All GERCOR presentations will be available at canceronet/

1. Duration of Disease Control (DDC)or Time to Failure of Strategy (TFS)to evaluate a chemotherapy strategyin advanced colorectal cancer (ACC). 1,2B Chibaudel, 1,4C Tournigand, 1N Perez-Staub, 1O Bourges, 1F Maindrault-Goebel, 3,4T André, 5G Lledo, 1,4C Louvet, 6F Bonnetain, 1,4A de Gramont (1) Hôpital Saint-Antoine, APHP, université Paris VI, Paris, France (2) GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie, Paris, France (3)Hôpital La Pitié-Salpétrière, APHP, université Paris VI, Paris, France (4) INSERM U8106 (5) Clinique Jean Mermoz, Lyon, France (6) Unité de biostatistique et de méthodologie FFCD, INSERM U866, Dijon, France All GERCOR presentations will be available at http://www.canceronet.com/

2. Introduction • Therapeutic strategies are needed when several regimens, surgery, maintenance or chemotherapy-free intervals are available: fixed sequence of two therapies (1), stop & go or alternated therapies (2,3) • PFS is not an optimal endpoint to evaluate therapeutic strategies (4): Treatment effect on OS, based on the effect on PFS, ispredicted extremely well when patients receive no effectivesecond line therapy, but not in patients receiving subsequent lines of treatment → PFS offers the direct measure of a single treatment course • Composite endpoints have been proposed to evaluate efficacy of these strategies: • Duration of Disease Control (DDC): previously used as first endpoint in several randomized studies (2,3) • Time to Failure of Strategy (TFS) (5) • Our goal was to compare these two composite endpoints and evaluate if they could be potential surrogate endpoints for OS (1) Tournigand et al, JCO 2004 (2) Tournigand et al, JCO 2006 (3) Maindrault et al, ASCO 2007 (4) Buyse et al, JCO 2007 (5) Allegra et al, JCO 2007

3. Methods Progression • Trials : Pooled analysis of individual patient data from 3 randomized studies evaluating therapeutic strategies • Groups : The OPTIMOX 1 study was divided in 3 groups according to the number of inclusions per centre, to finally obtain groups of about one hundred patients, like the arms of the other studies • All endpoints were calculated using the Kaplan-Meier method • Effect of treatment on PFS, DDC, TFS and OS was quantified through hazard ratios (HRs) • Coefficient correlation was estimated through a linear regression model

4. Definitions (1) DDC TFS • Cessation of therapy as a result of toxicity is not considered as an endpoint • Agent not included in the original strategy ; endpoint measured at the first of either PD or initiation of new agent

5. 10 Must-have items 1 2 3 4 5 6 7 8 9 10

6. General Definitions (2) Progression Progression Treatment course 1 Treatment course 2 New Agent Uncontrolled disease PFScourse2 PFScourse1 Interval TFS = PFScourse1 + Interval + PFScourse2 DDC = PFScourse1 + PFScourse2

7. Endpoints & Censoring Rules1. End of study with no PD Censored subjects : 0 Event : 1 PD during interval No PD No PD 0 DDC = PFScourse1 + PFScourse2 Course 1 Course 2 0 TFS = PFScourse1 + Interval + PFScourse2 DDC / TFS PD during interval No PD No PD 0 DDC = PFScourse1 + PFScourse2 Course1 Course2 >1month 1 TFS = PFScourse1 DDC TFS No PD No PD 0 DDC = PFScourse1 Course 1 0 TFS = PFScourse1 DDC / TFS

8. Endpoints & Censoring Rules2. End of study with PD Censored subjects : 0 Event : 1 PD during interval PD at first evaluation No PD 1 DDC = PFScourse1 Course 1 Course 2 1 TFS = PFScourse1 + Interval + PFScourse2 DDC TFS PD during interval PD at first evaluation No PD 1 DDC = PFScourse1 Course1 Course2 >1month 1 TFS = PFScourse1 DDC / TFS

9. Results • N = 1042 patients • Median potential follow-up : 39.8 months • Median age : 64 years [29-80] Patients Characteristics (%)

10. Correlation between PFSand Overall Survival (OS) Correlation between median PFS and median OS Correlation between Log HR PFS and Log HR OS PFS is not an optimal endpoint to evaluate therapeutic strategies

11. Survivals

12. DDCvs. TFS OPTIMOX 1 study OPTIMOX 2 study C97-3 study % % % % % %

13. Distribution 59.5% 39% 1.5%

14. Advantages & Drawbacks • Exclusion of uncontrolled disease interval • Exclusion of inactive second course → direct measure of treatment effect • Statistically significant correlation between median DDC and OS • Median DDC shorter than median TFS → smaller sample size • Based on pragmatic approach • Uncontrolled disease interval included • Active treatment delayed ≥1 month after minimal PD not included • Extension of duration in case of no evaluation between the end of treatment and the following line DDC TFS

15. Correlation between median endpointsand median Overall Survival (OS) TFS DDC

16. Correlation between Log Hazard Ratios Endpointsand Log Hazard Ratio Overall Survival (OS)(logarithmic scale is used for both axes) TFS DDC

17. Conclusions • PFS is not an optimal endpoint when patients can receive several lines ot treatment • DDC and TFS achieve roughly the same results in the studies reviewed here. • However, DDC could capture better the effect of a treatment in a stop and go strategy or a multiline strategy. It is adaptable to every strategies, requires a marginaly smaller sample size and in some cases will require less time to reach the endpoint • Validation of these composite endpoints as surrogate for OS will require other statistical tests like the surrogate threshold effect