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

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

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

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

0.5

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0.9

1

1.1

1.2

1.3

0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3

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

Relevance to current practice

• Increased survival following recurrence More effective advanced disease therapy Improved detection of recurrence

Median survival now ~ 2 years

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

1.0

0.9

0.8

0.7

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0.5

0.3

0.4

0.2

0.1

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)

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%

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

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

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

Time from Relapse to Death: ITT

Time from relapse to death (months)

Pro

bab

ilit

y

1.0

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0

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0.1

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

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 R2 estimated by bivariate copula survival model (Burzykowski, 2001)

3 Year DFS As Surrogate For OS

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4 5 6 7 8

OS Years

R-Squared

Actual Data

3 Year DFS As Surrogate For OS

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OS Years

R-Squared

All PatientsDoubled

Actual Data

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0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3

HR for 3 Year DFS

HR for 5 Year OSR2 = 0.80

Actual Data – 3yr DFS v. 5yr OS

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0.9

1

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0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3

HR for 3 Year DFS

HR for 5 Year OSR2 = 0.55

Hypothetical – 3yr DFS v. 5yr OS

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1

1.1

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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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0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3

HR for 3 Year DFS

HR for 7 Year OS

Hypothetical – 3yr DFS v. 7yr OS

R2 = 0.75

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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4 5 6 7 8

OS Years

R-Squared

Actual Data

All PatientsDoubled

Survival ExtensionRec TimeDependent

Survival ExtensionStageDependent

Impact of differing extensions of survival following recurrence

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

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

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)