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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, MD for the ACCENT collaborative group ASCO 2008 May 31, 2008
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
ACCENT: Trials included
No Treatment Control Trial N N784852 INT 0035 247 926 N874651 Siena NCIC FFCD NSABP C01 NSABP C02 GIVIO 408 239 359 259 773 718 867 Trial Active Control N NSABP C03 NSABP C04 1081 2151 NSABP C05 N894651 N914653 SWOG 9415 INT 0089 GERCOR QUASAR 2176 915 878 1078 3547 905 3517 Total: 43 treatment arms; 20,898 pts
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
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ACCENT: 3yr DFS vs 5yr OS 0.6
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May 2004: ODAC recommends 3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancer
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HR for 3 Year DFS
R 2 = 0.80
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Relevance to current practice • Increased survival following recurrence More effective advanced disease therapy Improved detection of recurrence Median survival now ~ 2 years
R
MOSAIC: Study Design
FOLFOX4 : LV5FU2 + oxaliplatin 85 mg/m² LV5FU2
N=2246 Stage II: 40% Stage III: 60% Primary end-point: disease-free survival Secondary end-points: safety, overall survival
ASCO 2005
MOSAIC: Disease-free Survival (ITT) 1.0
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5.1%
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3-year 0.4
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FOLFOX (n=1123) 77.9% LV5FU2 (n=1123) 72.8%
p < 0.01
hazard ratio: 0.77 [0.65 – 0.92]
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0 6 12 Data cut-off: January 16, 2005 18 24 30
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36 42 48 54 60 66
ASCO 2003
MOSAIC: Disease-free Survival (ITT) 1.0
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Oxaliplatin + 5-FU/LV FDA approved based on 3 yr DFS endpoint
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FOLFOX4 LV5FU2 Events 279/1123 (24.8%) 345/1123 (30.7%) 0.1
p<0.001
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0 6 12 Data cut-off: January 16, 2005 18 HR [95% CI]: 0.77 [0.65
–0.90
] 24 30
Months
36 42 48 54 60 66
ASCO 2005
MOSAIC Update: OS with 6 years minimum follow-up
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p=0.996
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p=0.029
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4.4% 0.6
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HR [95% CI] Stage II 1.00 [0.71
–1.42] Stage III 0.80 [0.66
–0.98]
FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0 0 6 12 18 24
Data cut-off: January 2007
30 36 42 48 54 60 66 Overall survival (months) 72 78 84 90 96
ASCO 2007
Time from Relapse to Death: ITT 1.0
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FOLFOX4 n= 258 LV5FU2 n=334
median 24 months median 21 months
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Patients alive with relapse (%) FOLFOX4 69 (6.1) LV5FU2 88 (7.8) 0 0 6
Exploratory analysis
12 18 24 30 36 42 48 54 60 66 Time from relapse to death (months) 72 78 84
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
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 R 2 estimated by bivariate copula survival model (Burzykowski, 2001)
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3 Year DFS As Surrogate For OS Actual Data 0.8
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OS Years
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3 Year DFS As Surrogate For OS Actual Data 0.8
All Patients Doubled 0.7
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OS Years
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Actual Data – 3yr DFS v. 5yr OS 1.2
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R 2 = 0.80
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HR for 3 Year DFS
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Hypothetical – 3yr DFS v. 5yr OS 1.2
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R 2 = 0.55
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HR for 3 Year DFS
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Hypothetical – 3yr DFS v. 6yr OS 1.2
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R 2 = 0.68
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HR for 3 Year DFS
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Hypothetical – 3yr DFS v. 7yr OS 1.2
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R 2 = 0.75
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HR for 3 Year DFS
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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
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Impact of differing extensions of survival following recurrence
Actual Data 0.8
All Patients Doubled 0.7
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Survival Extension Rec Time Dependent Survival Extension Stage Dependent 0.4
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OS Years
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
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
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
Building an endpoint model Actual Data Mathematical Model Hypothetic al Data Estimates of Surrogacy Measures Investigator Chooses Endpoint User Inputs:
-Agent Mechanism of
Action
-Stage Mix -Age Mix -Survival Following
Recurrence
-Post-recurrence
resections
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)