1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. Past FDA Approvals in Colorectal Cancer Amna Ibrahim M.D DODP, FDA

3. Outline of Presentation Drugs approved for colon cancer (adjuvant, first-line and second-line therapy) Studies supporting drug approval Drugs discussed at ODAC without subsequent drug approval Endpoints supporting approval

4. Agents Approved AdjuvantFirst-LineRecurrent -Levamisole (with 5FU) 1990 -Leucovorin (with 5FU) 1991 -Irinotecan 1996,1998 -Irinotecan (with 5FU/LV) 2000 -Oxaliplatin (with 5FU/LV) 2002 -Capecitabine 2001

5. Historical Endpoints for Approved Agents OS TTP & RR Superiority Noninferiority

6. Agents for Adjuvant Therapy

7. Levamisole (Adjuvant Rx) ArmsNFollow up (Yrs) Reduction in Recurrence % Reduction in Death % Study 1 Duke C Subset 5FU+lev26253627 lev28 Observe Study 25FU+lev92924133 lev26 Observe

8. Agents for First-line Therapy

9. 5FU+leucovorin (First-line Rx) StudyArmsNRR % TTP mo OS mo P (one-sided) 15FU70102.97.7 5FU+LV(HD)69266.712.20.04 5FU+LV(LD)73446.7120.05 2 (Study 1 ext) 5FU+LV(HD)1493112.70.04 5FU+LV(LD)1534212.70.01 5FU+MTX+LV155148.4

10. Irinotecan (First-line Rx) StudyArmsNRRTTPOSP (one-sided) 1CPT 11 wkly x 4 (q 6 wks) 226184.212 CPT11 + 5FU/LV wkly x 4 (q 6 wks) 23139714.8<0.05 5FU/LV qd x 5 (q 6 wks) 226214.312.6 2CPT11 + inf 5FU/LV 198356.717.4<0.05 5FU/LV187224.414.1

11. Capecitabine (First-line Rx) StudyArmsNRR (%) TTP (mo.) OS (mo.) Hazard ratio 1Cap302214.312.71.00 0.84 – 1.18 5FU/LV303114.413.6 2Cap301214.613.50.92 0.78 – 1.09 5FU/LV301144.412.3

12. Agents for Recurrent Cancer

13. Irinotecan (Recurrent) (accelerated approval) StudyArmsNRR (%) TTP (mo.) OS (mo.) Med Resp Duration 1Wkly CPT 1148216.410.45.8 mo. (2.6-15.2) 2Wkly CPT 1190135.98.1 3Wkly CPT 11 125 mg/m 2 64145.610.7 Wkly CPT 11 100 mg/m 2 10296.49.3

14. Irinotecan (Recurrent) (full reg. approval) StudyArmsNOS (mo.) p 1CPT 111899.20.0001 Best Supportive Care 906.5 2CPT 1112710.80.035 5FU-based regimens 1298.5

15. Oxaliplatin (Recurrent) (accelerated approval) StudyArmsNRR (%) TTP (mo. with 95% CI) P for RR 1Oxaliplatin + 5FU/LV (FOLFOX4) 15294.6 (4.2 – 6.1) 0.0002 5FU + LV15102.7 (1.8-3.0) Oxaliplatin15611.6 (1.4-2.7)

16. NDAs Discussed at ODAC but not Approved Issues at ODAC UFT - contribution of uracil to UFT -analysis and interpretation of non-inferiority Oxaliplatin (2000) -trials designed for RR & PFS did not demonstrate OS improvement

17. Basis of Approval Adjuvant Therapy (1 full approval) Superiority in Survival (1) First-line Therapy (3 full approvals) Superiority in Survival (2) Non-inferiority in Survival (1) Therapy for Recurrent Disease (2 AA; 1 full approval) Survival (1 full for CPT-11) RR and/or TTP (1 AA for oxal, 1 for CPT-11)

19. Oxaliplatin for first-line therapy (2000)