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2 or 3 Year DFS is an Appropriate Primary Endpoint in Stage III Adjuvant Colon Cancer Trials with Fluoropyrimidines with or without Oxaliplatin or Irinotecan.

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  1. 2 or 3 Year DFS is an Appropriate Primary Endpoint in Stage III Adjuvant Colon Cancer Trials with Fluoropyrimidines with or without Oxaliplatin or Irinotecan D Sargent, G Yothers, E Van Cutsem, J Cassidy, L Saltz, N Wolmark, B Bot, Q Shi, M Buyse, and A de Gramont for the Adjuvant Colon Cancer Endpoints (ACCENT) Group ASCO 2009

  2. Disclosure Consulting/Honoraria • Pfizer • Sanofi • Genentech • Amgen • Roche for work unrelated to the current project

  3. The Adjuvant Colon Cancer Endpoints (ACCENT) database • Established in 2003, to validate disease-free survival (DFS) as an endpoint in adjuvant colon cancer • Originally included individual patient data from 18 large adjuvant clinical trials, 21,000 pts • Jointly owned by all contributors

  4. Previous ACCENT findings • DFS surrogate for OS1 • Concordancehigher in stage III vs II2 • 2 yr DFS may be adequate2 • Post-recurrent OS ↑ for stage II vs III3 • Majority of rx benefit in first 2 years4 • At least 6 yrs for OS benefit in new trials5 1Sargent et al, JCO 2005; 2Sargent et al JCO 2007; 3O’Connell et al JCO 2008 4Sargent et al JCO 2009; 5DeGramont et al ASCO 2008

  5. ACCENT update: 6 adjuvant trials added • Total addition 12,676 new patients • Median follow-up on living patients: 6 years • Median survival following recurrence: 20 months

  6. Goals of new analysis • Confirm association between DFS & OS in new trials • Validate that the DFS/OS association is stronger in pts with stage III than II disease • Validate 2 yr DFS time-point • Explore duration of OS follow-up required to demonstrate surrogacy (5 v 6 or more yrs)

  7. Methods • Included only patients from new trials not included in previous ACCENT analyses • Graphical representation of hazard functions • Association of within trial hazard ratios • Compare DFS, OS btwn arms within each study • Landmarks: 2, 3 yr for DFS, 5, 6 yr for OS • Weighted regression (WLS) – simple • Bivariate survival analysis1 (Copula)- complex • Goal: All methods give consistent results 1Burzykowski JRSS-C 2001

  8. Recurrence rate over time 83% of recurrences occur within the first 3 years

  9. DFS: experimental vs control pooled across trials

  10. Within trial hazard ratios for3 year DFS vs 5 year OS WLS R2 = 0.60 Copula R2 = 0.20

  11. Within trial hazard ratios for3 year DFS vs 5 & 6 year OS WLS R2 = 0.60 Copula R2 = 0.20 WLS R2 = 0.75 Copula R2 = 0.17

  12. Within trial hazard ratios for2 year DFS vs 5 year OS WLS R2 = 0.58 Copula R2 = 0.37

  13. Within trial hazard ratios for2 year DFS vs 5 & 6 year OS WLS R2 = 0.58 Copula R2 = 0.37 WLS R2 = 0.76 Copula R2 = 0.49

  14. Conclusions: DFS as an endpoint in joint stage II/III trials • Association higher for DFS with 6 vs 5 yr OS • Associations with 2 and 3 yr DFS and OS similar • Overall, modest associations

  15. Stage III within trial HR3 year DFS v 5 year OS WLS R2 = 0.93 Copula R2 = 0.81

  16. Stage III within trial HR3 year DFS v 5 & 6 year OS WLS R2 = 0.93 Copula R2 = 0.81 WLS R2 = 0.87 Copula R2 = 0.79

  17. Stage III within trial HR2 year DFS v 5 year OS WLS R2 = 0.91 Copula R2 = 0.86

  18. Stage III within trial HR2 year DFS v 5 & 6 year OS WLS R2 = 0.91 Copula R2 = 0.86 WLS R2 = 0.93 Copula R2 = 0.88

  19. Conclusions: DFS as a stage III endpoint • Concordance high for DFS with both 5 & 6 yr OS • DFS at 2 and 3 years very similar • Strong association

  20. Forest plot: 2 Yr DFS v 6 Yr OSstage III DFS OS

  21. How well did previous ACCENT model predict these results? • Prior analyses testing only 5-FU-based treatment produced a predictive model to use early DFS to predict later OS • Used observed early DFS HRs from the new trials, and the previous model, to predict OS HRs in the 6 new trials

  22. Prediction plot: 2 Yr DFS v 6 Yr OS: stage III Predicted HR

  23. Prediction plot: 2 Yr DFS v 6 Yr OS: stage III Predicted HR Actual HR

  24. Discussion • Follow-up beyond 6 years not available at this time • All trials used cytotoxic drugs, no biologics • If new agents change pattern of cancer recurrence (delay vs prevent), relationship between DFS and OS could change

  25. Validation of previous ACCENT findings? • DFS surrogate for OS– Confirmed (with conditions) • Concordancehigher in stage III vs II- Confirmed • 2 yr DFS may be adequate- Confirmed • > 6 yrs for OS benefit in new joint stage II/III trials – Requires further confirmation

  26. Conclusions • Based on modern adjuvant colon cancer trials • In joint stage II & III trials, even 6 yrs follow-up demonstrates only modest association between DFS and OS • In stage III patients, trial level DFS & OS association remains strong • Association between 2 yr DFS as strong as 3 yr DFS with OS

  27. Conclusion DFS assessed after 2 or 3 years remains an appropriate primary endpoint for stage III adjuvant colon cancer trials

  28. ACCENT collaborators S Wieand, G Yothers, M O’Connell, N Wolmark – NSABP J Benedetti, C Blanke – SWOG R Labianca – Ospedali Riuniti (Italy) D Haller, P Catalano, A Benson – ECOG C O’Callaghan – NCIC JF Seitz – University of the Mediterranean (France) G Francini – University of Siena (Italy) A de Gramont, T Andre – GERCOR R Goldberg, L Saltz, J Meyerhardt, N Jackson – CALGB M Buyse – IDDI (Belgium) R Gray, D Kerr – QUASAR A Grothey, S Alberts, B Bot, E Green, Q Shi –Mayo Clinic C Twelves -University of Bradford (UK) J Cassidy – University of Glasgow (UK) F Sirzen – Roche ; L Cisar - Pfizer E Van Cutsem –University Hospital Gasthuisberg (Belgium); A Sobrero - Ospedale San Martino (Italy)

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