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.

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Presentation transcript:

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 It was current when produced, but is no longer maintained and may be outdated.

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

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

Agents Approved AdjuvantFirst-LineRecurrent -Levamisole (with 5FU) Leucovorin (with 5FU) Irinotecan 1996,1998 -Irinotecan (with 5FU/LV) Oxaliplatin (with 5FU/LV) Capecitabine 2001

Historical Endpoints for Approved Agents OS TTP & RR Superiority Noninferiority

Agents for Adjuvant Therapy

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

Agents for First-line Therapy

5FU+leucovorin (First-line Rx) StudyArmsNRR % TTP mo OS mo P (one-sided) 15FU FU+LV(HD) FU+LV(LD) (Study 1 ext) 5FU+LV(HD) FU+LV(LD) FU+MTX+LV

Irinotecan (First-line Rx) StudyArmsNRRTTPOSP (one-sided) 1CPT 11 wkly x 4 (q 6 wks) CPT11 + 5FU/LV wkly x 4 (q 6 wks) <0.05 5FU/LV qd x 5 (q 6 wks) CPT11 + inf 5FU/LV <0.05 5FU/LV

Capecitabine (First-line Rx) StudyArmsNRR (%) TTP (mo.) OS (mo.) Hazard ratio 1Cap – FU/LV Cap – FU/LV

Agents for Recurrent Cancer

Irinotecan (Recurrent) (accelerated approval) StudyArmsNRR (%) TTP (mo.) OS (mo.) Med Resp Duration 1Wkly CPT mo. ( ) 2Wkly CPT Wkly CPT mg/m Wkly CPT mg/m

Irinotecan (Recurrent) (full reg. approval) StudyArmsNOS (mo.) p 1CPT Best Supportive Care CPT FU-based regimens

Oxaliplatin (Recurrent) (accelerated approval) StudyArmsNRR (%) TTP (mo. with 95% CI) P for RR 1Oxaliplatin + 5FU/LV (FOLFOX4) (4.2 – 6.1) FU + LV ( ) Oxaliplatin ( )

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

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)

Oxaliplatin for first-line therapy (2000)