1. Should database studies effect patient management and clinical trial design? Discussion of abstracts #4010 and #4011 Howard S. Hochster, MD Professor of Medicine, NYU School of Medicine Director, GI Program NYU Cancer Institute

2. What kind of database?  Prospective clinical data –SEER data base  Published clinical trial data –Validated and audited –Accurate for trial result reporting  Amalgamated (“pooled”) clinical trial data

3. Why meta-analysis?  Provides greater power than any single trial  Answer subset questions that no individual trial could address  Findings more robust due to real world heterogeneity  Examines the consistency of findings across trials

4. The Magic of Meta-analysis Σ 95% CI Its significant!!

5. Wagner, A. D. et al. J Clin Oncol; 24:2903-2909 2006 Fig 4. Effect of fluorouracil (FU)/cisplatin (P)/anthracycline combinations versus FU/anthracycline combinations (without cisplatin) Gastric Cancer: Meta-analysis of adjuvant chemotherapy trials

6. Pitfalls of meta-analysis  Publication bias –‘Positive’ trials more likely to be published rapidly, in more prominent journals –Will skew results if only these trials included  Prevent bias by –Thorough literature search –Explicit inclusion/ exclusion criteria –Test for bias: funnel plot

7. Meta Analysis vs Pooled Analysis  Meta analysis: A comprehensive systematic review to address a question using all available data  Pooled analysis: Trials are selected for inclusion based on quality, size, relevance –Can re-analyze data set for new and consistent endpoints across studies

8. Specific Examples of Pooled Analyses  Overall treatment effects  Subsets –Benefit of chemotherapy in the elderly –Benefit of chemotherapy by stage/grade/# nodes/sex/site –Benefit of chemotherapy by MSI status  Consistency across endpoints –Disease Free vs Overall Survival

9. Is 2-year DFS a “good” surrogate for OS?

10. CM923700-10 Total: 43 treatment arms; 20,898 pts 3517QUASAR 867GIVIO 905GERCOR718NSABP C02 3547INT 0089773NSABP C01 1078SWOG 9415259FFCD 878N914653359NCIC 915N894651239Siena 2176NSABP C05408N874651 2151NSABP C04926INT 0035 1081NSABP C03247N784852 NTrialN Active ControlNo Treatment Control ACCENT: Trials included Sargent, 2008

11. CM923700-11 Recurrence Rate by 6 mo Intervals Sargent, 2008

12. CM923700-12 Time from Recurrence to Death Sargent, 2008 A problem??

13. Hazard ratios: DFS vs OS OS HR = 0.05 + 0.97 * DFS HR

14. ACCENT update: 6 adjuvant trials added TrialAccrual Period # patientsExperimental treatment arm % stage III MOSAIC1998-012246FOLFOX460 X-ACT1998-011987Capecitabine100 NSABP C-061997-991557Uracil/tegafur53 NSABP C-072000-022434FLOX71 CALGB 898031999-011264IFL100 PETACC-32000-023188FOLFIRI71 Total addition 12,676 patients Median follow-up on living patients 6 years Median survival following recurrence: 20 months

15. Recurrence Rate over Time 83% of recurrences occur within the first 3 years Same as previous analysis

16. Within Trial Hazard Ratios for 2 Year DFS vs 5 & 6 Year OS WLS R 2 = 0.58 Copula R 2 = 0.37 WLS R 2 = 0.76 Copula R 2 = 0.49

17. Forest Plot: 2 Yr DFS v 6 Yr OS Stage III DFS OS

18. Conclusions: DFS as a stage III endpoint Concordance high for DFS with both 5 & 6 yr OS DFS at 2 and 3 years very similar Strong association DFS yrsOS yrsWLS R 2 Copula R 2 250.910.86 260.930.88 350.930.81 360.870.79

19. Good news and bad news:  Good news: patients living longer with advanced CRC –5 yr survival 20%; median > 2 yrs  Bad news: 5-yr survival follow-up no longer sufficient for adjuvant trials –Maybe we need 7-year follow-up (deGramont, 2008)  Good news: 3-yr DFS is predictive for 5-yr OS  Better news: 2-yr DFS just as good as 3-yr DFS for predicting 6-yr OS

20. Do elderly patients (>70 yrs) benefit from newer adjuvant chemotherapy regimens?

21. Issues  Small numbers of elderly patients  Under-represented in clinical trials  Difficult to perform single adjuvant trial for the elderly & questionable use of resources  Prior analyses were well received  Unplanned subset analysis –(but pre-specified by ACCENT group)

22. Questions that might explain these observations in the elderly?  Adequate analysis?  How does it compare with other analyses?  Is there a reason to believe combination therapy affects elderly differentially in the adjuvant therapy as c/w advanced disease?  Function of other effects on survival endpoint? –Should we be looking at disease specific OS?

23. Is this the correct analysis?

24. ACCENT update: 6 trials added TrialAccrual Period # pts% pts ≥70yrs Experimental treatment arm † % stage III ‡ MOSAIC1998-01224614FOLFOX460 X-ACT1998-01198320Capecitabine100 NSABP C-061997-99155723Uracil/tegafur53 NSABP C-072000-02243416FLOX71 CALGB 898031999-01126324IFL98 PETACC-32000-02318613FOLFIRI71 † Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and leucovorin (LV) ‡ Remaining patients were stage II or unknown

25. Forest Plots of Hazard Ratios Disease-Free Survival

26. Forest Plots of Hazard Ratios Overall Survival

27. Efficacy – oxaliplatin-based therapy * Values < 1 favor experimental arm Age Endpoint HR (95% CI) Experimental v Control IV 5-FU/LV Deaths within 6 mo Exp v Control % (p-value) DFS * OS * TTR * <70 n = 3,977 0.77 (0.68,0.86) 0.81 (0.71,0.93) 0.76 (0.67,0.86) 0.81 v 0.81 (p=1.0) ≥ 70 n = 703 1.04 (0.80,1.35) 1.19 (0.90,1.57) 0.92 (0.69,1.23) 2.57 v 1.37 (p=0.25) Interaction of age by treatment p-value 0.0160.0370.21

28. How do these data compare with other data on elderly and combination chemotherapy for CRC? Is there a reason to expect a differential benefit on older patients receiving adjuvant therapy compared with advanced disease?

29. Prior age-related analysis Metastatic setting Folprecht JCO 2008 - N=2,692 (22%  70 yrs) 4 trials of irinotecan-based therapy Improved PFS, trend to improved OS for elderly w/addition of irinotecan Goldberg JCO 2006 - N=3,742 (16%  70 yrs) 4 trials of oxaliplatin-based therapy Similar survival benefit and toxicity in age subgroups Adjuvant setting Sargent NEJM 2001 – N=3351 (15%  70 yrs) 7 trials of 5-FU + levamisole/leucovorin v surgery No significant interaction observed between age and efficacy of treatment

30. 30 Studies Included 1 Andre et al, NEJM 2004; 2 Goldberg et al, JCO 2004; 3 de Gramont et al, JCO 2000; 4 Rothenberg et al, JCO 2003 Sargent, et. al, Proc ASCO 2006

31. 31 Treatment Benefit Consistent across age groups Consistent across age groups P/DFS: Same hazard ratio P/DFS: Same hazard ratio <70 year olds: HR = 0.7 <70 year olds: HR = 0.7 > 70 year olds HR = 0.65 (p=0.42) > 70 year olds HR = 0.65 (p=0.42) Advanced disease trials Advanced disease trials Response rate: Same odds ratio for response in young vs. old (p=0.38) Response rate: Same odds ratio for response in young vs. old (p=0.38) OS: Same hazard ratio (young HR= 0.77) vs. old HR = 0.82) (p=0.79) OS: Same hazard ratio (young HR= 0.77) vs. old HR = 0.82) (p=0.79) Consistent across age groups Consistent across age groups P/DFS: Same hazard ratio P/DFS: Same hazard ratio <70 year olds: HR = 0.7 <70 year olds: HR = 0.7 > 70 year olds HR = 0.65 (p=0.42) > 70 year olds HR = 0.65 (p=0.42) Advanced disease trials Advanced disease trials Response rate: Same odds ratio for response in young vs. old (p=0.38) Response rate: Same odds ratio for response in young vs. old (p=0.38) OS: Same hazard ratio (young HR= 0.77) vs. old HR = 0.82) (p=0.79) OS: Same hazard ratio (young HR= 0.77) vs. old HR = 0.82) (p=0.79) Sargent, et. al, Proc ASCO 2006

32. 32 Age < 70Age > 70 DFS - Adjuvant Sargent, et. al, Proc ASCO 2006

33. 33 Age < 70Age > 70 PFS - First Line de Gramont, Goldberg Studies Sargent, et. al, Proc ASCO 2006

34. 34 Age < 70Age > 70 OS - First line de Gramont, Goldberg Studies Sargent, et. al, Proc ASCO 2006

35. A dilemma?  How to integrate into patient management?  Only “best” elderly are entered in trials  Previously benefit was shown –Adjuvant and advanced disease with both FU/LV FOLFOX  Final analysis of MOSAIC trial shows small survival differences –Stage III vs. Combined Stage II/III  But these two studies seem to suggest a lack of benefit –Adequate power given a 2 study meta-analysis?

36. Is there chemo “after 70”?  Elderly benefit from adjuvant and advanced disease FU/LV (and advanced disease FOLFOX) –Possible differential effects with combination therapy –Possible survival influences of intercurrent disease  Toxicities and drug administration may differ in the elderly as new agents are introduced –Especially biologics  However, this meta-analysis is based on 2-trial analysis –MOSAIC and NSABP C-06  This observation can inform trial design (especially with newer metrics) –but for individual management?  More data are needed: Addition of C-08 and AVANT data may give us a better analysis of elderly patients and adjuvant oxaliplatin

37. 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 D Sargent, 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) OUR THANKS!