Adjuvant Therapy of Colon Cancer: Where are we now ?

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. Why do we give adjuvant treatment? • “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. Survival: Second Line IrinotecanCunningham et al. Lancet 352:1413, 1998. 1.0 0.9 0.8 0.7 0.6 CPT-11 0.5 Probability 0.4 BSC 0.3 0.2 0.1 p=0.0001* 0 0 3 6 9 12 15 18 21 Months *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) Censored p=0.03* * 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 N=216 Infusion N=217 RR 14 % 33 % p=.0004 PFS 22 wks 28 wks p=.0012 Gr3/4 tox 24% 11% p=.0004 Survival 57 wks 62 wks p=.067 Bolus vs Biweekly Infusional 5FU/LVin Metastatic CRCDe Gramont et al. JCO Feb 1 1997: 808-815

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

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

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

15. MOSAIC: Stage II + IIIDisease-free Survival 1.0 0.9 0.8 0.7 0.6 Events FOLFOX4 279/1123 (24.8%) LV5FU2 345/1123 (30.7%) HR [95% CI]: 0.77 [0.65–0.90] 0.5 DFS probability 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Months 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 DFS probability FOLFOX4 – Stage II LV5FU2 – Stage II FOLFOX4 – Stage III LV5FU2 – Stage III 0.4 0.3 HR [95% CI]: 0.82 [0.60–1.13] Stage II 0.75 [0.62–0.89] Stage III 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Months Data cut-off: January 16, 2005

17. Disease-free Survival in Stage III Patients: N1 & N2 1.0 0.9 0.8 7.2% 0.7 0.6 11.5% 0.5 DFS probability 0.4 FOLFOX4 – N1 LV5FU2 – N1 FOLFOX4 – N2 LV5FU2 – N2 HR: 0.76 0.3 0.2 HR: 0.72 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Months Data cut-off: January 16, 2005

18. NSABP C-07 FU B Rest 500 LV 500 2hr x3 R FU 500 Rest LV 500 OHP 85 2hr Week 1 2 3 4 5 6 7 8

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

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 #pts RR* mFOLFOX6 41 47% bFOL 39 32%(p=.049) TREE-2 mFOLFOX6/bev 71 62% bFOL/bev 70 43% (p=.029) *Responses unconfirmed H Hochster: Presented at GI symposium Jan 05

23. Cross-Study ComparisonEfficacy

24. Cross-Study ComparisonToxicity

25. Planned Oxaliplatin Usage

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. MOSAIC: Overall Survival 1.0 0.9 0.8 0.7 0.6 FOLFOX4 LV5FU2 HR [95% CI]: 0.91 [0.75–1.11] 0.5 OS probability 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Months Data cut-off: January 16, 2005

31. Phase III Stage III Adjuvant Intergroup N0147 Accrual ~ 250 R A N D O M I Z A T I O N FOLFOX FOLFOX/ FOLFIRI FOLFIRI

32. Phase III Stage III Adjuvant N0147 R A N D O M I Z A T I O N FOLFOX FOLFOX/ FOLFIRI +/- Cetuximab FOLFIRI

33. Phase III Stage III Adjuvant (N0147)Possible Modification: R A N D O M I Z A T I O N FOLFOX FOLFOX + Cetuximab

34. NSABP C-08Phase III Trial, Stage II and IIIColon Cancer R A N D O M I Z A T I O N FOLFOX FOLFOX + Bev

35. NSABP C-08Phase III Trial, Stage II and IIIColon Cancer R A N D O M I Z A T I O N FOLFOX FOLFOX + Bev 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 • Leucovorin 500 mg/m2 $ 47 • Xeloda 2000 mg/m2/d $ 1065 • Camptosar 180 mg/m2 $ 2135 • Eloxatin 85 mg/m2 $ 3296 • Avastin 5 mg/kg $ 2283 • Erbitux 250 mg/m2 $ 4964

37. 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 Adjuvant Therapy of Colon CancerEstimated Cost Per Patient (ASP + 6%)

38. 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 Estimated Cost Per Year if 55,000 Patients Treated (ASP + 6%)

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.