U.S. Food and Drug Administration

Notice: Archived DocumentThe content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

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3 Year DFS vs. 5 Year OS as an 3 Year DFS vs. 5 Year OS as an endpoint for Adjuvant Colon endpoint for Adjuvant Colon Cancer Studies: Data from Cancer Studies: Data from

Randomized TrialsRandomized Trials

3 Year DFS vs. 5 Year OS as an 3 Year DFS vs. 5 Year OS as an endpoint for Adjuvant Colon endpoint for Adjuvant Colon Cancer Studies: Data from Cancer Studies: Data from

Randomized TrialsRandomized Trials

D SargentD Sargent11, S Wieand, S Wieand22, R Goldberg, R Goldberg11, M , M O’ConnellO’Connell22, A Benson, A Benson33, P Catalano, P Catalano33, J , J

BenedettiBenedetti44, G Francini, G Francini55, L Shepherd, L Shepherd66, JF , JF SeitzSeitz77, R Labianca, R Labianca88

D SargentD Sargent11, S Wieand, S Wieand22, R Goldberg, R Goldberg11, M , M O’ConnellO’Connell22, A Benson, A Benson33, P Catalano, P Catalano33, J , J

BenedettiBenedetti44, G Francini, G Francini55, L Shepherd, L Shepherd66, JF , JF SeitzSeitz77, R Labianca, R Labianca88

1Mayo Clinic-NCCTG, 2NSABP, 3ECOG, 4SWOG, 5University of Siena (Italy), 6NCIC-CTG

(Canada), 7University of the Mediterranean (France), 8Ospedali Riuniti (Italy)

1Mayo Clinic-NCCTG, 2NSABP, 3ECOG, 4SWOG, 5University of Siena (Italy), 6NCIC-CTG

(Canada), 7University of the Mediterranean (France), 8Ospedali Riuniti (Italy)

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DisclosureDisclosureDisclosureDisclosure

• Very preliminary workVery preliminary work

• Further analyses underwayFurther analyses underway

• Not for distribution or citationNot for distribution or citation

• Very preliminary workVery preliminary work

• Further analyses underwayFurther analyses underway

• Not for distribution or citationNot for distribution or citation

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SuggestionSuggestionSuggestionSuggestion

• 3 year disease free survival (DFS) 3 year disease free survival (DFS) is an appropriate endpoint to is an appropriate endpoint to replace 5 year overall survival (OS) replace 5 year overall survival (OS) as an endpoint in adjuvant colon as an endpoint in adjuvant colon trialstrials• Would allow more rapid Would allow more rapid

completion, reporting of trialscompletion, reporting of trials

• 3 year disease free survival (DFS) 3 year disease free survival (DFS) is an appropriate endpoint to is an appropriate endpoint to replace 5 year overall survival (OS) replace 5 year overall survival (OS) as an endpoint in adjuvant colon as an endpoint in adjuvant colon trialstrials• Would allow more rapid Would allow more rapid

completion, reporting of trialscompletion, reporting of trials

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MethodsMethodsMethodsMethods• Data from large randomized trialsData from large randomized trials

• Individual patient data (when available), Individual patient data (when available), or investigator furnished summaries. or investigator furnished summaries.

• Compare 3 year DFS, 5 year OS for each Compare 3 year DFS, 5 year OS for each armarm

• Compare difference between ‘control’ and Compare difference between ‘control’ and experimental armsexperimental arms

• Weighted linear regressionWeighted linear regression

• Data from large randomized trialsData from large randomized trials• Individual patient data (when available), Individual patient data (when available),

or investigator furnished summaries. or investigator furnished summaries.

• Compare 3 year DFS, 5 year OS for each Compare 3 year DFS, 5 year OS for each armarm

• Compare difference between ‘control’ and Compare difference between ‘control’ and experimental armsexperimental arms

• Weighted linear regressionWeighted linear regression

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Trial FirstAccrual

Treatment Arm N

NCCTG 784852 1978 5-FU/lev 247INT 0035 1985 5-FU/lev 926NCCTG 874651 1988 5-FU/CF 408Siena 1985 5-FU/CF 239NCIC 1987 5-FU/CF 359FFCD 1982 5-FU/CF 259NSABP C01 1977 MOF 773NSABP C02 1984 PVI 5-FU 718GIVIO 1989 5-FU/CF 867NCCTG 894651* 1989 5FU/Lev/CF 915NCCTG 914653* 1993 5FU/Lev/CF 878INT 0089* 1990 5FU/Lev/CF 3549

Total 10138

Trial FirstAccrual

Treatment Arm N

NCCTG 784852 1978 5-FU/lev 247INT 0035 1985 5-FU/lev 926NCCTG 874651 1988 5-FU/CF 408Siena 1985 5-FU/CF 239NCIC 1987 5-FU/CF 359FFCD 1982 5-FU/CF 259NSABP C01 1977 MOF 773NSABP C02 1984 PVI 5-FU 718GIVIO 1989 5-FU/CF 867NCCTG 894651* 1989 5FU/Lev/CF 915NCCTG 914653* 1993 5FU/Lev/CF 878INT 0089* 1990 5FU/Lev/CF 3549

Total 10138

*Did not include a no treatment control arm

Total: 38 treatment arms

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~1980: C01

NCCTG-784852

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

5 Year OS

3 Y

ea

r D

FS

3 year DFS vs 5 year OS

8

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

5 Year OS

3 Y

ea

r D

FS

~1985: INT0035

CO2

3 year DFS vs 5 year OS

9

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

5 Year OS

3 Y

ea

r D

FS

~1988: NCIC

NCCTG-874651 Siena FFCD

GIVIO

3 year DFS vs 5 year OS

10

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

5 Year OS

3 Y

ea

r D

FS

~1990: INT0089

NCCTG-894651

3 year DFS vs 5 year OS

11

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

5 Year OS

3 Y

ea

r D

FS

~1995: NCCTG-914653

3 year DFS vs 5 year OS

12

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

5 Year OS

3 Y

ea

r D

FS

3 year DFS vs 5 year OS

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ResultsResultsResultsResults

• Regression equation:Regression equation:• 3 yr DFS=0.05+.93*5 yr OS3 yr DFS=0.05+.93*5 yr OS• Coefficients not significantly Coefficients not significantly

different from 0 and 1different from 0 and 1• Correlation 0.92, RCorrelation 0.92, R22 = 0.85 = 0.85

• Largest difference 6%, 36 of 38 Largest difference 6%, 36 of 38 << 3% difference3% difference

• Regression equation:Regression equation:• 3 yr DFS=0.05+.93*5 yr OS3 yr DFS=0.05+.93*5 yr OS• Coefficients not significantly Coefficients not significantly

different from 0 and 1different from 0 and 1• Correlation 0.92, RCorrelation 0.92, R22 = 0.85 = 0.85

• Largest difference 6%, 36 of 38 Largest difference 6%, 36 of 38 << 3% difference3% difference

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Conclusion (1)Conclusion (1)Conclusion (1)Conclusion (1)

• On an arm by arm basis, 3 year On an arm by arm basis, 3 year DFS is an excellent predictor of 5 DFS is an excellent predictor of 5 year OSyear OS

• Event rates virtually identicalEvent rates virtually identical• No impact on sample sizeNo impact on sample size• Power for 3 yr DFS will Power for 3 yr DFS will

adequately power 5 yr OSadequately power 5 yr OS

• On an arm by arm basis, 3 year On an arm by arm basis, 3 year DFS is an excellent predictor of 5 DFS is an excellent predictor of 5 year OSyear OS

• Event rates virtually identicalEvent rates virtually identical• No impact on sample sizeNo impact on sample size• Power for 3 yr DFS will Power for 3 yr DFS will

adequately power 5 yr OSadequately power 5 yr OS

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Within study comparisonsWithin study comparisonsWithin study comparisonsWithin study comparisons

• Does a comparison of arms using 3 Does a comparison of arms using 3 yr DFS reach the same conclusion yr DFS reach the same conclusion as using 5 yr OS?as using 5 yr OS?

• Does a comparison of arms using 3 Does a comparison of arms using 3 yr DFS reach the same conclusion yr DFS reach the same conclusion as using 5 yr OS?as using 5 yr OS?

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0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

5 Year OS

3 Y

ea

r D

FS

3 year DFS vs 5 year OS

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0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

5 Year OS

3 Y

ea

r D

FS

Experimental

Control

3 yr DFS > 5 yr OS6 ‘Experimental’3 ‘Control’

3 yr DFS < 5 yr OS5 ‘Experimental’7 ‘Control’

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-0.1

-0.05

0

0.05

0.1

0.15

-0.1 -0.05 0 0.05 0.1 0.15

Change in 5 Year OS

Ch

an

ge

in

3 Y

ea

r D

FS

Difference in 3 yr DFS vs Difference in 5 yr OS

In 8 of 16 within studycomparisons, differencein 3 yr DFS > differencein 5 yr OS, 4 had the same difference.

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ResultsResultsResultsResults

• Regression equation:Regression equation:• 5 yr OS = 0.85* 5 yr OS = 0.85* 3 yr DFS 3 yr DFS• Correlation 0.87Correlation 0.87• RR22 = 0.75 = 0.75

• Of 16 total comparisonsOf 16 total comparisons• 12 same conclusion both DFS & OS12 same conclusion both DFS & OS

• 9 No difference, 3 significant difference9 No difference, 3 significant difference

• 3 significant only for DFS3 significant only for DFS• 1 significant only for OS1 significant only for OS

• Regression equation:Regression equation:• 5 yr OS = 0.85* 5 yr OS = 0.85* 3 yr DFS 3 yr DFS• Correlation 0.87Correlation 0.87• RR22 = 0.75 = 0.75

• Of 16 total comparisonsOf 16 total comparisons• 12 same conclusion both DFS & OS12 same conclusion both DFS & OS

• 9 No difference, 3 significant difference9 No difference, 3 significant difference

• 3 significant only for DFS3 significant only for DFS• 1 significant only for OS1 significant only for OS

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Conclusion (2)Conclusion (2)Conclusion (2)Conclusion (2)

• As an endpoint for comparison, 3 yr As an endpoint for comparison, 3 yr DFS DFS may slightly overestimate 5 yr may slightly overestimate 5 yr OS OS • May change the conclusion in a non-May change the conclusion in a non-

trivial proportion of trialstrivial proportion of trials

• If long-term OS is what we really care If long-term OS is what we really care about, conclusions based on 3 yr DFS about, conclusions based on 3 yr DFS must be considered ‘subject to must be considered ‘subject to confirmation’confirmation’

• As an endpoint for comparison, 3 yr As an endpoint for comparison, 3 yr DFS DFS may slightly overestimate 5 yr may slightly overestimate 5 yr OS OS • May change the conclusion in a non-May change the conclusion in a non-

trivial proportion of trialstrivial proportion of trials

• If long-term OS is what we really care If long-term OS is what we really care about, conclusions based on 3 yr DFS about, conclusions based on 3 yr DFS must be considered ‘subject to must be considered ‘subject to confirmation’confirmation’

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DiscussionDiscussionDiscussionDiscussion

• Did not have individual patient data Did not have individual patient data from all trialsfrom all trials

• Most had a no treatment controlMost had a no treatment control• Need to study more trials with ‘active’ Need to study more trials with ‘active’

treatment in all armstreatment in all arms

• B’s and C’s mixed together, may be B’s and C’s mixed together, may be beneficial to separatebeneficial to separate

• Relevance for non-cytotoxic agentsRelevance for non-cytotoxic agents

• Did not have individual patient data Did not have individual patient data from all trialsfrom all trials

• Most had a no treatment controlMost had a no treatment control• Need to study more trials with ‘active’ Need to study more trials with ‘active’

treatment in all armstreatment in all arms

• B’s and C’s mixed together, may be B’s and C’s mixed together, may be beneficial to separatebeneficial to separate

• Relevance for non-cytotoxic agentsRelevance for non-cytotoxic agents

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Future workFuture workFuture workFuture work

• More trialsMore trials

• Mimic actual trial conductMimic actual trial conduct• Recreate dataset that would Recreate dataset that would

have been available at each have been available at each given time-pointgiven time-point

• Other endpoints: 2 yr DFS, 3 yr OSOther endpoints: 2 yr DFS, 3 yr OS

• More trialsMore trials

• Mimic actual trial conductMimic actual trial conduct• Recreate dataset that would Recreate dataset that would

have been available at each have been available at each given time-pointgiven time-point

• Other endpoints: 2 yr DFS, 3 yr OSOther endpoints: 2 yr DFS, 3 yr OS