1. Adjuvant Therapy of Colon Cancer: Where are we now ? Leonard Saltz, MD Memorial Sloan Kettering Cancer Center New York, NY

2. Why do we give adjuvant treatment?

3. “Because its there.”

4. The Drug Development Paradigm Identify a new active agent in refractory disease. Combine that active agent with standard agent(s) in refractory disease. Take new active combination to front line phase III metastatic trial. Move new front line metastatic therapy into adjuvant trials to try to increase the cure rate. But…..

5. Maybe this paradigm is wrong.

6. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 036912151821 Months Probability Survival: Second Line Irinotecan Cunningham et al. Lancet 352:1413, 1998. p=0.0001* CPT-11 BSC *log-rank test

7. Phase III Irinotecan/5FU/LV in Metastatic Colorectal Cancer (from Saltz et al,NEJM, 2000)

8. Infusional 5FU/LV +/- Irinotecan Overall Survival (Douillard et al) p=0.03* Censored * log-rank test

9. C89803: IFL vs. FL (Stage III) Failure-Free Survival by Arm

10. C89803: IFL vs. FL (Stage III) Overall Survival by Arm

11. Bolus vs Biweekly Infusional 5FU/LV in Metastatic CRC De Gramont et al. JCO Feb 1 1997: 808-815 p=.067 62 wks 57 wksSurvival p=.0004 11% 24%Gr3/4 tox p=.0012 28 wks 22 wksPFS p=.0004 33 % 14 %RR Infusion N=217 Bolus N=216

12. FNCLCC ACCORD-02/FFCD 9802, ASCO 2005 3-year DFS: 60% vs. 51%

13. FNCLCC ACCORD-02/FFCD 9802, ASCO 2005 3-year DFS: 59% vs. 53%

14. Phase III Oxaliplatin/5FU/LV in Metastatic Colorectal Cancer (from DeGramont. J Clin Oncol 18:2938, 2000)

15. MOSAIC: Stage II + III Disease-free Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0666121824303642485460 Months Events FOLFOX4 279/1123 (24.8%) LV5FU2 345/1123 (30.7%) HR [95% CI]: 0.77 [0.65 – 0.90] DFS probability Data cut-off: January 16, 2005

16. MOSAIC: Disease-free Survival Stage II and Stage III Patients 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0 FOLFOX4 – Stage II LV5FU2 – Stage II FOLFOX4 – Stage III LV5FU2 – Stage III HR [95% CI]: 0.82 [0.60 – 1.13] Stage II 0.75 [0.62 – 0.89] Stage III Months DFS probability 666121824303642485460 Data cut-off: January 16, 2005

17. Disease-free Survival in Stage III Patients: N1 & N2 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0 FOLFOX4 – N1 LV5FU2 – N1 FOLFOX4 – N2 LV5FU2 – N2 Months DFS probability 666121824303642485460 Data cut-off: January 16, 2005 7.2% 11.5% HR: 0.76 HR: 0.72

18. FUB Rest LV500 FU500 Rest LV500 OHP 852hr 500 Week 1 2 3 4 5 6 7 8 R NSABP C-07 2hr x3

19. Ev # 3yr DFS FLOX 272 76.5% FULV 332 71.6% p < 0.004 HR: 0.79 [0.67 – 0.93] 21 % risk reduction NSABP C-07 Trial (FLOX vs. FULV) 3 year Disease-Free Survival

20. Possible Conclusions Maybe our drug development paradigm is wrong? Corollary: How tumor cells survive therapy in the adjuvant (minimal disease) setting may differ from how they survive in the bulky metastatic setting. Therefore: what works in the metastatic setting may not work in the adjuvant setting and vice versa.

21. Does FLOX = FOLFOX ??

22. Oxaliplatin + Bolus vs. Infusion 5FU in Metastatic CRC: The TREE Studies TREE-1 #ptsRR* mFOLFOX6 4147% bFOL 3932% (p=.049) TREE-2 mFOLFOX6/bev 7162% bFOL/bev 7043% (p=.029) *Responses unconfirmed H Hochster: Presented at GI symposium Jan 05

23. Cross-Study Comparison Efficacy FOLFOX 4 (MOSAIC) FLOX (C-07) 3 Year DFS78 %77 % % improvement over 5FU/LV 5 % Hazard Ratio0.770.79

24. Cross-Study Comparison Toxicity FOLFOX 4 (MOSAIC) FLOX (C-07) Gr 3-4 Neutropenia 41% (2% neut. fever) 4% Gr 3-4 Diarrhea 11%38% All Cause Mortality 0.5%1%

25. Planned Oxaliplatin Usage FOLFOX 4 (MOSAIC) FLOX (C-07) # office visits for treatment 24 (12 for mFOLFOX 6) 18 # oxali doses129 Oxali cost (ASP+6%) 1.8 m2 $39,552$29,664

26. Do we need 12 doses of oxaliplatin when using FOLFOX? 9 ?? 6 ??

27. Do we need 500 mg/m2 of LV?

28. QUASAR TRIAL

29. Is Disease Free Survival the true Endpoint?

30. FOLFOX4 LV5FU2 HR [95% CI]: 0.91 [0.75 – 1.11] MOSAIC: Overall Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0 666121824303642485460 Months OS probability Data cut-off: January 16, 2005

31. RANDOMIZATIONRANDOMIZATION FOLFIRI FOLFOX FOLFOX/ FOLFIRI Phase III Stage III Adjuvant Intergroup N0147 Accrual ~ 250

32. RANDOMIZATIONRANDOMIZATION FOLFIRI FOLFOX FOLFOX/ FOLFIRI Phase III Stage III Adjuvant N0147 +/- Cetuximab

33. RANDOMIZATIONRANDOMIZATION FOLFOX + Cetuximab FOLFOX + Cetuximab FOLFOX Phase III Stage III Adjuvant (N0147) Possible Modification:

34. RANDOMIZATIONRANDOMIZATION FOLFOX + Bev FOLFOX + Bev FOLFOX NSABP C-08 Phase III Trial, Stage II and III Colon Cancer

35. RANDOMIZATIONRANDOMIZATION FOLFOX + Bev FOLFOX + Bev FOLFOX NSABP C-08 Phase III Trial, Stage II and III Colon Cancer 6 months bev alone →

36. Average Selling Price (ASP) + 6% (Patient assumption: 75 kg, 1.8 m2 patient, two weeks Rx) 5FU 500 mg/m2 $ 7 Leucovorin500 mg/m2 $ 47 Xeloda 2000 mg/m2/d $ 1065 Camptosar180 mg/m2 $ 2135 Eloxatin 85 mg/m2 $ 3296 Avastin 5 mg/kg $ 2283 Erbitux 250 mg/m2 $ 4964

37. Adjuvant Therapy of Colon Cancer Estimated Cost Per Patient (ASP + 6%) 5FU/LV (HD) 5FU/LV (LD) FLOX FOLFOX FOLFOX/cetuximab FOLFOX/bev 6 m FOLFOX/bev 12 m $954 $162 $30,618 $40,506 $100,074 $67,902 $95,298

38. Estimated Cost Per Year if 55,000 Patients Treated (ASP + 6%) 5FU/LV (HD) 5FU/LV (LD) FLOX FOLFOX FOLFOX/cetuximab FOLFOX/Bev 6 m FOLFOX/Bev 12 m $55,000,000 $9,000,000 $1,680,000,000 $2,230,000,000 $5,500,000,000 $3,730,000,000 $5,240,000,000

39. Challenges Evaluate duration of therapy questions Select therapies rationally –Molecular markers –Genetics Assure availability of appropriate therapies to all patients

40. Conclusions Until we do the trial, we don’t know the answer. Negative trials are as helpful and informative as positive trials.

41. Conclusions Adjuvant treatment options for colon cancer patients are better than they were, but not as good as they need to be. Please offer clinical trials to your patients. Without your help and theirs, we can’t make the progress that we so desperately need.