1. A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG) Randomized Phase III Trial of Cetuximab + Best Supportive Care (BSC) versus BSC Alone in Patients with Pre-treated Metastatic EGFR-Positive Colorectal Cancer (NCIC CTG CO.17)

2. NCIC CTG CO.17 Abstract Authors NCIC CTG Derek Jonker, M.D.Derek Jonker, M.D. Chris O’Callaghan, D.V.M. Ph.D.Chris O’Callaghan, D.V.M. Ph.D. Dongsheng Tu, Ph.D.Dongsheng Tu, Ph.D. Scott Berry, M.D.Scott Berry, M.D. Sheryl Koski, M.D.Sheryl Koski, M.D. Marianne Krahn, M.D.Marianne Krahn, M.D. Malcolm Moore, M.D.Malcolm Moore, M.D.AGITG Christos Karapetis, M.D.Christos Karapetis, M.D. Niall Tebbutt, M.D.Niall Tebbutt, M.D. Guy van Hazel, M.B.B.SGuy van Hazel, M.B.B.S R. John Simes, M.D.R. John Simes, M.D. John Zalcberg, M.D., Ph.DJohn Zalcberg, M.D., Ph.D

3. Disclosures AuthorEmployment Consultant / Advisor Stock Owner Honoraria N. Tebbutt Merck/AmgenMerck/Amgen J. Zalcberg Amgen D. Jonker No Conflicts of Interest C. Karapetis No Conflicts of Interest M. Moore No Conflicts of Interest S. Berry No Conflicts of Interest S. Koski No Conflicts of Interest M. Krahn No Conflicts of Interest J. Simes No Conflicts of Interest D. Tu No Conflicts of Interest G. Van Hazel No Conflicts of Interest C. O’Callaghan No Conflicts of Interest Study supported by Bristol-Myers-Squibb Company and ImClone Systems Inc.

4. Cetuximab: Multiple Mechanisms of Action IgG1 monoclonal antibodyIgG1 monoclonal antibody Binds to EGFR and competitively inhibits ligand binding (e.g. EGF)Binds to EGFR and competitively inhibits ligand binding (e.g. EGF) Blocks receptor dimerization, tyrosine kinase phosphorylation, and signal transductionBlocks receptor dimerization, tyrosine kinase phosphorylation, and signal transduction IgG1-induced Antibody- Dependent Cell Cytotoxicity (ADCC)IgG1-induced Antibody- Dependent Cell Cytotoxicity (ADCC) Harari P. Clin Cancer Res. 2004;10:428. Cetuximab EGFR IgG1 MAb ADCC

5. IgG1 (cetuximab) IgG1 (cetuximab) Lysis of antibody-coated cell MAXIMIZE ANTI-TUMOUR ACTIVITY EGFR MEDIATED Anti-tumour Activity IgG1 MEDIATED ADCC Fan Z, et al. Cancer Res.1993;53:4322-8 Cetuximab: IgG1-Induced Antibody-Dependent Cell Cytotoxicity (ADCC)

6. Cetuximab: Phase II Clinical Data Study StudyTreatment N Efficacy Efficacy ORRTTP Irinotecan Failure Cunningham D. N Eng J Med 2004 (EMR 007 / BOND) Cetuximab11110.8% 1.5 mo Cetuximab + Irinotecan 21822.9% 4.1 mo Saltz L. J Clin Oncol 2004 (IMC 0141) Cetuximab 57 578.8% 1.4 mo Irinotecan, Oxaliplatin, Fluoropyrimidine Failure Lenz H-J. J Clin Oncol 2006 (IMC 0144) Cetuximab Cetuximab34612.4% 1.4 mo

7. NCIC CTG CO.17: Randomized Phase III Trial in mCRC EGFR testing by IHC * Cetuximab 400 mg/m 2 IV week 1 then 250 mg/m 2 IV weekly Disease Progression or Unacceptable Toxicity Stratification: Centre Centre ECOG PS (0 or 1 vs. 2) ECOG PS (0 or 1 vs. 2) REGISTERREGISTERREGISTERREGISTER RANDOMIZERANDOMIZERANDOMIZERANDOMIZE 1:1 Cetuximab* + BSC BSC alone Failed or intolerant to all recommended therapies

8. NCIC CTG CO.17: EGFR IHC testing – Dako pharmDx TM Graded by area of highest intensity 0 to 3+Graded by area of highest intensity 0 to 3+ Considered EGFR detectable (positive) if any stained cellsConsidered EGFR detectable (positive) if any stained cells mouse anti-EGFR primary Ab goat anti-mouse secondary Ab labeled with horesradish peroxidase EGFR DAB (colour)

9. NCIC CTG CO.17: Study Endpoints* Primary: Overall SurvivalPrimary: Overall Survival SecondarySecondary –Progression Free Survival –Objective Response Rate (RECIST criteria) –Safety –Quality of Life (to be reported later in 2007) * All primary and secondary analyses ITT (except safety)

10. NCIC CTG CO.17: Key Eligibility Criteria Inclusion CriteriaInclusion Criteria –Histologically proven EGFR detectable (by IHC) mCRC –ECOG performance status 0, 1 or 2 –Prior anti-TS therapy –Prior irinotecan or oxaliplatin therapy Failed for metastastic disease orFailed for metastastic disease or Relapsed within 6 months orRelapsed within 6 months or Documented as unsuitable for therapyDocumented as unsuitable for therapy Exclusion CriteriaExclusion Criteria –Prior therapy with an EGFR inhibitor

11. NCIC CTG CO.17: Statistical Considerations Survival Analysis / Sample SizeSurvival Analysis / Sample Size –Two-sided alpha of 5% –90% power to detect: 9.6% difference in 1-year survival9.6% difference in 1-year survival hazard ratio [HR] of 0.74hazard ratio [HR] of 0.74 assuming a 14.1% 1-year survival for the BSC groupassuming a 14.1% 1-year survival for the BSC group –445 deaths needed The analysis was conducted after 572 subjects were randomized and 456 deaths were recordedThe analysis was conducted after 572 subjects were randomized and 456 deaths were recorded

12. NCIC CTG CO.17: Subject Disposition Registered N = 1243* Randomized N = 572 Cetuximab N = 287 BSC N = 285 On Treatment N = 17 On Treatment N = 0 Off Treatment N = 271 Off Treatment N = 274 EGFR detectable; N = 981 (79%) * Patients were allowed to be enrolled at the time of previous chemotherapy Clinical Cut Off Deaths (N = 12)Deaths (N = 12) PD (N = 205)PD (N = 205) Symptomatic progression (N = 27)Symptomatic progression (N = 27) Drug toxicity (N = 9)Drug toxicity (N = 9) Subject request (N = 10)Subject request (N = 10) Treated N = 288 Treated N = 274 No Cetuximab N = 4 N = 4 Withdrew Consent N = 6 N = 6 N = 5

13. NCIC CTG CO.17: Demographic Characteristics All Randomized Patients Cetuximab + BSC Cetuximab + BSC N = 287 (%) N = 287 (%)BSC N = 285 (%) N = 285 (%) GENDERMale 64.8 64.863.9 Female 35.236.1 AGE (years) Median 6364 Range 28.6 - 88.1 28.7 - 85.9 <65 years 61.755.4 > 65 years 38.344.6 ECOG Performance Status 025.122.5 151.654.0 223.323.5

14. NCIC CTG CO.17: Prior Chemotherapies Number of Prior Chemotherapy Regimens Cetuximab + BSC N = 287 (%) BSC N = 285 (%) 1 - 2 17.418.9 3 - 4 68.263.2 ≥ 5≥ 5≥ 5≥ 514.417.9 Type of Regimen Prior TS Inhibitor 100.0100.0 Prior Irinotecan Regimen 96.595.8 Prior Oxaliplatin Regimen 97.997.5

15. NCIC CTG CO.17: Overall Survival Cetuximab + BSC BSC N287285 Median Survival (Months) (95% CI) 6.1 (5.4, 6.7) 4.6 (4.2, 4.9) 6 Month Survival Rate (95% CI) 0.50 (0.45, 0.56) 0.33 (0.28, 0.39) 12 Month Survival Rate (95% CI) 0.21 (0.16, 0.27) 0.16 (0.11, 0.21) Hazard Ratio* 0.77 95% CI (0.64, 0.92) Log-Rank* p-value = 0.0046 * Stratified by ECOG PS (0-1 versus 2) at randomization

16. CETUXIMAB + BSC CENSORED BSC CENSORED NCIC CTG CO.17: Overall Survival HR 0.77 (95% CI =0.64 – 0.92) Stratified log rank p-value = 0.0046 Study arm MS (months) 95% CI Cetuximab + BSC 6.1 5.4 – 6.7 BSC alone 4.6 4.2 – 4.9

17. NCIC CTG CO.17: Survival Result by Subgroups Subset Hazard Ratio and 95% CI Median Survival CetuxBSC 0.77 (0.64 – 0.92) 6.1 mo 4.6 mo 0.72 (0.58 – 0.89) 7.1 mo 5.0 mo 0.89 (0.62 – 1.27) 3.4 mo 3.0 mo 0.77 (0.61 – 0.98) 6.1 mo 4.6 mo 0.75 (0.56 – 1.00) 5.9 mo 4.5 mo 0.69 (0.50 – 0.94) 5.5 mo 4.2 mo 0.80 (0.63 – 1.01) 6.5 mo 4.8 mo All randomized ECOG 0-1 ECOG 2 Age <65 Age ≤65 Female Male Favours BSC 0.4 0.6 0.8 Favours Cetuximab 1.2 1.4 1.6

18. NCIC CTG CO.17: Progression Free Survival Cetuximab + BSC Cetuximab + BSCBSC N287285 2 Month PF Survival Rate (95% CI) 0.45 (0.40, 0.51) 0.39 (0.33, 0.45) 4 Month PF Survival Rate 4 Month PF Survival Rate (95% CI) (95% CI) 0.28 (0.23, 0.33) 0.13 (0.09, 0.18) 6 Month PF Survival Rate (95% CI) 6 Month PF Survival Rate (95% CI) 0.15 (0.10, 0.19) 0.03 (0.01, 0.06) Hazard Ratio* 0.68 95% CI (0.57, 0.80) Log-Rank* p-value < 0.0001 * Stratified by ECOG PS (0-1 versus 2) at randomization

19. NCIC CTG CO.17: Progression Free Survival CETUXIMAB + BSC CENSORED BSC CENSORED Proportion Progression-Free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 MONTHS 03691215 HR 0.68 (95% CI =0.57 – 0.80) HR 0.68 (95% CI =0.57 – 0.80) Stratified log rank p-value < 0.0001 Study arm Med PFS (months) 95% CI Cetuximab + BSC 1.9 1.8 – 2.1 BSC alone 1.8 1.8 – 1.9

20. NCIC CTG CO.17: Overall Best Response Cetuximab + BSC N = 287 (%) BSC N = 285 (%) Partial Response 19 (6.6)* 0 Stable Disease 84 (29.3)* 84 (29.3)* 29 (10.2)* 29 (10.2)* Progressive Disease 133 (46.3) 155 (54.4) Inevaluable for Response 35 (12.2) 35 (12.2) 98 (34.4) 98 (34.4) Unknown 16 (5.6) 16 (5.6) 3 ( 1.1) 3 ( 1.1) Objective Response Rate (ORR) (95% CI) 6.6%* (4.0, 10.2) 0% Disease Control Rate 35.9%10.2% * 4 Cetuximab patients with PR and 6 with SD, and 2 BSC patients with SD were still active at data cut-off and not included (censored) in data above for “best” response data cut-off and not included (censored) in data above for “best” response Difference in ORR (95% CI) 6.6% (4.0, 10.2) CMH p-value < 0.0001

21. NCIC CTG CO17: Unplanned Anti-Cancer Therapy* Cetuximab + BSC N = 287 (%) BSC BSC N = 285 (%) Patients with any anti- cancer treatment before progression 4 (1.4) 45 (15.4) Radiotherapy 2 (0.7) 2 (0.7) 24 (8.4) Chemotherapy 1 (0.3) 20 (7.0) Hormonal therapy 0 (0.0) 4 (1.4) Immunotherapy 0 (0.0) 4 (1.4) Other 1 (0.3) 9 (3.2) * Not allowed per protocol

22. NCIC CTG CO.17: Specific Therapies Before Progression* Number of Patients Cetuximab + BSC BSC BSC TS Inhibitors 18 Mitomycin-C04 Oxaliplatin01 Irinotecan17 Cetuximab06 VEGF Inhibitors 03 * Not allowed per protocol

23. NCIC CTG CO17: Therapy Post-Progression Cetuximab + BSC N = 287 (%) BSC BSC N = 285 (%) Patients with any anti- cancer treatment after progression 79 (27.5) 66 (23.2) Radiotherapy 52 (18.1) 41 (14.4) Chemotherapy 36 (12.5) 38 (13.3) Hormonal therapy 6 (2.1) 9 (3.2) Immunotherapy 5 (1.7) 11 (3.9) Other 13 (4.5) 13 (4.6)

24. NCIC CTG CO.17: Specific Post-Progression Anti-Cancer Therapies Number of Patients Cetuximab + BSC BSC BSC TS Inhibitors 2420 Irinotecan1113 Mitomycin-C128 Cetuximab116 Oxaliplatin95 VEGF Inhibitors 106

25. NCIC CTG CO.17: Grade 3 / 4 Adverse Events Grade 3 / 4 AE > 10% Cetuximab + BSC N = 288 (%) BSC N = 274 (%) P Value Any Grade 3 / 4 AE 226 (78.5) 162 (59.1) <0.0001 Fatigue 95 (33.0) 95 (33.0) 71(25.9) 71(25.9) Dyspnea 47 (16.3) 47 (16.3) 34 (12.4) 34 (12.4) Abdominal Pain 38 (13.2) 38 (13.2) 43 (15.7) 43 (15.7) Pain-Other 43 (14.9) 43 (14.9) 20 (7.3) 20 (7.3)0.005 Infection w/o Neutropenia 37 (12.8) 37 (12.8) 15 (5.5) 0.003 Rash / Desquamation 34 (11.8) 34 (11.8) 1 (0.4) 1 (0.4)<0.0001 * Hypomagnesemia as a laboratory toxicity was not correlated to clinical symptoms/ AEs Other Grade 3 / 4 Toxicity Hypomagnesemia* 15 (5.8) 0<0.0001 Hypersensitivity Reaction 13 (4.5) 0<0.0001

26. NCIC CTG CO17: OS by Worst Grade of RashGraden Median Survival 032 2.6 mo 1115 4.8 mo 2+136 8.4 mo Proportion Alive Months - Landmark-type analysis excluding all patients dying within 28 days of entry - 90% experienced rash by 29 days, Median time to rash = 10 days GradeHR95%CIp-value 2+ vs 0 0.33 (0.22, 0.50) <0.0001 1 vs 0 0.61 (0.40, 0.93) 0.021 2+ vs 1 0.54 (0.41, 0.72) <0.0001

27. NCIC CTG CO.17: Conclusions Cetuximab significantly prolonged OS compared to BSC in patients in which all other therapy had failedCetuximab significantly prolonged OS compared to BSC in patients in which all other therapy had failed This is the first time single-agent biologic targeted therapy has shown a survival benefit in colorectal cancerThis is the first time single-agent biologic targeted therapy has shown a survival benefit in colorectal cancer PFS and RR were also significantly improved with cetuximab over BSCPFS and RR were also significantly improved with cetuximab over BSC The safety profile of cetuximab monotherapy is acceptable and consistent with the reported incidence from previous mono-therapy studiesThe safety profile of cetuximab monotherapy is acceptable and consistent with the reported incidence from previous mono-therapy studies The results of this study add to the large body of evidence suggesting benefit for cetuximab in metastatic colorectal cancerThe results of this study add to the large body of evidence suggesting benefit for cetuximab in metastatic colorectal cancer

28. Acknowledgements NCIC CTG and AGITG Investigators and Central Office StaffNCIC CTG and AGITG Investigators and Central Office Staff BMS / ImCloneBMS / ImClone Study Nurses, Coordinators, MonitorsStudy Nurses, Coordinators, Monitors Patients and their FamiliesPatients and their Families