1. www.OncologyEducation.ca Defining the Role of EGFR Monoclonal Antibody Therapy in Metastatic Colorectal Cancer Author: Dr. Phil Bedard Date Posted: December 12, 2007

2. www.OncologyEducation.ca Objectives Review the rationale for targeting EGFR in metastatic colorectal cancer therapy Outline the differences between the monoclonal antibodies against EGFR Understand the common toxicities associated with EGFR monoclonal antibodies Summarize the evidence supporting the use of EGFR monoclonal antibody therapy in the first-, second-, and third-line treatment of metastatic CRC Discuss possible methods of selection of patients most likely to benefit from EGFR monoclonal antibody blockade with metastatic CRC

3. www.OncologyEducation.ca Epidermal Growth Factor Receptor (EGFR) Member of the epidermal growth factor receptor tyrosine kinase family Ligand binding to extracellular domain leads to activation of intracellular signaling cascade, including Akt and MAPK Results in proliferation, angiogenesis, increased cell motility, and resistance to chemotherapy

4. www.OncologyEducation.ca EGFR in Colorectal Cancer Expressed in 60-80% CRC –Risk factor for poor prognosis Monoclonal antibodies (mAb) demonstrate activity as single agents and in combination with chemotherapy in CRC To date, there is no proof that small molecular tyrosine kinase inhibitors (TKIs) are of benefit –CRC lacks EGFR mutations that have been asssociated with response to TKIs in other disease sites Townsley CA Br J Cancer 2006 Rothernberg ML JCO 2005

5. www.OncologyEducation.ca Monoclonal Antibodies Against EGFR For treatment of metastatic colorectal cancer: –Cetuximab approved by Health Canada and FDA –Panitumumab approved by FDA

6. www.OncologyEducation.ca Comparison: Cetuximab vs Panitumumab CetuximabPanitumumab BackboneChimericHuman ClassIgG1IgG2 Half-life5-7.5 days7.5 days Loading DoseYesNo Dosing Schedule Qweekly Q2weekly PremedicationH1-antagonistNone

7. www.OncologyEducation.ca First-line Therapy: Cetuximab + Chemotherapy

8. www.OncologyEducation.ca CRYSTAL Trial Van Custem E Proc ASCO 2007 RANDOMIZERANDOMIZE 1:1 FOLFIRI + Cetuximab N=648 FOLFIRI N=650 1 0 Endpoint= PFS N=1198 EGFR expression via IHC * Cetuximab 400 mg/m 2 IV week 1 then 250 mg/m 2 IV weekly

9. www.OncologyEducation.ca Grade 3/4 Events FOLFIRI+ Cetuximab (%) FOLFIRI (%) Febrile Neutropenia2.72.2 Diarrhea15.210.5 Vomiting4.55.0 Fatigue5.04.5 Skin Reactions18.70.2 Infusion Related Reactions 2.30 Hypomagnesemia (only available for 20% of patients) 1.80.2 Toxicity

10. www.OncologyEducation.ca Efficacy Grade 3/4 toxicity FOLFIRI + Cetuximab N = 648 (%) FOLFIRI N = 650 (%) Response Rate4739 Median PFS8.98.0 1 yr PFS3423 Median OSNR HR = 0.85 (0.73-0.99); p=0.048 p=0.0038

11. www.OncologyEducation.ca PFS by Skin Reaction: FOLFIRI + Cetuximab Skin ReactionMedian PFS Grade 15.4 months Grade 29.4 months Grade 311.3 months * No Grade 4 Reaction Reported

12. www.OncologyEducation.ca OPUS: Phase II RANDOMIZERANDOMIZE 1:1 FOLFOX + Cetuximab N=170 FOLFOX N=168 N=338 EGFR+ Metasatic CRC * Cetuximab 400 mg/m 2 IV week 1 then 250 mg/m 2 IV weekly

13. www.OncologyEducation.ca Toxicity Grade 3/4 events FOLFOX+ Cetuximab FOLFOX Neutropenia27.631.5 Diarrhea7.16.0 Fatigue3.53.0 Neurotoxicity3.56.0 Acne-like skin rash 14.10

14. www.OncologyEducation.ca Efficacy FOLFOX+ Cetuximab FOLFOX Response Rate45.6%35.7% * No Survival Data Reported

15. www.OncologyEducation.ca Response Rate by Skin Rash FOLFOX+ Cetuximab Grade 013.0% Grade 142.2% Grade 253.2% Grade 3-466.4%

16. www.OncologyEducation.ca SWOG 80203 Venook A Proc ASCO 2006 RANDOMIZERANDOMIZE 1:1 FOLFOX + Cetuximab REGISTERREGISTER FOLFOX Inv choice FOLFIRI Inv choice FOLFOX alone FOLFIRI + Cetuximab FOLFIRI alone N=258 Metastatic Colorectal CA No EGFR expression required 1 0 Endpoint= OS

17. www.OncologyEducation.ca SWOG 80203 Planned sample size N=2200 Trial stopped early January 2005 because of poor accrual –Publication of Hurwitz data with IFL + Bevacizumab (NEJM 2004)NEJM 2004 Data reported with median F/U 16 months

18. www.OncologyEducation.ca Efficacy Cetuximab+ FOLFIRI Cetuximab+ FOLFOX FOLFOX Response CR + PR 44%36%60%40% Stable Disease 32%38%26%30% Median PFS (95% CI) 10.6 mos (6.2-14.1) 8.4 mos (6.5-10.3) 8.2 mos (7.0-12.7) 9.8 mos (8.3-12.4)

19. www.OncologyEducation.ca Toxicity Grade 3/4Cetuximab+ FOLFIRI Cetuximab+ FOLFOX FOLFOX Diarrhea22%15%14%10% Neutropenia34%27%38%36%

20. www.OncologyEducation.ca Efficacy: Cetuximab versus Chemotherapy Alone Cetuximab+CTCT alone Response Rate52%38% Median PFS (95%CI) 8.5 mos (7.0-12.5) 9.4 mos (8.2-10.8) Median OS (95%CI) 16.9 mos (15.9-?) ? (17.9-?)

21. www.OncologyEducation.ca Medical Research Council: COIN Trial (Ongoing) RANDOMIZERANDOMIZE 1:1:1 FOLFOX/CapeOX until progression/intolerance FOLFOX/CapeOX + Cetuximab until progression/intolerance N=2421 (Target) No EGFR testing 1 0 Endpoint= OS FOLFOX/CapeOXx12 weeks “Stop & Go” Strategy

22. www.OncologyEducation.ca First-line Therapy: Panitumumab + Chemotherapy

23. www.OncologyEducation.ca PRIME Trial: Ongoing Expected Completion: March 2010 RANDOMIZERANDOMIZE 1:1 Panitumumab + FOLFOX FOLFOX alone N=900 (Target Accrual) Metastatic Colorectal CA No EGFR testing 1 0 Endpoint= PFS

24. www.OncologyEducation.ca First-line Therapy: Ceutximab + Chemotherapy + anti-VEGF

25. www.OncologyEducation.ca CALGB/SWOG 80405: Ongoing RANDOMIZERANDOMIZE 1:1:1 FOLFOX or FOLFIRI + Bevacizumab + Cetuximab FOLFOX or FOLFIRI + Cetuximab N=2300 (Target) Metastatic Colorectal CA No EGFR testing 1 0 Endpoint= OS FOLFOX or FOLFIRI + Bevacizumab

26. www.OncologyEducation.ca Dutch Colorectal Cancer Group CAIRO-2: Ongoing Expected Completion: December 2007 RANDOMIZERANDOMIZE 1:1 CapeOX + Bevacizumab + Ceutximab CapeOX + Bevacizumab N=750 (Target Accrual) Metastatic Colorectal CA No EGFR testing 1 0 Endpoint= PFS & Toxicity

27. www.OncologyEducation.ca Preliminary Toxicity Data Grade 3/4 Adverse Events CAPOX-Bev+ Cetuximab CAPOX-Bev Hand-Foot Syndrome 13%12% Diarrhea23%17% Febrile Neutropenia 0%1% Acne-like Rash20%0% Death <60days3%

28. www.OncologyEducation.ca First-line Therapy: Panitumumab + Chemotherapy + anti-VEGF

29. www.OncologyEducation.ca Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) RANDOMIZERANDOMIZE 1:1 Panitumumab + Oxali- CT + Bevacizumab REGISTERREGISTER Oxali-based CT (ie FOLFOX) Inv choice Iri-based CT (ie FOLFIRI) Inv choice Oxali-CT + Bevacizumab Panitumumab + Iri-CT + Bevacizumab Iri-CT + Bevacizumab Hecht JR GI World Congress 2007

30. www.OncologyEducation.ca PACCE Trial stopped early after interim analysis suggested excess toxicity and inferior efficacy in treatment arm

31. www.OncologyEducation.ca Toxicity Pmab+ Bev/Ox N=401 Bev/Ox N=392 Gr 3 (%)Gr 4 (%)Gr 3 (%)Gr 4 (%) Skin33<110 Diarrhea212121 Dehydration14241 Hypokalemia8231 Hypomagnesemia3100 Neutropenia1210177 Neuropathy9<126<1 Nausea1004<1 Infection16272 DVT6070 PE0604

32. www.OncologyEducation.ca Efficacy Pmab+Bev/OxBev/OxPmab+Bev/IriBev/Iri Response39%41%38%31% CR0% <1%0% PR39%40%38%31% Median PFS 9.0 mos10.5 mos----- Median OS 18.6 mosNot reached----- HR = 1.29 (1.05-1.58) HR = 1.44 (1.10-1.88)

33. www.OncologyEducation.ca Summary: First Line CRYSTAL trial suggests that Cetuximab can be safely combined with FOLFIRI in first line setting, with very modest lengthening of PFS of uncertain clinical importance PACCE trial demonstrates significant added toxicity with combination of chemotherapy, anti-VEGF therapy and Panitimumab –Similar toxicity not reported with CAIRO-2 trial using chemotherapy, anti-VEGF therapy and Cetuximab Data presently do not support routine use of EGFR mAb therapy in combination with chemotherapy +/- anti-VEGF therapy in first-line setting

34. www.OncologyEducation.ca Second-line Therapy: Cetuximab + Chemotherapy

35. www.OncologyEducation.ca Erbitux Plus Irinotecan in Colorectal Cancer (EPIC) RANDOMIZERANDOMIZE 1:1 Cetuximab + Irinotecan N=648 Irinotecan alone N=650 Prior Oxaliplatin Chemotherapy EGFR+ (IHC) Sobrero AF AACR 2007 400mg/m2 week 1; then 250mg/m2 weekly Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly Irinotecan 350mg/m2 q3weekly 1 0 Endpoint= PFS

36. www.OncologyEducation.ca Prior Therapy Prior Anti- Cancer Therapy Cetuximab + Irinotecan N = 648 (%) Irinotecan N = 650 (%) Oxaliplatin99.5 Fluoropyrimidine97.897.2 Bevacizumab13.012.6

37. www.OncologyEducation.ca Toxicity Grade 3/4 Toxicity Cetuximab + Irinotecan N = 638, % Irinotecan N = 629, % Any AE > 5%71.656.8 Diarrhea28.816.2 Vomiting6.16.4 Fatigue9.24.9 Acne-like Rash8.20.5 Infusion Reaction1.40.8 Hypomagnesemia3.30.4

38. www.OncologyEducation.ca Efficacy Cetuximab + Irinotecan N=648 Irinotecan N=650 P-value Overall Response16.4%4.2%0.0001 CR1.4%0.2% PR15.0%4.0% Disease Control (CR+PR+SD) 61.4%45.8%0.0001 Median PFS4.0 months2.6 months0.0001 Median OS10.7 months9.9 months0.7115 HR = 0.69 (0.62-0.78) HR = 0.98 (0.85-1.11)

39. www.OncologyEducation.ca Post-Study Therapy Cetuximab + Irinotecan (N = 648) Irinotecan (N = 650) Any 3 rd Line Rx 57%65% Cetuximab11%47% Bevacizumab16%14%

40. www.OncologyEducation.ca Survival by Skin Reaction: Cetuximab + Irinotecan Skin ReactionMedian OS None5.8 months Grade 1/211.7 months Grade 3/415.6 months

41. www.OncologyEducation.ca MRC: EXPLORE RANDOMIZERANDOMIZE 1:1 Cetuximab + FOLFOX N=52 FOLFOX N=50 Prior Irinotecan Chemotherapy EGFR+ (IHC) Metastatic CRC N=102 Polikoff Proc ASCO 2005 400mg/m2 week 1; then 250mg/m2 weekly Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly 1 0 Endpoint= OS

42. www.OncologyEducation.ca EXPLORE Planned sample size N=1100 Trial stopped early December 2004 because of poor accrual –Widespread adoption of FOLFOX in first-line setting

43. www.OncologyEducation.ca Efficacy Cetuximab + FOLFOX N=43 FOLFOX N=42 Response Rate20.9%9.5% Stable Disease Rate 46.5%61.9% Median PFS4.4 months4.1 months p=0.48

44. www.OncologyEducation.ca Second-line Therapy: Panitumumab + Chemotherapy

45. www.OncologyEducation.ca Panitumumab, Irinotecan & Cyclosporin in COLOrectal Cancer Therapy (PICCOLO): Ongoing RANDOMIZERANDOMIZE 1:1:1 Irinotecan + Panitumumab Irinotecan + Cyclosporin N=1269 (Target) Prior 5-FU +/- Oxali +/- Bev No EGFR testing 1 0 Endpoint= PFS Irinotecan alone

46. www.OncologyEducation.ca Second-line Therapy: Cetuximab + Chemotherapy + anti-VEGF

47. www.OncologyEducation.ca SWOG S0600/ECOG/ NCCTG/NCIC: Ongoing RANDOMIZERANDOMIZE 1:1:1 Irinotecan/FOLFIRI + Cetuximab + Bevacizumab Irinotecan/FOLFIRI + Cetuximab N=1250 (Target) Prior Oxali-based CT Prior Bev allowed No EGFR testing No Prior anti-EGFR therapy 1 0 Endpoint= OS Irinotecan/FOLFIRI + Bevacizumab

48. www.OncologyEducation.ca Summary - Second Line EPIC trial shows that addition of Cetuximab to FOLFIRI produces statistically significant improvement in response rate and PFS PFS improvement of questionable clinical significance with no overall survival benefit and added toxicity –lack of OS benefit due to cross over to cetuximab setting on progression in standard arm S0600 will address whether addition of Cetuximab + anti-VEGF therapy to Irinotecan-based treatment can improve OS after progression on oxaliplatin-based chemotherapy At present, data do not support routine use of anti-EGFR mAb therapy in 2 nd line setting

49. www.OncologyEducation.ca Third-line Therapy: Cetuximab Monotherapy

50. www.OncologyEducation.ca EGFR testing by IHC * Cetuximab 400 mg/m 2 IV week 1 then 250 mg/m 2 IV weekly Stratification: Centre Centre ECOG PS (0 or 1 vs. 2) ECOG PS (0 or 1 vs. 2) REGISTERREGISTER RANDOMIZERANDOMIZE 1:1 Cetuximab* + BSC Best Supportive Care alone NCIC CO.17 Jonker DJ NEJM 2007 N=572 Prior 5FU, Iri, and Oxali-CT EGFR expression required 1 0 Endpoint= OS

51. www.OncologyEducation.ca Patient Characteristics Cetuximab + BSC N = 287 (%) BSC N = 285 (%) GENDERMale/ Female 64.8/35.263.9/36.1 AGE (years)Median [range] 63 [28.6 - 88.1]64 [28.7 - 85.9] > 65 years38.344.6 ECOG Performance Status 025.122.5 151.654.0 223.323.5 Type of Prior Treatment TS Inhibitor 100.0 Irinotecan 96.595.8 Oxaliplatin 97.997.5

52. www.OncologyEducation.ca Toxicity: Key Differences Grade 3/4 toxicity Cetuximab + BSC N = 287 (%) BSC N = 285 (%) Rash11.80.4 Non-neutropenic Infection 12.85.5 Hypomagnesemia5.80 Pain (other than abdominal) 14.97.3

53. www.OncologyEducation.ca Efficacy Grade 3/4 toxicity Cetuximab + BSC N = 287 (%) BSC N = 285 (%) Partial Response8.00 Stable Disease31.410.9 Median PFS1.9 months1.8 months Median OS6.1 months4.6 months HR = 0.71 (0.59-0.85) HR = 0.79 (0.65-0.95)

54. www.OncologyEducation.ca Survival by Skin Reaction: Cetuximab Monotherapy Skin ReactionMedian OS None2.6 months Grade 14.8 months Grade 2 or higher 8.4 months

55. www.OncologyEducation.ca Quality of Life Improved at 8 & 16 weeks in physical functioning and global QoL in Cetuximab + BSC arm vs. BSC alone Au H Proc ASCO 2007

56. www.OncologyEducation.ca Panitumumab 3 rd Line Monotherapy Trial EGFR testing by IHC REGISTERREGISTER RANDOMIZERANDOMIZE 1:1 Panitumumab + BSC N=231 BSC alone N=232 1 0 Endpoint= PFS Panitumumab + BSC N=176 * Panitumumab 6 mg/m 2 IV Q2weekly N=463 Prior 5FU, Iri, and Oxali-CT EGFR expression required Optional Cross-Over on Progression Van Cutsem E JCO 2007

57. www.OncologyEducation.ca Patient Characteristics Panitumumab + BSC N = 231 (%) BSC N = 232 (%) GENDERMale/ Female 63/3764/36 AGE (years)Median [range] 62 [27 - 82]64 [27 - 83] ECOG Performance Status 04640 14145 2 3 13 0 14 1 Prior lines of Chemotherapy 2 lines 100 3 lines 3638

58. www.OncologyEducation.ca Toxicity Grade 3/4 toxicity Panitumumab + BSC N = 231 (%) BSC N = 232 (%) Acne-like Rash70 Abdominal Pain74 Erythema52 General Physical Deterioration 72

59. www.OncologyEducation.ca Efficacy Grade 3/4 toxicity Panitumumab + BSC N = 231 (%) BSC N = 232 (%) Partial Response100 Stable Disease2710 Median PFS2.0 months1.8 months Median OSNR HR = 0. 54 (0.44-0.66); p<0.0001 HR = 1.00 (0.82-1.22)

60. www.OncologyEducation.ca Survival by Skin Reaction: Panitumumab Monotherapy Worst Skin Reaction Median OS Grade 15.9 months Grade 2 or higher 7.9 months Humblet Y Proc ASCO 2007 HR = 0.68; p=0.03

61. www.OncologyEducation.ca Quality of Life Trend towards improvement for Colorectal Cancer Related symptoms and overall health-related QoL in Panitumumab group Patients who developed skin rash on Panitumumab were bothered by their symptoms Humblet Y Proc ASCO 2007

62. www.OncologyEducation.ca Third-line Therapy: Cetuximab + Chemotherapy

63. www.OncologyEducation.ca Bowel Oncology with Cetuximab Antibody (BOND-1) RANDOMIZERANDOMIZE 2:1 Cetuximab alone N=111 N=329 Prior Iri-CT within 3 months EGFR+ (IHC) 400mg/m2 week 1; then 250mg/m2 weekly Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly 1 0 Endpoint= Response Cetuximab + Irinotecan N=56 Cetuximab + Irinotecan N=218 Cunningham DR NEJM 2004

64. www.OncologyEducation.ca Prior Therapy Cetuximab + Irinotecan N = 218 (%) Cetuximab alone N = 111 (%) Lines of Prior Therapy 1 st line18.824.3 2 nd line36.236.9 ≥3 rd line45.038.7 Prior Oxaliplatin61.964.0

65. www.OncologyEducation.ca Toxicity Grade 3/4 toxicity Cetuximab + Irinotecan N = 218 (%) Cetuximab alone N = 111 (%) Diarrhea21.21.7 Acne-like Rash9.45.2 Neutropenia9.40 Hypersensitivity Reaction 03.5

66. www.OncologyEducation.ca Efficacy Cetuximab + Irinotecan N = 218 (%) Cetuximab alone N = 111 (%) Response22.710.8 Disease Control55.132.4 Time to Progression4.1 months1.9 months Median OS8.6 months6.9 months HR = 0.54 (0.42-0.71) HR = 0.91 (0.69-1.21)

67. www.OncologyEducation.ca Response Rate by EGFR staining EGFR staining intensity Cetuximab+ Irinotecan Cetuximab alone Faint20.8%4.8% Weak or Moderate 24.7%12.8% Strong22.7%11.7% p=0.64

68. www.OncologyEducation.ca Response Rate by Skin Reaction Skin Reaction Cetuximab+ Irinotecan Cetuximab alone None6.3%0 Grade 1 or 220.4%11.6% Grade 3 or 455.3%33.3% p<0.0001

69. www.OncologyEducation.ca BOND-2: Phase II RANDOMIZERANDOMIZE 1:1 Cetuximab + Bevacizumab N=41 N=81 Prior Iri-CT within 3 months EGFR expression not required Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly Bevacizumab 5mg/kg every Q2weekly Cetuximab + Bevacizumab + Irinotecan N=40 Saltz L Proc ASCO 2005

70. www.OncologyEducation.ca Prior Therapy Cetuximab + Bevacizumab + Irinotecan N = 40 Cetuximab + Bevacizumab N = 41 Median # Lines of Prior Therapy 33 Prior Oxaliplatin85%90%

71. www.OncologyEducation.ca Toxicity Grade 3/4 toxicity Cetuximab + Bevacizumab + Irinotecan N = 40 (%) Cetuximab + Bevacizumab N = 41(%) Diarrhea240 Acne-like Rash1720 Neutropenia220 Fatigue100

72. www.OncologyEducation.ca Efficacy Cetuximab + Bevacizumab + Irinotecan N = 40 (%) Cetuximab + Bevacizumab N = 41 (%) Partial Response37%20% Disease ControlNR Median Time to Progression 7.9 months5.6 months Median OSNR

73. www.OncologyEducation.ca Third-line Therapy: Cetuximab + Chemotherapy + anti-VEGF

74. www.OncologyEducation.ca BOND-3: Phase II (Ongoing) RANDOMIZERANDOMIZE 1:1 Cetuximab + Bevacizumab Prior Bevacizumab + Chemotherapy Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly Bevacizumab 5mg/kg every Q2weekly Cetuximab + Bevacizumab + Irinotecan

75. www.OncologyEducation.ca Summary – Third line Cetuximab monotherapy after progression on oxaliplatin and irinotecan based chemotherapy is the only setting in which EGFR monoclonal antibody therapy has shown a survival benefit in colorectal cancer –Survival benefit modest but cetuximab monotherapy also associated with significant improvement in quality of life Panitumumab alone and Cetuximab + Irinotecan both demonstrate a significant improvement in PFS in the third-line setting

76. www.OncologyEducation.ca Summary – Third line Should Cetuximab be given with Irinotecan in 3rd line? –Cetuximab + Irinotecan combination demonstrates best response rates and TTP benefits (cross trial comparisons) but unable to determine impact of irinotecan on QOL

77. www.OncologyEducation.ca # ptsRR %Median PFS/TTP Median OSQoL FIRST LINE PACCE (Oxali only) 79339 vs 419.0 vs 10.518.6 vs NR? CRYSTAL119847 vs 398.9 vs 8.0?? SWOG 80203 23852 vs 388.5 vs 9.4? vs 16.9? OPUS33846 vs 37??? SECOND LINE EPIC129816 vs 44.0 vs 2.610.7 vs 9.9Improved EXPLORE10221 vs 104.4 vs 4.1?? THIRD LINE BOND-132923 vs 114.1 vs 1.98.6 vs 6.9? P-mab 3 rd line 46310 vs 02.0 vs 1.8NS?Improved NCIC CO.175728 vs 01.9 vs 1.86.1 vs 4.6Improved statistically significant results in RED

78. www.OncologyEducation.ca The Bottom Line for Canadian Medical Oncologists

79. www.OncologyEducation.ca EGFR monoclonal antibody therapy is active in metastatic disease with relatively mild toxicity as monotherapy Clinical trial data most strongly support use of EGFR monoclonal antibody therapy in the third- line setting, after progression on Oxaliplatin and Irinotecan based therapy –According to BOND-1 data, combination of Cetuximab + Irinotecan in 3 rd line more active than Cetuximab alone Efficacy and Toxicity

80. www.OncologyEducation.ca Cetuximab and Panitumumab appear to have similar efficacy and toxicity in the third line setting as monotherapy Access to Cetuximab and Panitumumab is difficult in Canada –Only cetuximab is approved by Health Canada and it is not being marketed (or funded) Efficacy and Toxicity

81. www.OncologyEducation.ca Results of PACCE suggest that the combination of Panitumumab, Bevacizumab, and chemotherapy is toxic with less efficacy in the first line setting Excess toxicity of anti-EGFR therapy with anti-VEGF agent and chemotherapy not seen with Cetuximab in BOND 2 or CAIRO-2 –Suggests that Cetuximab may be more easily combined with anti-VEGF and chemotherapy than Panitumumab –Results of SWOG 80405 and CAIRO-2 trial will provide further insight Anti-EGFR and Anti-VEGF Combinations

82. www.OncologyEducation.ca Future biomarker studies will attempt to address which subgroups of patients will derive benefit from EGFR blockade To date, studies suggests that level of EGFR expression via IHC is NOT a useful predictor of response CRYSTAL, BOND-1, NCIC CO.17, and Panitumumab 3 rd line monotherapy trial demonstrate that skin rash may be an early surrogate marker for favourable clinical outcome –However, it is not clear from the current data if skin rash on EGFR monoclonal antibody therapy is an early surrogate marker for BENEFIT from EGFR blockade or simply an early surrogate marker of a favourable prognosis –Early data from EVEREST raises the intriguing possibility that “early skin rash non-responders” may benefit from dose- escalation of Cetuximab  needs further testing Patient Selection for anti-EGFR Therapy

83. www.OncologyEducation.ca Preliminary data from Panitumumab 3 rd line monotherapy trial suggests that patients with K-RAS mutation do not benefit from EGFR blockade (Amado ECCO 2007) –Similar to data from EGFR therapy in non- small cell lung cancer and pancreatic cancer –Analyses of K-RAS status from other EGFR monoclonal antibody trials are in progress Patient Selection for anti-EGFR Therapy

84. www.OncologyEducation.ca Acknowledgements We would like to thank Dr. Mark Rother for his helpful contributions to this educational program