regimen in select patients

11. FIRE: Commentary Infusional 5FU-irinotecan and IROX results for both arms are similar to those from previous phase III studies IROX was previously shown to offer similar PFS and improved overall survival vs. bolus IFL There may be a hint that IROX is not quite as good as regimens (irinotecan or oxaliplatin-based) that include infusional 5FU IROX would not be my first choice –IROX remains a perfectly reasonable regimen in select patients

12. FIRE: Commentary Infusional 5FU-irinotecan and IROX results for both arms are similar to those from previous phase III studies IROX was previously shown to offer similar PFS and improved overall survival vs. bolus IFL There may be a hint that IROX is not quite as good as regimens (irinotecan or oxaliplatin-based) that include infusional 5FU IROX would not be my first choice –IROX remains a perfectly reasonable regimen in select patients

13. FIRE: Commentary Infusional 5FU-irinotecan and IROX results for both arms are similar to those from previous phase III studies IROX was previously shown to offer similar PFS and improved overall survival vs. bolus IFL There may be a hint that IROX is not quite as good as regimens (irinotecan or oxaliplatin-based) that include infusional 5FU IROX would not be my first choice –IROX remains a perfectly reasonable regimen in select patients

14. FIRE: Commentary Infusional 5FU-irinotecan and IROX results for both arms are similar to those from previous phase III studies IROX was previously shown to offer similar PFS and improved overall survival vs. bolus IFL There may be a hint that IROX is not quite as good as regimens (irinotecan or oxaliplatin-based) that include infusional 5FU IROX would not be my first choice –IROX remains a perfectly reasonable regimen in select patients

15. FIRE: Commentary Infusional 5FU-irinotecan and IROX results for both arms are similar to those from previous phase III studies IROX was previously shown to offer similar PFS and improved overall survival vs. bolus IFL There may be a hint that IROX is not quite as good as regimens (irinotecan or oxaliplatin-based) that include infusional 5FU IROX would not be my first choice –IROX remains a perfectly reasonable regimen in select patients

16. LIFE Trial: Abstract #3517 5FU monotherapy (Lokich or de Gramont) 5FU + oxaliplatin RANDOMIZATIONRANDOMIZATION Primary endpoint : 10% increase 2-year survival (20 to 30%) Note: FOLFOX4 2-year survival on N9741 was ~40% 725 pts IrinotecanIrinotecan PROGRESSIONPROGRESSION A. Pluzanska et al.

17. LIFE Trial: Abstract #3517 5FU monotherapy (Lokich or de Gramont) 5FU + oxaliplatin RANDOMIZATIONRANDOMIZATION Primary endpoint : 10% increase 2-year survival (20 to 30%) Note: FOLFOX4 2-year survival on N9741 was ~40% 725 pts IrinotecanIrinotecan PROGRESSIONPROGRESSION

18. LIFE Trial: Abstract #3517 5FU monotherapy (Lokich or de Gramont) 5FU + oxaliplatin RANDOMIZATIONRANDOMIZATION Primary endpoint : 10% increase 2-year survival (20 to 30%) Note: FOLFOX4 2-year survival on N9741 was ~40% 725 pts IrinotecanIrinotecan PROGRESSIONPROGRESSION

19. LIFE Trial: Abstract #3517 5FU monotherapy (Lokich or de Gramont) 5FU + oxaliplatin RANDOMIZATIONRANDOMIZATION Primary endpoint : 10% increase 2-year survival (20 to 30%) Note: FOLFOX4 2-year survival on N9741 was ~40% 725 pts IrinotecanIrinotecan PROGRESSIONPROGRESSION

20. LIFE Results and Conclusions* Oxaliplatin5FU alonep Objective response rate (%)5430<0.0001 PFS (months)7.95.9<0.0001 2-year survival (%)2523NS ORR and PFS are improved with combination therapy Survival results are explained by the low percentage getting irinotecan *

21. LIFE Results and Conclusions* Oxaliplatin5FU alonep Objective response rate (%)5430<0.0001 PFS (months)7.95.9<0.0001 2-year survival (%)2523NS ORR and PFS are improved with combination therapy Survival results are explained by the low percentage getting irinotecan *

22. LIFE Results and Conclusions* Oxaliplatin5FU alonep Objective response rate (%)5430<0.0001 PFS (months)7.95.9<0.0001 2-year survival (%)2523NS ORR and PFS are improved with combination therapy Survival results are explained by the low percentage getting irinotecan *

23. LIFE Results and Conclusions* Oxaliplatin5FU alonep Objective response rate (%)5430<0.0001 PFS (months)7.95.9<0.0001 2-year survival (%)2523NS ORR and PFS are improved with combination therapy Survival results are explained by the low percentage getting irinotecan *

24. FOCUS: Abstract #3518 Upfront Strategies for Chemotherapy Drug A until it fails… then B until it fails “staged single agents” A Drug A until it fails… then add drug B until both fail “staged combination” B Drugs A + B together until both fail “1 st -line combination” C M.T. Seymour, et al.

25. FOCUS: Abstract #3518 Upfront Strategies for Chemotherapy Drug A until it fails… then B until it fails “staged single agents” A Drug A until it fails… then add drug B until both fail “staged combination” B Drugs A + B together until both fail “1 st -line combination” C

26. FOCUS: Abstract #3518 Upfront Strategies for Chemotherapy Drug A until it fails… then B until it fails “staged single agents” A Drug A until it fails… then add drug B until both fail “staged combination” B Drugs A + B together until both fail “1 st -line combination” C

27. FOCUS: Abstract #3518 Upfront Strategies for Chemotherapy Drug A until it fails… then B until it fails “staged single agents” A Drug A until it fails… then add drug B until both fail “staged combination” B Drugs A + B together until both fail “1 st -line combination” C

28. A: FU until it fails, then change to Ir B(ir): FU until it fails, then add Ir B(ox): FU until it fails, then add Ox C(ir): FU+Ir from the start, until it fails C(ox): FU+Ox from the start, until it fails 1/3 1/6 2100 patients FOCUS Primary endpoint: Overall Survival

29. A: FU until it fails, then change to Ir B(ir): FU until it fails, then add Ir B(ox): FU until it fails, then add Ox C(ir): FU+Ir from the start, until it fails C(ox): FU+Ox from the start, until it fails 1/3 1/6 2100 patients FOCUS Primary endpoint: Overall Survival

30. A: FU until it fails, then change to Ir B(ir): FU until it fails, then add Ir B(ox): FU until it fails, then add Ox C(ir): FU+Ir from the start, until it fails C(ox): FU+Ox from the start, until it fails 1/3 1/6 2100 patients FOCUS Primary endpoint: Overall Survival

31. A: FU until it fails, then change to Ir B(ir): FU until it fails, then add Ir B(ox): FU until it fails, then add Ox C(ir): FU+Ir from the start, until it fails C(ox): FU+Ox from the start, until it fails 1/3 1/6 2100 patients FOCUS Primary endpoint: Overall Survival

32. A: FU until it fails, then change to Ir 3 rd drug salvage B(ir): FU until it fails, then add Ir B(ox): FU until it fails, then add Ox C(ir): FU+Ir from the start, until it fails C(ox): FU+Ox from the start, until it fails 1/3 1/6 2100 patients FOCUS Primary endpoint: Overall Survival OxCap IrCap OxCap IrCap

33. A: FU until it fails, then change to Ir 3 rd drug salvage B(ir): FU until it fails, then add Ir B(ox): FU until it fails, then add Ox C(ir): FU+Ir from the start, until it fails C(ox): FU+Ox from the start, until it fails 1/3 1/6 2100 patients FOCUS Primary endpoint: Overall Survival OxCap IrCap OxCap IrCap

34. FOCUS Response to 1 st -Line Chemotherapy MdG Plans A & B IrMdG Plan C(ir) OxMdG Plan C(ox) n1132275291 CR+PR28.9%51.3%57.0% SD47.5%37.8%29.2% PD23.7%10.9%13.8%

35. FOCUS Response to 1 st -Line Chemotherapy MdG Plans A & B IrMdG Plan C(ir) OxMdG Plan C(ox) n1132275291 CR+PR28.9%51.3%57.0% SD47.5%37.8%29.2% PD23.7%10.9%13.8%

36. FOCUS Response to 1 st -Line Chemotherapy MdG Plans A & B IrMdG Plan C(ir) OxMdG Plan C(ox) n1132275291 CR+PR 28.9% 51.3%57.0% SD47.5%37.8%29.2% PD23.7%10.9%13.8%

37. 0.00 0.20 0.40 0.60 0.80 1.00 Proportion 061218243036 Months Plan regimen median PFS A MdG 6.3 mo B(ir) MdG 6.7 mo B(ox) MdG 6.4 mo C(ir) IrMdG 8.6 mo C(ox) OxMdG 8.8 mo Progression-Free Survival, 1st Line

38. Plan A Plan B(ir) Plan C(ir) Plan B(ox) Plan C(ox) S u r v i v a l 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 061218243036 Overall Survival by Individual Treatment Arm

39. FOCUS Author Conclusions: Confirms higher RR, PFS and toxicity of combination chemotherapy However, deferring the combination until after optimum FU alone gave equal overall survival with less early toxicity

40. FOCUS Author Conclusions: Confirms higher RR, PFS and toxicity of combination chemotherapy However, deferring the combination until after optimum FU alone gave equal overall survival with less early toxicity

41. Problems in LIFE/FOCUS Interpretation Median survival low throughout all arms of both studies Why did irinotecan added to 5FU after 5FU failure, work better than replacing 5FU with irinotecan? How do we integrate biologic therapy into the sequencing question?

42. Problems in LIFE/FOCUS Interpretation Median survival low throughout all arms of both studies Why did irinotecan added to 5FU after 5FU failure, work better than replacing 5FU with irinotecan? How do we integrate biologic therapy into the sequencing question?

43. Problems in LIFE/FOCUS Interpretation Median survival low throughout all arms of both studies Why did irinotecan added to 5FU after 5FU failure, work better than replacing 5FU with irinotecan? How do we integrate biologic therapy into the sequencing question?

44. Problems in LIFE/FOCUS Interpretation Median survival low throughout all arms of both studies Why did irinotecan added to 5FU after 5FU failure, work better than replacing 5FU with irinotecan? How do we integrate biologic therapy into the sequencing question?

45. Additional LIFE/FOCUS Commentary There are patients who should receive combination therapy up- front –Potentially resectable for cure –Highly symptomatic patients –?Poor PS patients, related to cancer –Asymptomatic intact primary, not going to surgery –Carcinomatosis This provides additional impetus for using FOLFIRI (or CapIRI) after FOLFOX failure, instead of irinotecan alone FOLFOX = FOLFIRI

46. Additional LIFE/FOCUS Commentary There are patients who should receive combination therapy up- front –Potentially resectable for cure –Highly symptomatic patients –?Poor PS patients, related to cancer –Asymptomatic intact primary, not going to surgery –Carcinomatosis This provides additional impetus for using FOLFIRI (or CapIRI) after FOLFOX failure, instead of irinotecan alone FOLFOX = FOLFIRI

47. Additional LIFE/FOCUS Commentary There are patients who should receive combination therapy up- front –Potentially resectable for cure –Highly symptomatic patients –?Poor PS patients, related to cancer –Asymptomatic intact primary, not going to surgery –Carcinomatosis This provides additional impetus for using FOLFIRI (or CapIRI) after FOLFOX failure, instead of irinotecan alone FOLFOX = FOLFIRI

48. Additional LIFE/FOCUS Commentary There are patients who should receive combination therapy up- front –Potentially resectable for cure –Highly symptomatic patients –?Poor PS patients, related to cancer –Asymptomatic intact primary, not going to surgery –Carcinomatosis This provides additional impetus for using FOLFIRI (or CapIRI) after FOLFOX failure, instead of irinotecan alone FOLFOX = FOLFIRI

49. Additional LIFE/FOCUS Commentary There are patients who should receive combination therapy up- front –Potentially resectable for cure –Highly symptomatic patients –?Poor PS patients, related to cancer –Asymptomatic intact primary, not going to surgery –Carcinomatosis This provides additional impetus for using FOLFIRI (or CapIRI) after FOLFOX failure, instead of irinotecan alone FOLFOX = FOLFIRI

50. Additional LIFE/FOCUS Commentary There are patients who should receive combination therapy up- front –Potentially resectable for cure –Highly symptomatic patients –?Poor PS patients, related to cancer –Asymptomatic intact primary, not going to surgery –Carcinomatosis This provides additional impetus for using FOLFIRI (or CapIRI) after FOLFOX failure, instead of irinotecan alone FOLFOX = FOLFIRI

51. N9841: Results of Third-Line Therapy (Abstract #3519) N9841: Randomized phase III trial of second-line FOLFOX4 versus CPT-11 in 5FU failures Patients failing second-line were crossed over to the “opposite” regimen This is a report of third-line results: Protocol-mandated but not randomized EndpointCPT-11FOLFOX4p ORR (%)1527<0.01 Median TTP (mo)4.05.20.10 K.M. Rowland, et al.

52. N9841: Results of Third-Line Therapy (Abstract #3519) N9841: Randomized phase III trial of second-line FOLFOX4 versus CPT-11 in 5FU failures Patients failing second-line were crossed over to the “opposite” regimen This is a report of third-line results: Protocol-mandated but not randomized EndpointCPT-11FOLFOX4p ORR (%)1527<0.01 Median TTP (mo)4.05.20.10

53. N9841: Results of Third-Line Therapy (Abstract #3519) N9841: Randomized phase III trial of second-line FOLFOX4 versus CPT-11 in 5FU failures Patients failing second-line were crossed over to the “opposite” regimen This is a report of third-line results: Protocol-mandated but not randomized EndpointCPT-11FOLFOX4p ORR (%)1527<0.01 Median TTP (mo)4.05.20.10

54. N9841: Results of Third-Line Therapy (Abstract #3519) N9841: Randomized phase III trial of second-line FOLFOX4 versus CPT-11 in 5FU failures Patients failing second-line were crossed over to the “opposite” regimen This is a report of third-line results: Protocol-mandated but not randomized EndpointCPT-11FOLFOX4p ORR (%)1527<0.01 Median TTP (mo)4.05.20.10

55. N9841: Results of Third-Line Therapy (Abstract #3519) N9841: Randomized phase III trial of second-line FOLFOX4 versus CPT-11 in 5FU failures Patients failing second-line were crossed over to the “opposite” regimen This is a report of third-line results: Protocol-mandated but not randomized EndpointCPT-11FOLFOX4p ORR (%)1527<0.01 Median TTP (mo)4.05.20.10

56. N9841 Results and Conclusion(s)* CPT-11 FOLFOX N = 126 FOLFOX CPT-11 N = 94 ORR (%)164 Median TTP (mo)52.7 Median Survival (mo)10.08.7 Severe Diarrhea (%)1728 Paresthesias (%)124 Both regimens are active third-line*

57. N9841 Results and Conclusion(s)* CPT-11 FOLFOX N = 126 FOLFOX CPT-11 N = 94 ORR (%)164 Median TTP (mo)52.7 Median Survival (mo)10.08.7 Severe Diarrhea (%)1728 Paresthesias (%)124 Both regimens are active third-line*

58. N9841 Results and Conclusion(s)* CPT-11 FOLFOX N = 126 FOLFOX CPT-11 N = 94 ORR (%)164 Median TTP (mo)52.7 Median Survival (mo)10.08.7 Severe Diarrhea (%)1728 Paresthesias (%)124 Both regimens are active third-line*

59. N9841 Results and Conclusion(s)* CPT-11 FOLFOX N = 126 FOLFOX CPT-11 N = 94 ORR (%)164 Median TTP (mo)52.7 Median Survival (mo)10.08.7 Severe Diarrhea (%)1728 Paresthesias (%)124 Both regimens are active third-line*

60. N9841 Results and Conclusion(s)* CPT-11 FOLFOX N = 126 FOLFOX CPT-11 N = 94 ORR (%)164 Median TTP (mo)52.7 Median Survival (mo)10.08.7 Severe Diarrhea (%)1728 Paresthesias (%)124 Both regimens are active third-line*

61. N9841: Commentary Results look remarkably like 2 nd -line crossover results from Tournigand: –FOLFOX 15% ORR; 4.2 month PFS –FOLFIRI 4% ORR; 2.5 month PFS No shockers in toxicity patterns Only 44% of patients received third-line therapy Back to confusion over FOLFIRI versus irinotecan alone after fluoropyrimidine failure

62. N9841: Commentary Results look remarkably like 2 nd -line crossover results from Tournigand: –FOLFOX 15% ORR; 4.2 month PFS –FOLFIRI 4% ORR; 2.5 month PFS No shockers in toxicity patterns Only 44% of patients received third-line therapy Back to confusion over FOLFIRI versus irinotecan alone after fluoropyrimidine failure

63. N9841: Commentary Results look remarkably like 2 nd -line crossover results from Tournigand: –FOLFOX 15% ORR; 4.2 month PFS –FOLFIRI 4% ORR; 2.5 month PFS No shockers in toxicity patterns Only 44% of patients received third-line therapy Back to confusion over FOLFIRI versus irinotecan alone after fluoropyrimidine failure

64. N9841: Commentary Results look remarkably like 2 nd -line crossover results from Tournigand: –FOLFOX 15% ORR; 4.2 month PFS –FOLFIRI 4% ORR; 2.5 month PFS No shockers in toxicity patterns Only 44% of patients received third-line therapy Back to confusion over FOLFIRI versus irinotecan alone after fluoropyrimidine failure

65. N9841: Commentary Results look remarkably like 2 nd -line crossover results from Tournigand: –FOLFOX 15% ORR; 4.2 month PFS –FOLFIRI 4% ORR; 2.5 month PFS No shockers in toxicity patterns Only 44% of patients received third-line therapy Back to confusion over FOLFIRI versus irinotecan alone after fluoropyrimidine failure

66. mFOLFOX6mFOLFOX6 CapOXCapOX bFOLbFOL RANDOMIZATIONRANDOMIZATION TREE Studies: TREE-1 Abstract #3515 H.S.Hochster, et al.

67. mFOLFOX6 + bevacizumab 5 mg/kg mFOLFOX6 + bevacizumab 5 mg/kg CapOX + bevacizumab 7.5mg/kg bFOL + bevacizumab 5mg/kg RANDOMIZATIONRANDOMIZATION TREE Studies: TREE-2

68. mFOLFOX6 + bevacizumab 5 mg/kg mFOLFOX6 + bevacizumab 5 mg/kg CapOX + bevacizumab 7.5mg/kg bFOL + bevacizumab 5mg/kg RANDOMIZATIONRANDOMIZATION TREE Studies: TREE-2 *Doses same TREE- 1 + 2 except capecitabine 850/m2 BID vs 1000

69. mFOLFOX6 + bevacizumab 5 mg/kg mFOLFOX6 + bevacizumab 5 mg/kg CapOX + bevacizumab 7.5mg/kg bFOL + bevacizumab 5mg/kg RANDOMIZATIONRANDOMIZATION TREE Studies Primary endpoint was grade 3/4 toxicity Secondary endpoints: ORR, TTP, OS, TTF, comparative safety

70. mFOLFOX6 + bevacizumab 5 mg/kg mFOLFOX6 + bevacizumab 5 mg/kg CapOX + bevacizumab 7.5mg/kg bFOL + bevacizumab 5mg/kg RANDOMIZATIONRANDOMIZATION TREE Studies Primary endpoint was grade 3/4 toxicity Secondary endpoints: ORR, TTP, OS, TTF, comparative safety

71. Response Rates: TREE 1 and 2 mFOLFOXbFOLCAPOX WithoutWith bevWithoutWith bevWithoutWith bev ORR (%) (95% CI) 41 (27-56) 52 (39-64) 20 (10-34) 34 (23-75) 27 (15-42) 46 (34-58)

72. Response Rates: TREE 1 and 2 mFOLFOXbFOLCAPOX WithoutWith bevWithoutWith bevWithoutWith bev ORR (%) (95% CI) 41 (27-56) 52 (39-64) 20 (10-34) 34 (23-75) 27 (15-42) 46 (34-58)

73. Response Rates: TREE 1 and 2 mFOLFOXbFOLCAPOX WithoutWith bevWithoutWith bevWithoutWith bev ORR (%) (95% CI) 41 (27-56) 52 (39-64) 20 (10-34) 34 (23-75) 27 (15-42) 46 (34-58)

74. Response Rates: TREE 1 and 2 mFOLFOXbFOLCAPOX WithoutWith bevWithoutWith bevWithoutWith bev ORR (%) (95% CI) 41 (27-56) 52 (39-64) 20 (10-34) 34 (23-75) 27 (15-42) 46 (34-58)

75. Response Rates: bFOL versus Others mFOLFOXbFOLCAPOX With bev ORR (%) (95% CI) 52 (39-64) 34 (23-75) 46 (34-58)

76. TREE-1 vs. TREE-2 Comparative Time to Treatment Failure (TTF) Events mFOLFOXmFOLFOX-BbFOLbFOL-BCapOXCapOX-B TTF (mo)6.45.24.95.34.45.4 95% CI(5.3-8.3)(4.8-6.6)(3.4-6.1)(3.9-6.3)(3.0-5.8)(4.4-6.2)

77. TREE Commentary While TREE 1 and 2 were not a randomized comparison, similarity of patient population allows fairly robust comparison Bevacizumab greatly improved response rates of all 3 regimens –Bolus 5FU with oxaliplatin appears less effective than infusional and CapOX Eagerly await TTP and OS data Bevacizumab improved time-to-treatment failure for bFOL and CapOX, but not FOLFOX

78. TREE Commentary While TREE 1 and 2 were not a randomized comparison, similarity of patient population allows fairly robust comparison Bevacizumab greatly improved response rates of all 3 regimens –Bolus 5FU with oxaliplatin appears less effective than infusional and CapOX Eagerly await TTP and OS data Bevacizumab improved time-to-treatment failure for bFOL and CapOX, but not FOLFOX

79. TREE Commentary While TREE 1 and 2 were not a randomized comparison, similarity of patient population allows fairly robust comparison Bevacizumab greatly improved response rates of all 3 regimens –Bolus 5FU with oxaliplatin appears less effective than infusional and CapOX Eagerly await TTP and OS data Bevacizumab improved time-to-treatment failure for bFOL and CapOX, but not FOLFOX

80. TREE Commentary While TREE 1 and 2 were not a randomized comparison, similarity of patient population allows fairly robust comparison Bevacizumab greatly improved response rates of all 3 regimens –Bolus 5FU with oxaliplatin appears less effective than infusional and CapOX Eagerly await TTP and OS data Bevacizumab improved time-to-treatment failure for bFOL and CapOX, but not FOLFOX

81. Panitumumab Monotherapy in CRC: Abstract #3520 Background: Panitumumab is a fully humanized monoclonal Ab that inhibits EGFR Phase 2 trial in 148 patients failing standard chemotherapy –Failure of 5FU and CPT-11, oxali, or both Primary endpoint: Objective response –RECIST criteria Divided patients into 2 cohorts: A = High EGFR staining; B = low-level staining I. Malik, et al.

82. Panitumumab Monotherapy in CRC: Abstract #3520 Background: Panitumumab is a fully humanized monoclonal Ab that inhibits EGFR Phase 2 trial in 148 patients failing standard chemotherapy –Failure of 5FU and CPT-11, oxali, or both Primary endpoint: Objective response –RECIST criteria Divided patients into 2 cohorts: A = High EGFR staining; B = low-level staining

83. Panitumumab Monotherapy in CRC: Abstract #3520 Background: Panitumumab is a fully humanized monoclonal Ab that inhibits EGFR Phase 2 trial in 148 patients failing standard chemotherapy –Failure of 5FU and CPT-11, oxali, or both Primary endpoint: Objective response –RECIST criteria Divided patients into 2 cohorts: A = High EGFR staining; B = low-level staining

84. Panitumumab Monotherapy in CRC: Abstract #3520 Background: Panitumumab is a fully humanized monoclonal Ab that inhibits EGFR Phase 2 trial in 148 patients failing standard chemotherapy –Failure of 5FU and CPT-11, oxali, or both Primary endpoint: Objective response –RECIST criteria Divided patients into 2 cohorts: A = High EGFR staining; B = low-level staining

85. Panitumumab Monotherapy in CRC: Abstract #3520 Background: Panitumumab is a fully humanized monoclonal Ab that inhibits EGFR Phase 2 trial in 148 patients failing standard chemotherapy –Failure of 5FU and CPT-11, oxali, or both Primary endpoint: Objective response –RECIST criteria Divided patients into 2 cohorts: A = High EGFR staining; B = low-level staining

86. Panitumumab Results and Author Conclusions* High IHCLower IHCAll Patients ORR (%)7149 Median PFS (wks)168.313.6 Median OS (wks)4038 Gr 3/4 Skin Toxicity (%) 7 Panitumumab is active, not differing depending on EGFR status Panitumumab is well-tolerated *

87. Panitumumab Results and Author Conclusions* High IHCLower IHCAll Patients ORR (%)7149 Median PFS (wks)168.313.6 Median OS (wks)4038 Gr 3/4 Skin Toxicity (%) 7 Panitumumab is active, not differing depending on EGFR status Panitumumab is well-tolerated *

88. Panitumumab Results and Author Conclusions* High IHCLower IHCAll Patients ORR (%)7149 Median PFS (wks)168.313.6 Median OS (wks)4038 Gr 3/4 Skin Toxicity (%) 7 Panitumumab is active, not differing depending on EGFR status Panitumumab is well-tolerated *

89. Panitumumab Results and Author Conclusions* High IHCLower IHCAll Patients ORR (%)7149 Median PFS (wks)168.313.6 Median OS (wks)4038 Gr 3/4 Skin Toxicity (%) 7 Panitumumab is active, not differing depending on EGFR status Panitumumab is well-tolerated *

90. Panitumumab Results and Author Conclusions* High IHCLower IHCAll Patients ORR (%)7149 Median PFS (wks)168.313.6 Median OS (wks)4038 Gr 3/4 Skin Toxicity (%) 7 Panitumumab is active, not differing depending on EGFR status Panitumumab is well-tolerated *

91. Panitumumab Results and Author Conclusions* High IHCLower IHCAll Patients ORR (%)7149 Median PFS (wks)168.313.6 Median OS (wks)4038 Gr 3/4 Skin Toxicity (%) 7 Panitumumab is active, not differing depending on EGFR status Panitumumab is well-tolerated *

92. Panitumumab Commentary Panitumumab does appear active in pre-treated CRC In different populations, ORR of 9% and OS of 38 weeks seem roughly comparable to cetuximab Level of EGFR staining does not seem to predict activity –Non-expressers not tested on this trial There are multiple potential settings in which to test this antibody

93. Panitumumab Commentary Panitumumab does appear active in pre-treated CRC In different populations, ORR of 9% and OS of 38 weeks seem roughly comparable to cetuximab Level of EGFR staining does not seem to predict activity –Non-expressers not tested on this trial There are multiple potential settings in which to test this antibody

94. Panitumumab Commentary Panitumumab does appear active in pre-treated CRC In different populations, ORR of 9% and OS of 38 weeks seem roughly comparable to cetuximab Level of EGFR staining does not seem to predict activity –Non-expressers not tested on this trial There are multiple potential settings in which to test this antibody

95. Panitumumab Commentary Panitumumab does appear active in pre-treated CRC In different populations, ORR of 9% and OS of 38 weeks seem roughly comparable to cetuximab Level of EGFR staining does not seem to predict activity –Non-expressers not tested on this trial There are multiple potential settings in which to test this antibody

96. Overall Conclusions CD Blanke, MD: Liar extraordinaire FOLFOX and FOLFIRI excellent upfront chemotherapeutic choices –IROX slightly less so It is reasonable in selected patients to start with 5FU alone and add irinotecan or oxaliplatin later –Not a good strategy for many (?most) subpopulations –Many patients will not ultimately receive all 3 drugs using this strategy

97. Overall Conclusions CD Blanke, MD: Liar extraordinaire FOLFOX and FOLFIRI excellent upfront chemotherapeutic choices –IROX slightly less so It is reasonable in selected patients to start with 5FU alone and add irinotecan or oxaliplatin later –Not a good strategy for many (?most) subpopulations –Many patients will not ultimately receive all 3 drugs using this strategy

98. Overall Conclusions CD Blanke, MD: Liar extraordinaire FOLFOX and FOLFIRI excellent upfront chemotherapeutic choices –IROX slightly less so It is reasonable in selected patients to start with 5FU alone and add irinotecan or oxaliplatin later –Not a good strategy for many (?most) subpopulations –Many patients will not ultimately receive all 3 drugs using this strategy

99. Overall Conclusions CD Blanke, MD: Liar extraordinaire FOLFOX and FOLFIRI excellent upfront chemotherapeutic choices –IROX slightly less so It is reasonable in selected patients to start with 5FU alone and add irinotecan or oxaliplatin later –Not a good strategy for many (?most) subpopulations –Many patients will not ultimately receive all 3 drugs using this strategy

100. Overall Conclusions CD Blanke, MD: Liar extraordinaire FOLFOX and FOLFIRI excellent upfront chemotherapeutic choices –IROX slightly less so It is reasonable in selected patients to start with 5FU alone and add irinotecan or oxaliplatin later –Not a good strategy for many (?most) subpopulations –Many patients will not ultimately receive all 3 drugs using this strategy

101. Overall Conclusions CD Blanke, MD: Liar extraordinaire FOLFOX and FOLFIRI excellent upfront chemotherapeutic choices –IROX slightly less so It is reasonable in selected patients to start with 5FU alone and add irinotecan or oxaliplatin later –Not a good strategy for many (?most) subpopulations –Many patients will not ultimately receive all 3 drugs using this strategy

102. Overall Conclusions CD Blanke, MD: Liar extraordinaire FOLFOX and FOLFIRI excellent upfront chemotherapeutic choices –IROX slightly less so It is reasonable in selected patients to start with 5FU alone and add irinotecan or oxaliplatin later –Not a good strategy for many (?most) subpopulations –Many patients will not ultimately receive all 3 drugs using this strategy

103. Conclusions (cont.) Oxaliplatin and irinotecan are both effective salvage agents –Oxali may be slightly better –Question remains: FOLFIRI or single-agent irinotecan Bevacizumab enhances FOLFOX and irinotecan- containing regimens, first- and second-line Panitumumab appears promising in late-line therapy of colorectal cancer

104. Conclusions (cont.) Oxaliplatin and irinotecan are both effective salvage agents –Oxali may be slightly better –Question remains: FOLFIRI or single-agent irinotecan Bevacizumab enhances FOLFOX and irinotecan- containing regimens, first- and second-line Panitumumab appears promising in late-line therapy of colorectal cancer

105. Conclusions (cont.) Oxaliplatin and irinotecan are both effective salvage agents –Oxali may be slightly better –Question remains: FOLFIRI or single-agent irinotecan Bevacizumab enhances FOLFOX and irinotecan- containing regimens, first- and second-line Panitumumab appears promising in late-line therapy of colorectal cancer

106. Conclusions (cont.) Oxaliplatin and irinotecan are both effective salvage agents –Oxali may be slightly better –Question remains: FOLFIRI or single-agent irinotecan Bevacizumab enhances FOLFOX and irinotecan- containing regimens, first- and second-line Panitumumab appears promising in late-line therapy of colorectal cancer

107. Conclusions (cont.) Oxaliplatin and irinotecan are both effective salvage agents –Oxali may be slightly better –Question remains: FOLFIRI or single-agent irinotecan Bevacizumab enhances FOLFOX and irinotecan- containing regimens, first- and second-line Panitumumab appears promising in late-line therapy of colorectal cancer

108. Colleagues…………………..………

109. Colorectal cancer is hot!