2 or 3 Year DFS is an Appropriate Primary Endpoint in Stage III Adjuvant Colon Cancer Trials with Fluoropyrimidines with or without Oxaliplatin or Irinotecan D Sargent, G Yothers, E Van Cutsem, J Cassidy, L Saltz, N Wolmark, B Bot, Q Shi, M Buyse, and A de Gramont for the Adjuvant Colon Cancer Endpoints (ACCENT) Group ASCO 2009

Disclosure Consulting/Honoraria Pfizer Sanofi Genentech Amgen Roche for work unrelated to the current project

The Adjuvant Colon Cancer Endpoints (ACCENT) database Established in 2003, to validate disease-free survival (DFS) as an endpoint in adjuvant colon cancer Originally included individual patient data from 18 large adjuvant clinical trials, 21,000 pts Jointly owned by all contributors

Previous ACCENT findings DFS surrogate for OS1 Concordance higher in stage III vs II2 2 yr DFS may be adequate2 Post-recurrent OS ↑ for stage II vs III3 Majority of rx benefit in first 2 years4 At least 6 yrs for OS benefit in new trials5 1Sargent et al, JCO 2005; 2Sargent et al JCO 2007; 3O’Connell et al JCO 2008 4Sargent et al JCO 2009; 5DeGramont et al ASCO 2008

ACCENT update: 6 adjuvant trials added Accrual Period # patients Experimental treatment arm % stage III MOSAIC 1998-01 2246 FOLFOX4 60 X-ACT 1987 Capecitabine 100 NSABP C-06 1997-99 1557 Uracil/tegafur 53 NSABP C-07 2000-02 2434 FLOX 71 CALGB 89803 1999-01 1264 IFL PETACC-3 3188 FOLFIRI † Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and leucovorin (LV) ‡ Remaining patients were stage II or unknown Recently added data from 6 newer studies evaluating the survival benefit of either intravenous (IV) FU combination chemotherapy or oral FU chemotherapy compared to standard IV FU/LV monotherapy in stage II and III CRC Abbreviations: MOSAIC, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; XACT, Xeloda in Adjuvant Colon Cancer Therapy; NSABP, National Surgical Adjuvant Breast and Bowel Project; CALGB, Cancer and Leukemia Group B; PETACC, Pan-European Trials in Adjuvant Colon Cancer; FOLFOX, infusional 5-FU/LV + oxaliplatin; FLOX, bolus IV 5-fluorouracil (FU)/ leucovorin (LV) + oxaliplatin; IFL, bolus IV 5-FU/LV + irinotecan; FOLFIRI, infusional 5-FU/LV + irinotecan Total addition 12,676 new patients Median follow-up on living patients: 6 years Median survival following recurrence: 20 months

Goals of new analysis Confirm association between DFS & OS in new trials Validate that the DFS/OS association is stronger in pts with stage III than II disease Validate 2 yr DFS time-point Explore duration of OS follow-up required to demonstrate surrogacy (5 v 6 or more yrs)

Methods Included only patients from new trials not included in previous ACCENT analyses Graphical representation of hazard functions Association of within trial hazard ratios Compare DFS, OS btwn arms within each study Landmarks: 2, 3 yr for DFS, 5, 6 yr for OS Weighted regression (WLS) – simple Bivariate survival analysis1 (Copula) - complex Goal: All methods give consistent results 1Burzykowski JRSS-C 2001

Recurrence rate over time 83% of recurrences occur within the first 3 years

DFS: experimental vs control pooled across trials

Within trial hazard ratios for 3 year DFS vs 5 year OS WLS R2 = 0.60 Copula R2 = 0.20

Within trial hazard ratios for 3 year DFS vs 5 & 6 year OS WLS R2 = 0.60 Copula R2 = 0.20 WLS R2 = 0.75 Copula R2 = 0.17

Within trial hazard ratios for 2 year DFS vs 5 year OS WLS R2 = 0.58 Copula R2 = 0.37

Within trial hazard ratios for 2 year DFS vs 5 & 6 year OS WLS R2 = 0.58 Copula R2 = 0.37 WLS R2 = 0.76 Copula R2 = 0.49

Conclusions: DFS as an endpoint in joint stage II/III trials DFS yrs OS yrs WLS R2 Copula R2 2 5 0.58 0.37 6 0.76 0.49 3 0.60 0.20 0.75 0.17 Association higher for DFS with 6 vs 5 yr OS Associations with 2 and 3 yr DFS and OS similar Overall, modest associations

Stage III within trial HR 3 year DFS v 5 year OS WLS R2 = 0.93 Copula R2 = 0.81

Stage III within trial HR 3 year DFS v 5 & 6 year OS WLS R2 = 0.93 Copula R2 = 0.81 WLS R2 = 0.87 Copula R2 = 0.79

Stage III within trial HR 2 year DFS v 5 year OS WLS R2 = 0.91 Copula R2 = 0.86

Stage III within trial HR 2 year DFS v 5 & 6 year OS WLS R2 = 0.91 Copula R2 = 0.86 WLS R2 = 0.93 Copula R2 = 0.88

Conclusions: DFS as a stage III endpoint DFS yrs OS yrs WLS R2 Copula R2 2 5 0.91 0.86 6 0.93 0.88 3 0.81 0.87 0.79 Concordance high for DFS with both 5 & 6 yr OS DFS at 2 and 3 years very similar Strong association

Forest plot: 2 Yr DFS v 6 Yr OS stage III

How well did previous ACCENT model predict these results? Prior analyses testing only 5-FU-based treatment produced a predictive model to use early DFS to predict later OS Used observed early DFS HRs from the new trials, and the previous model, to predict OS HRs in the 6 new trials

Prediction plot: 2 Yr DFS v 6 Yr OS: stage III Predicted HR

Prediction plot: 2 Yr DFS v 6 Yr OS: stage III Predicted HR Actual HR

Discussion Follow-up beyond 6 years not available at this time All trials used cytotoxic drugs, no biologics If new agents change pattern of cancer recurrence (delay vs prevent), relationship between DFS and OS could change

Validation of previous ACCENT findings? DFS surrogate for OS – Confirmed (with conditions) Concordance higher in stage III vs II - Confirmed 2 yr DFS may be adequate - Confirmed > 6 yrs for OS benefit in new joint stage II/III trials – Requires further confirmation

Conclusions Based on modern adjuvant colon cancer trials In joint stage II & III trials, even 6 yrs follow-up demonstrates only modest association between DFS and OS In stage III patients, trial level DFS & OS association remains strong Association between 2 yr DFS as strong as 3 yr DFS with OS

Conclusion DFS assessed after 2 or 3 years remains an appropriate primary endpoint for stage III adjuvant colon cancer trials

ACCENT 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, L Saltz, J Meyerhardt, N Jackson – CALGB M Buyse – IDDI (Belgium) R Gray, D Kerr – QUASAR A Grothey, S Alberts, B Bot, E Green, Q Shi –Mayo Clinic C Twelves -University of Bradford (UK) J Cassidy – University of Glasgow (UK) F Sirzen – Roche ; L Cisar - Pfizer E Van Cutsem –University Hospital Gasthuisberg (Belgium); A Sobrero - Ospedale San Martino (Italy)