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NCIC CTG CO.17 Abstract Authors

A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG).

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NCIC CTG CO.17 Abstract Authors

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  1. A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG)and theAustralasian 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. • Chris O’Callaghan, D.V.M. Ph.D. • Dongsheng Tu, Ph.D. • Scott Berry, M.D. • Sheryl Koski, M.D. • Marianne Krahn, M.D. • Malcolm Moore, M.D. AGITG • Christos Karapetis, M.D. • Niall Tebbutt, M.D. • Guy van Hazel, M.B.B.S • R. John Simes, M.D. • John Zalcberg, M.D., Ph.D

  3. Disclosures Study supported by Bristol-Myers-Squibb Company and ImClone Systems Inc.

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

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

  6. Cetuximab: Phase II Clinical Data

  7. NCIC CTG CO.17: Randomized Phase III Trial in mCRC Failed or intolerant to all recommended therapies REGISTER RANDOMI ZE Cetuximab* + BSC Disease Progression or Unacceptable Toxicity EGFR testing by IHC BSC alone * Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly 1:1 • Stratification: • Centre • ECOG PS (0 or 1 vs. 2)

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

  9. NCIC CTG CO.17: Study Endpoints* • Primary: Overall Survival • Secondary • 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 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 or • Relapsed within 6 months or • Documented as unsuitable for therapy • Exclusion Criteria • Prior therapy with an EGFR inhibitor

  11. NCIC CTG CO.17: Statistical Considerations • Survival Analysis / Sample Size • Two-sided alpha of 5% • 90% power to detect: • 9.6% difference in 1-year survival • hazard ratio [HR] of 0.74 • assuming 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 recorded

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

  13. NCIC CTG CO.17: Demographic Characteristics

  14. NCIC CTG CO.17: Prior Chemotherapies

  15. NCIC CTG CO.17: Overall Survival * Stratified by ECOG PS (0-1 versus 2) at randomization

  16. 1.0 0.9 0.8 0.7 0.6 Proportion Alive 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 SUBJECTS AT RISK MONTHS CET+BSC 287 217 136 78 37 14 4 0 0 0 BSC 285 197 85 44 26 12 8 2 1 0 NCIC CTG CO.17: Overall Survival HR 0.77 (95% CI =0.64 – 0.92) Stratified log rank p-value = 0.0046 CETUXIMAB + BSC BSC CENSORED CENSORED

  17. NCIC CTG CO.17: Survival Result by Subgroups SubsetHazard Ratio and 95% CI All randomized ECOG 0-1 ECOG 2 Age <65 Age ≤65 Female Male 1.2 1.6 1.4 0.4 0.8 0.6 Favours Cetuximab Favours BSC

  18. NCIC CTG CO.17: Progression Free Survival * Stratified by ECOG PS (0-1 versus 2) at randomization

  19. NCIC CTG CO.17: Progression Free Survival 1.0 0.9 0.8 0.7 0.6 HR 0.68 (95% CI =0.57 – 0.80) Stratified log rank p-value < 0.0001 0.5 Proportion Progression-Free 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 MONTHS CETUXIMAB + BSC BSC CENSORED CENSORED

  20. NCIC CTG CO.17: Overall Best Response * 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

  21. NCIC CTG CO17: Unplanned Anti-Cancer Therapy* * Not allowed per protocol

  22. NCIC CTG CO.17: Specific Therapies Before Progression* * Not allowed per protocol

  23. NCIC CTG CO17: Therapy Post-Progression

  24. NCIC CTG CO.17: Specific Post-Progression Anti-Cancer Therapies

  25. NCIC CTG CO.17: Grade 3 / 4 Adverse Events * Hypomagnesemia as a laboratory toxicity was not correlated to clinical symptoms/ AEs

  26. NCIC CTG CO17: OS by Worst Grade of Rash 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

  27. NCIC CTG CO.17: Conclusions • Cetuximab 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 cancer • PFS 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 studies • The 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 Staff • BMS / ImClone • Study Nurses, Coordinators, Monitors • Patients and their Families

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