1 / 26

Aimery de Gramont

Aimery de Gramont.

cheryl
Download Presentation

Aimery de Gramont

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Aimery de Gramont Association between 3 year Disease Free Survival and Overall Survival delayed with improved survival after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: Findings from the 20,898 patient ACCENT dataset Aimery de Gramont, MDfor the ACCENT collaborative groupASCO 2008May 31, 2008

  2. The Adjuvant Colon Cancer Endpoints (ACCENT) Collaboration • Established in 2003 to evaluate novel endpoints in adjuvant colon cancer • Pooled analysis of individual patient data from large randomized Phase III clinical trials world-wide

  3. No Treatment Control Active Control Trial N Trial N N784852 247 NSABP C03 1081 INT 0035 926 NSABP C04 2151 N874651 408 NSABP C05 2176 Siena 239 N894651 915 NCIC 359 N914653 878 FFCD 259 SWOG 9415 1078 NSABP C01 773 INT 0089 3547 NSABP C02 718 GERCOR 905 GIVIO 867 QUASAR 3517 ACCENT: Trials included Total: 43 treatment arms; 20,898 pts

  4. Mining the ACCENT database • ASCO 2004: 3 yr DFS surrogate for OS • ASCO 2005 • Concordance stronger in stage III than stage II • 2 yr DFS a promising earlier surrogate • ASCO 2007 • Survival after recurrence • Patterns of recurrence and adjuvant therapy benefit

  5. ACCENT: 3yr DFS vs 5yr OS R2 = 0.80 May 2004: ODAC recommends3-yr DFS as new regulatory endpointfor FULL approval in adjuvant colon cancer

  6. Relevance to current practice • Increased survival following recurrence • More effective advanced disease therapy • Improved detection of recurrence • Median survival now ~ 2 years

  7. R MOSAIC: Study Design FOLFOX4: LV5FU2+ oxaliplatin 85 mg/m² N=2246 Stage II: 40% Stage III: 60% LV5FU2 Primary end-point: disease-free survival Secondary end-points: safety, overall survival ASCO 2005

  8. MOSAIC: Disease-free Survival (ITT) 1.0 0.9 5.1% 0.8 0.7 0.6 DFS probability 0.5 3-year 0.4 FOLFOX (n=1123) 77.9% LV5FU2 (n=1123) 72.8% 0.3 0.2 p < 0.01 hazard ratio: 0.77 [0.65 – 0.92] 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Months Data cut-off: January 16, 2005 ASCO 2003

  9. MOSAIC: Disease-free Survival (ITT) 1.0 0.9 6.6% 0.8 0.7 Oxaliplatin + 5-FU/LV FDA approved based on 3 yr DFS endpoint 0.6 DFS probability 0.5 Events FOLFOX4 279/1123 (24.8%) LV5FU2 345/1123 (30.7%) HR [95% CI]: 0.77 [0.65–0.90] 0.4 0.3 0.2 p<0.001 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Months Data cut-off: January 16, 2005 ASCO 2005

  10. MOSAIC Update: OS with 6 years minimum follow-up 1.0 p=0.996 0.9 0.1% p=0.029 0.8 4.4% 0.7 0.6 0.5 Probability 0.4 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall survival (months) Data cut-off: January 2007 ASCO 2007

  11. Time from Relapse to Death: ITT 1.0 0.9 0.8 0.7 FOLFOX4 n= 258 median 24 months LV5FU2 n=334 median 21 months 0.6 0.5 Probability 0.4 0.3 Patients alive with relapse (%) FOLFOX4 69 (6.1) LV5FU2 88 (7.8) 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time from relapse to death (months) Exploratory analysis

  12. OS vs DFS: Why did MOSAIC take 6 years to become positive for OS? • Previous analyses with 5FU/LV showed excellent association between 3 yr DFS & 5 yr OS • Median time from recurrence to death: 12 months • MOSAIC: median ~ 24 months • Advances in monitoring, treatment post-recurrence • Additional factors can explain the better survival in the control arm: • the most active regimen is more active at relapse in patients not previously exposed • Second cancer might be better treated in patients who did not previously receive a platinum compound • We sought to examine the impact of longer survival following recurrence on the association between DFS and OS

  13. Impact of longer survival following recurrence • Hypothetical analysis: Take all patients who recurred in ACCENT (N=7269), and double time from recurrence to death (median ↑ from 12 to 24 months) • Examine association between true 3 yr DFS and hypothetical 5, 6, 7 yr OS in these artificial datasets • Trial level R2 estimated by bivariate copula survival model (Burzykowski, 2001)

  14. 3 Year DFS As Surrogate For OS Actual Data

  15. 3 Year DFS As Surrogate For OS Actual Data All Patients Doubled

  16. Actual Data – 3yr DFS v. 5yr OS R2 = 0.80

  17. Hypothetical – 3yr DFS v. 5yr OS R2 = 0.55

  18. Hypothetical – 3yr DFS v. 6yr OS R2 = 0.68

  19. Hypothetical – 3yr DFS v. 7yr OS R2 = 0.75

  20. Additional Hypothetical Analyses • O’Connell (JCO 2008) identified factors related to survival following recurrence • Time to recurrence • Initial stage • Repeated hypothetical analysis, extending survival differentially for different patients, based on pt specific characteristics

  21. Impact of differing extensions of survival following recurrence Actual Data All Patients Doubled Survival Extension Stage Dependent Survival Extension Rec Time Dependent

  22. Conclusions • Extended survival following recurrence reduces association between 3 yr DFS and 5 yr OS • Surrogacy improves between 3 yr DFS and OS after 6 or 7 years, depending on what factors influence survival following recurrence

  23. Impact of longer survival following recurrence on clinical trials • Expectation: Longer follow-up for OS will be required to observe benefit, due to improved post-recurrence treatment • DFS becomes even more important as an endpoint • Caveat: If treatments change pattern of cancer recurrence (delay vs prevent), then early DFS signals could mislead

  24. ACCENT: Future plans • Update ACCENT based on newer trials • Oxaliplatin: MOSAIC, C-07 • Irinotecan: PETACC-3; C89803 • Capecitabine: X-ACT • Validate existing model; extend based on new data • Develop interactive calculator to define optimal clinical trial endpoint, based on user defined inputs

  25. Building an endpoint model Actual Data Mathematical Model Hypothetical Data • User Inputs: • Agent Mechanism of Action • Stage Mix • Age Mix • Survival Following Recurrence • Post-recurrence resections Estimates of Surrogacy Measures Investigator Chooses Endpoint

  26. Acknowledgments 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 – UNC/CALGB M Buyse – IDDI (Belgium) R Gray, D Kerr – Oxford A Grothey, S Alberts, E Green, M Campbell, Q Shi (Mayo)

More Related