aimery de gramont
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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 group
ASCO 2008May 31, 2008
Aimery de Gramont
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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
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Total: 43 treatment arms; 20,898 pts
3517QUASAR867GIVIO
905GERCOR718NSABP C02
3547INT 0089773NSABP C01
1078SWOG 9415
259FFCD
878N914653359NCIC
915N894651239Siena
2176NSABP C05408N874651
2151NSABP C04926INT 0035
1081NSABP C03247N784852
NTrialNTrial
Active ControlNo Treatment Control
ACCENT: Trials included
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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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HR for 3 Year DFS
HR for 5 Year OSR2 = 0.80
ACCENT: 3yr DFS vs 5yr OS
May 2004: ODAC recommends3-yr DFS as new regulatory endpointfor FULL approval in adjuvant colon cancer
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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
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Primary end-point: disease-free survival
Secondary end-points: safety, overall survival
R
LV5FU2
FOLFOX4: LV5FU2 + oxaliplatin 85 mg/m²
N=2246
Stage II: 40%
Stage III: 60%
MOSAIC: Study Design
ASCO 2005
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1.0
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0.0 0 666 12 18 24 30 36 42 48 54 60
Months
DF
S p
roba
bilit
y
Data cut-off: January 16, 2005 ASCO 2003
p < 0.01 hazard ratio: 0.77 [0.65 – 0.92]
3-year
5.1%
FOLFOX (n=1123) 77.9%LV5FU2 (n=1123) 72.8%
MOSAIC: Disease-free Survival (ITT)
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MOSAIC: Disease-free Survival (ITT)1.0
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0.0 0 666 12 18 24 30 36 42 48 54 60
Months
Events
FOLFOX4 279/1123 (24.8%)
LV5FU2 345/1123 (30.7%)
HR [95% CI]: 0.77 [0.65 – 0.90]
DF
S p
roba
bilit
y
Data cut-off: January 16, 2005
p<0.001
ASCO 2005
Oxaliplatin + 5-FU/LVFDA approved based on 3 yr DFS endpoint
6.6%
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MOSAIC Update: OS with 6 years minimum follow-up
Data cut-off: January 2007
FOLFOX4 stage II
LV5FU2 stage II
FOLFOX4 stage III
LV5FU2 stage III
Overall survival (months)
Pro
bab
ilit
y
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0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90
HR [95% CI]
Stage II 1.00 [0.71–1.42]
Stage III 0.80 [0.66–0.98]
0.1%
4.4%
p=0.996
p=0.029
ASCO 2007
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Time from Relapse to Death: ITT
Time from relapse to death (months)
Pro
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FOLFOX4 n= 258 median 24 months
LV5FU2 n=334 median 21 months
0 6 12 18 24 6030 36 42 48 54 66 8472 78
Patients alive with relapse (%)
FOLFOX4 69 (6.1)
LV5FU2 88 (7.8)
Exploratory analysis
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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
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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)
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3 Year DFS As Surrogate For OS
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4 5 6 7 8
OS Years
R-Squared
Actual Data
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3 Year DFS As Surrogate For OS
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OS Years
R-Squared
All PatientsDoubled
Actual Data
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HR for 3 Year DFS
HR for 5 Year OSR2 = 0.80
Actual Data – 3yr DFS v. 5yr OS
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HR for 3 Year DFS
HR for 5 Year OSR2 = 0.55
Hypothetical – 3yr DFS v. 5yr OS
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HR for 3 Year DFS
HR for 6 Year OSR2 = 0.68
Hypothetical – 3yr DFS v. 6yr OS
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HR for 3 Year DFS
HR for 7 Year OS
Hypothetical – 3yr DFS v. 7yr OS
R2 = 0.75
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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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OS Years
R-Squared
Actual Data
All PatientsDoubled
Survival ExtensionRec TimeDependent
Survival ExtensionStageDependent
Impact of differing extensions of survival following recurrence
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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
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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
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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
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Actual DataActual Data
Hypothetical Data
Hypothetical Data
Estimates of Surrogacy Measures
Estimates of Surrogacy Measures
Investigator Chooses Endpoint
Mathematical Model
Mathematical Model
User Inputs: -Agent Mechanism of Action-Stage Mix-Age Mix-Survival Following Recurrence-Post-recurrence resections
Building an endpoint model
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Acknowledgments
Collaborators S Wieand, G Yothers, M O’Connell, N Wolmark – NSABPJ Benedetti, C Blanke – SWOGR Labianca – Ospedali Riuniti (Italy)D Haller, P Catalano, A Benson – ECOGC O’Callaghan – NCICJF Seitz – University of the Mediterranean (France)G Francini – University of Siena (Italy)A de Gramont, T Andre – GERCORR Goldberg – UNC/CALGBM Buyse – IDDI (Belgium)R Gray, D Kerr – OxfordA Grothey, S Alberts, E Green, M Campbell, Q Shi (Mayo)