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A trial of the National Cancer Institute of Canada Clinical Trials Group

Quality of Life in Patients with Advanced Colorectal Cancer Treated with Cetuximab: Results of the NCIC CTG and AGITG CO.17 Trial. H. Au, C. Karapetis, D. Jonker, C. O'Callaghan, H. Kennecke, J. Shapiro, D. Tu, R. Wierzbicki, J. Zalcberg, M. Moore.

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A trial of the National Cancer Institute of Canada Clinical Trials Group

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  1. Quality of Life in Patients with Advanced Colorectal Cancer Treated with Cetuximab:Results of the NCIC CTG and AGITG CO.17 Trial H. Au, C. Karapetis, D. Jonker, C. O'Callaghan, H. Kennecke, J. Shapiro, D. Tu, R. Wierzbicki, J. Zalcberg, M. Moore A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG)

  2. 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 detectable by IHC BSC alone * Cetuximab 400 mg/m2 IV day 1 then 250 mg/m2 IV weekly 1:1 • Stratification: • Centre • ECOG PS (0 or 1 vs. 2) D Jonker et al AACR 2007

  3. 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 D Jonker et al AACR 2007

  4. NCIC CTG CO.17: Study Endpoints • Primary • Overall Survival • Secondary • Progression Free Survival • Objective Response Rate (RECIST criteria) • Safety • Quality of Life • Cost Effectiveness Analysis/Cost Utility Analysis (to be reported later) D Jonker et al AACR 2007

  5. NCIC CTG CO.17: Demographic Characteristics D Jonker et al AACR 2007

  6. 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 Proportion Progression-Free 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 MONTHS D Jonker et al AACR 2007 CETUXIMAB + BSC BSC CENSORED CENSORED

  7. 1.0 0.9 0.8 0.7 Proportion Alive 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 MONTHS SUBJECTS AT RISK 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 D Jonker et al AACR 2007 CETUXIMAB + BSC BSC CENSORED CENSORED

  8. NCIC CTG CO.17 HRQoL Hypothesis • In this population of heavily pre-treated advanced CRC pts, in whom all other treatments have failed and deterioration in HRQoL may be imminent, we hypothesized that pts may benefit from cetuximab with • A decrease in the magnitude & rate of decline in their HRQoL, particularly with regards to their physical functioning and overall wellbeing

  9. HRQoL Instrument • EORTC QLQ-C30 • 5 functional scales • Physical, Role, Cognitive, Emotional, Social • Global health status • 3 symptom scales • Fatigue, Pain, Nausea & Vomiting • 6 single items • Dyspnea, Sleep disturbance, Appetite loss, Constipation, Diarrhea, Financial impact • Schedule • Baseline, 4, 8, 16, 24 weeks • Regardless of disease progression

  10. Pre-specified CO.17 HRQoL Endpoints • Primary • Compare mean change scores of Physical Function (PF) and Global Health Status (Global) at 8 and 16 weeks • Secondary • Compare proportion of pts with worsened PF and Global change scores at 8 and 16 weeks • Compare Median Time to Deterioration in PF and Global HRQoL • Compare exploratory HRQoL Response analyses of all scales/items

  11. Pre-specified CO.17 HRQoL Analyses • 10 unit difference in HRQoL change score pre-defined as clinically important • Previously demonstrated that this is a degree of change that is perceptible and meaningful to pts* • All randomized patients who had a measurement at baseline and at least one other measurement by ITT • Questionnaire compliance rates ascertained • No adjustments made for multiple comparisons *D Osoba et al. J Clin Oncol 16:139-144, 1998

  12. HRQoL Results • Baseline HRQoL scores were comparable in both arms • Questionnaire compliance

  13. Mean & Proportion with DeteriorationChange Scores at 8 and 16 Weeks *Change score from baseline ≤ -10; Fisher’s exact test

  14. 100 e e r f 80 n o i t a r 60 o i r e t e 40 D n o i t 20 r o p ro P 0 0.0 2.0 4.0 6.0 8.0 235 123 77 8 0 0 202 79 37 6 Time from randomization (months) # At Risk(CETUXIMAB+BSC) # At Risk(BSC) CETUXIMAB+BSC BSC Time to HRQoL Deterioration: Physical Function Log rank p=.022

  15. 100 e e r f 80 n o i t a r 60 o i r e t e 40 D n o i t 20 r o p ro P 0 0.0 2.0 4.0 6.0 8.0 235 123 77 8 0 202 79 37 6 0 Time from randomization (months) # At Risk(CETUXIMAB+BSC) # At Risk(BSC) CETUXIMAB+BSC BSC Time to HRQoL Deterioration: Global Health Status Log rank p=.062

  16. Role function Social function Fatigue Nausea Pain Dyspnea Appetite Sleep Constipation Financial impact Exploratory Analyses • All other scale and symptom change scores at 8 and 16 • weeks with differences of p<.05 favored cetuximab

  17. Proportion of Patients Improved* at Any Time in Other Scales/Items All p <.05 * Change score from baseline ≤-10 at any time

  18. Proportion of Patients Worsened* inOther Scales/Items All p<.05 * No change score < -10 with at least one change score >10

  19. Missing Data • HRQoL Questionnaire Compliance Rates • Lower with time • More so on BSC arm • Not missing at random (NMR) • Likely cause for NMR data? • Pts with missing data may be doing more poorly; not well enough to complete questionnaires • Consider in what direction this may bias results • Magnitude of HRQoL differences between the two arms may be even greater

  20. NCIC CTG CO.17HRQoL Summary & Conclusions • This study met its primary HRQoL endpoints demonstrating improved physical function and global health scores at 8 & 16 weeks with cetuximab compared to BSC. • Cetuximab resulted in better HRQoL than BSC alone. • Patients on cetuximab experienced significantly less HRQoL deterioration and a longer time before this deterioration occurred. NCIC CTG CO.17 demonstrates that cetuximab offers survival and HRQoL benefits for patients with advanced colorectal cancer.

  21. Thank you to: • The Patients and their Families • Study Nurses, Coordinators, Monitors • NCIC CTG and AGITG Investigators and Central Office Staff • Bristol-Myers Squibb Company and ImClone Systems Inc. for supporting this study • ASCO

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