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
Concordance higher 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
Accrual
Period
# patients
Experimental
treatment arm
% stage III
MOSAIC
2246
FOLFOX4 60
X-ACT
1987
Capecitabine
100
NSABP C-06
1557
Uracil/tegafur 53
NSABP C-07
2434
FLOX 71
CALGB 89803
1264
IFL
PETACC-3
3188
FOLFIRI
† Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and leucovorin (LV)
‡ Remaining patients were stage II or unknown
Recently added data from 6 newer studies evaluating the survival benefit of either intravenous (IV) FU combination chemotherapy or oral FU chemotherapy compared to standard IV FU/LV monotherapy in stage II and III CRC
Abbreviations: MOSAIC, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; XACT, Xeloda in Adjuvant Colon Cancer Therapy; NSABP, National Surgical Adjuvant Breast and Bowel Project; CALGB, Cancer and Leukemia Group B; PETACC, Pan-European Trials in Adjuvant Colon Cancer; FOLFOX, infusional 5-FU/LV + oxaliplatin; FLOX, bolus IV 5-fluorouracil (FU)/ leucovorin (LV) + oxaliplatin; IFL, bolus IV 5-FU/LV + irinotecan; FOLFIRI, infusional 5-FU/LV + irinotecan
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 for 3 year DFS vs 5 year OS
WLS R2 = 0.60
Copula R2 = 0.20

11. Within trial hazard ratios for 3 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 for 2 year DFS vs 5 year OS
WLS R2 = 0.58
Copula R2 = 0.37

13. Within trial hazard ratios for 2 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
DFS yrs
OS yrs
WLS R2
Copula R2 2 5
0.58
0.37 6
0.76
0.49 3
0.60
0.20
0.75
0.17
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 HR 3 year DFS v 5 year OS
WLS R2 = 0.93
Copula R2 = 0.81

16. Stage III within trial HR 3 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 HR 2 year DFS v 5 year OS
WLS R2 = 0.91
Copula R2 = 0.86

18. Stage III within trial HR 2 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
DFS yrs
OS yrs
WLS R2
Copula R2 2 5
0.91
0.86 6
0.93
0.88 3
0.81
0.87
0.79
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 OS stage III

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)
Concordance higher 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)