1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDAs website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. 2 3 Year DFS vs. 5 Year OS as an endpoint for Adjuvant Colon Cancer Studies: Data from Randomized Trials D Sargent 1, S Wieand 2, R Goldberg 1, M OConnell 2, A Benson 3, P Catalano 3, J Benedetti 4, G Francini 5, L Shepherd 6, JF Seitz 7, R Labianca 8 1 Mayo Clinic-NCCTG, 2 NSABP, 3 ECOG, 4 SWOG, 5 University of Siena (Italy), 6 NCIC-CTG (Canada), 7 University of the Mediterranean (France), 8 Ospedali Riuniti (Italy)

3. 3 DisclosureDisclosure Very preliminary work Very preliminary work Further analyses underway Further analyses underway Not for distribution or citation Not for distribution or citation Very preliminary work Very preliminary work Further analyses underway Further analyses underway Not for distribution or citation Not for distribution or citation

4. 4 SuggestionSuggestion 3 year disease free survival (DFS) is an appropriate endpoint to replace 5 year overall survival (OS) as an endpoint in adjuvant colon trials 3 year disease free survival (DFS) is an appropriate endpoint to replace 5 year overall survival (OS) as an endpoint in adjuvant colon trials Would allow more rapid completion, reporting of trials Would allow more rapid completion, reporting of trials 3 year disease free survival (DFS) is an appropriate endpoint to replace 5 year overall survival (OS) as an endpoint in adjuvant colon trials 3 year disease free survival (DFS) is an appropriate endpoint to replace 5 year overall survival (OS) as an endpoint in adjuvant colon trials Would allow more rapid completion, reporting of trials Would allow more rapid completion, reporting of trials

5. 5 MethodsMethods Data from large randomized trials Data from large randomized trials Individual patient data (when available), or investigator furnished summaries. Individual patient data (when available), or investigator furnished summaries. Compare 3 year DFS, 5 year OS for each arm Compare 3 year DFS, 5 year OS for each arm Compare difference between control and experimental arms Compare difference between control and experimental arms Weighted linear regression Weighted linear regression Data from large randomized trials Data from large randomized trials Individual patient data (when available), or investigator furnished summaries. Individual patient data (when available), or investigator furnished summaries. Compare 3 year DFS, 5 year OS for each arm Compare 3 year DFS, 5 year OS for each arm Compare difference between control and experimental arms Compare difference between control and experimental arms Weighted linear regression Weighted linear regression

6. 6 *Did not include a no treatment control arm Total: 38 treatment arms

7. 7 ~1980: C01 NCCTG-784852 3 year DFS vs 5 year OS

8. 8 ~1985: INT0035 CO2 3 year DFS vs 5 year OS

9. 9 ~1988: NCIC NCCTG-874651 Siena FFCD GIVIO 3 year DFS vs 5 year OS

10. 10 ~1990: INT0089 NCCTG-894651 3 year DFS vs 5 year OS

11. 11 ~1995: NCCTG-914653 3 year DFS vs 5 year OS

12. 12 3 year DFS vs 5 year OS

13. 13 ResultsResults Regression equation: Regression equation: 3 yr DFS=0.05+.93*5 yr OS 3 yr DFS=0.05+.93*5 yr OS Coefficients not significantly different from 0 and 1 Coefficients not significantly different from 0 and 1 Correlation 0.92, R 2 = 0.85 Correlation 0.92, R 2 = 0.85 Largest difference 6%, 36 of 38 < 3% difference Largest difference 6%, 36 of 38 < 3% difference Regression equation: Regression equation: 3 yr DFS=0.05+.93*5 yr OS 3 yr DFS=0.05+.93*5 yr OS Coefficients not significantly different from 0 and 1 Coefficients not significantly different from 0 and 1 Correlation 0.92, R 2 = 0.85 Correlation 0.92, R 2 = 0.85 Largest difference 6%, 36 of 38 < 3% difference Largest difference 6%, 36 of 38 < 3% difference

14. 14 Conclusion (1) On an arm by arm basis, 3 year DFS is an excellent predictor of 5 year OS On an arm by arm basis, 3 year DFS is an excellent predictor of 5 year OS Event rates virtually identical Event rates virtually identical No impact on sample size No impact on sample size Power for 3 yr DFS will adequately power 5 yr OS Power for 3 yr DFS will adequately power 5 yr OS On an arm by arm basis, 3 year DFS is an excellent predictor of 5 year OS On an arm by arm basis, 3 year DFS is an excellent predictor of 5 year OS Event rates virtually identical Event rates virtually identical No impact on sample size No impact on sample size Power for 3 yr DFS will adequately power 5 yr OS Power for 3 yr DFS will adequately power 5 yr OS

15. 15 Within study comparisons Does a comparison of arms using 3 yr DFS reach the same conclusion as using 5 yr OS? Does a comparison of arms using 3 yr DFS reach the same conclusion as using 5 yr OS?

16. 16 3 year DFS vs 5 year OS

17. 17 3 yr DFS > 5 yr OS 6 Experimental 3 Control 3 yr DFS < 5 yr OS 5 Experimental 7 Control

18. 18 Difference in 3 yr DFS vs Difference in 5 yr OS In 8 of 16 within study comparisons, difference in 3 yr DFS > difference in 5 yr OS, 4 had the same difference.

19. 19 ResultsResults Regression equation: Regression equation: 5 yr OS = 0.85* 3 yr DFS 5 yr OS = 0.85* 3 yr DFS Correlation 0.87 Correlation 0.87 R 2 = 0.75 R 2 = 0.75 Of 16 total comparisons Of 16 total comparisons 12 same conclusion both DFS & OS 12 same conclusion both DFS & OS 9 No difference, 3 significant difference 9 No difference, 3 significant difference 3 significant only for DFS 3 significant only for DFS 1 significant only for OS 1 significant only for OS Regression equation: Regression equation: 5 yr OS = 0.85* 3 yr DFS 5 yr OS = 0.85* 3 yr DFS Correlation 0.87 Correlation 0.87 R 2 = 0.75 R 2 = 0.75 Of 16 total comparisons Of 16 total comparisons 12 same conclusion both DFS & OS 12 same conclusion both DFS & OS 9 No difference, 3 significant difference 9 No difference, 3 significant difference 3 significant only for DFS 3 significant only for DFS 1 significant only for OS 1 significant only for OS

20. 20 Conclusion (2) As an endpoint for comparison, 3 yr DFS may slightly overestimate 5 yr OS As an endpoint for comparison, 3 yr DFS may slightly overestimate 5 yr OS May change the conclusion in a non-trivial proportion of trials May change the conclusion in a non-trivial proportion of trials If long-term OS is what we really care about, conclusions based on 3 yr DFS must be considered subject to confirmation If long-term OS is what we really care about, conclusions based on 3 yr DFS must be considered subject to confirmation As an endpoint for comparison, 3 yr DFS may slightly overestimate 5 yr OS As an endpoint for comparison, 3 yr DFS may slightly overestimate 5 yr OS May change the conclusion in a non-trivial proportion of trials May change the conclusion in a non-trivial proportion of trials If long-term OS is what we really care about, conclusions based on 3 yr DFS must be considered subject to confirmation If long-term OS is what we really care about, conclusions based on 3 yr DFS must be considered subject to confirmation

21. 21 DiscussionDiscussion Did not have individual patient data from all trials Did not have individual patient data from all trials Most had a no treatment control Most had a no treatment control Need to study more trials with active treatment in all arms Need to study more trials with active treatment in all arms Bs and Cs mixed together, may be beneficial to separate Bs and Cs mixed together, may be beneficial to separate Relevance for non-cytotoxic agents Relevance for non-cytotoxic agents Did not have individual patient data from all trials Did not have individual patient data from all trials Most had a no treatment control Most had a no treatment control Need to study more trials with active treatment in all arms Need to study more trials with active treatment in all arms Bs and Cs mixed together, may be beneficial to separate Bs and Cs mixed together, may be beneficial to separate Relevance for non-cytotoxic agents Relevance for non-cytotoxic agents

22. 22 Future work More trials More trials Mimic actual trial conduct Mimic actual trial conduct Recreate dataset that would have been available at each given time-point Recreate dataset that would have been available at each given time-point Other endpoints: 2 yr DFS, 3 yr OS Other endpoints: 2 yr DFS, 3 yr OS More trials More trials Mimic actual trial conduct Mimic actual trial conduct Recreate dataset that would have been available at each given time-point Recreate dataset that would have been available at each given time-point Other endpoints: 2 yr DFS, 3 yr OS Other endpoints: 2 yr DFS, 3 yr OS