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 It was current when produced, but is no longer maintained and may be outdated.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. ASCO/FDA Public Workshop on Clinical Trials Endpoints in Colorectal Cancer Rectal Cancer Endpoints November 12, 2003 Rectal Cancer Endpoints November 12, 2003

3. Evolution of Adjuvant Treatment Stage II/III Rectal Cancer (T3/T4, N+) Stage II/III Rectal Cancer (T3/T4, N+) Surgical Treatment Surgical Treatment + Radiation Therapy or Chemotherapy + Radiation Therapy or Chemotherapy + Post-operative Chemoradiation Therapy + Post-operative Chemoradiation Therapy + Neoadjuvant Chemoradiation Therapy and Post-operative Chemotherapy + Neoadjuvant Chemoradiation Therapy and Post-operative Chemotherapy Stage II/III Rectal Cancer (T3/T4, N+) Stage II/III Rectal Cancer (T3/T4, N+) Surgical Treatment Surgical Treatment + Radiation Therapy or Chemotherapy + Radiation Therapy or Chemotherapy + Post-operative Chemoradiation Therapy + Post-operative Chemoradiation Therapy + Neoadjuvant Chemoradiation Therapy and Post-operative Chemotherapy + Neoadjuvant Chemoradiation Therapy and Post-operative Chemotherapy

4. Proposed Rectal Cancer Endpoints Local Control Local Control Sphincter-Sparing Surgery Sphincter-Sparing Surgery Pathologic Complete Response Pathologic Complete Response Local Control Local Control Sphincter-Sparing Surgery Sphincter-Sparing Surgery Pathologic Complete Response Pathologic Complete Response

5. Local-Regional Failure “In contrast to colon cancer, there is a significant risk of local-regional failure as the only or 1 st site of recurrence in patients with curative resected rectal cancer.” Stage I 5% to 10% Stage I 5% to 10% Stage IIup to 25% to 30% Stage IIup to 25% to 30% Stage IIIup to 50% or higher Stage IIIup to 50% or higher “In contrast to colon cancer, there is a significant risk of local-regional failure as the only or 1 st site of recurrence in patients with curative resected rectal cancer.” Stage I 5% to 10% Stage I 5% to 10% Stage IIup to 25% to 30% Stage IIup to 25% to 30% Stage IIIup to 50% or higher Stage IIIup to 50% or higher NIH Consensus Conference on Adjuvant Therapy for Patients with Colon and Rectal Cancer, JAMA, Sept. 19, 1990

6. Local-Regional Failure Characteristics Main prognostic determinant is Stage Main prognostic determinant is Stage Local-Regional failure associated with significant morbidity Local-Regional failure associated with significant morbidity Major mode of failure (+/- distant metastases) Major mode of failure (+/- distant metastases) Most failures within 2-3 yrs and rare after 5 yrs (+/- distant metastases) Most failures within 2-3 yrs and rare after 5 yrs (+/- distant metastases) Successful salvage is rare Successful salvage is rare Main prognostic determinant is Stage Main prognostic determinant is Stage Local-Regional failure associated with significant morbidity Local-Regional failure associated with significant morbidity Major mode of failure (+/- distant metastases) Major mode of failure (+/- distant metastases) Most failures within 2-3 yrs and rare after 5 yrs (+/- distant metastases) Most failures within 2-3 yrs and rare after 5 yrs (+/- distant metastases) Successful salvage is rare Successful salvage is rare

7. Post-Op ChemoRT vs Surgery K. Hu and L. Harrison – Semin Surg Oncol 19:336-349, 2000 Trial Treatment Arms LFDMOS GITSG71751975-80 202 pts Surgery Alone RT (40-48 Gy) Chemo (MeCCNU/5FU) Chemo + RT 24%20%27%11%34%30%27%26%45%52%52%67% (5-yr DFS significant) NSABPR011977-86 555 pts Surgery Alone Chemo (MOF) RT (46-47 Gy) 25%22%26%26%24%31%43%53%41%(Males: 5-yr OS significant)

8. Post-Op ChemoRT vs Single Modality K. Hu and L. Harrison – Semin Surg Oncol 19:336-349, 2000 Trial Treatment Arms LFDMOS NSABPR021987-92 694 pts Chemo (MOF or 5FU/LV) Chemo + RT (50.4 Gy) 13%8%(p=.02)NS (DFS &OS) MayoNCCTG1980-1986 204 pts RT (45-50 Gy) RT + Chemo ( MeCCNU/Bolus 5FU) 25%14% 46%29% 46%53% (5-yr Act p=.025)

9. Short-Term Pre-Op Radiotherapy vs Surgery Alone Local Recurrence OS p- value Swedish Rectal Cancer Trial 1987-1990 - NEJM 1997 1,168 pts - Dukes A, B, and C Short Course RT + Surgery vs Surgery Alone 11%27% (5-yr FU) 58%48%(5-yr)LRp<.001OSp<.001 Dutch CRC Group Trial 1996-2000 - NEJM 2001 1,861 pts - Dukes A, B, and C Short Course RT + TME Surgery vs TME Surgery Alone 2.4%8.2%(2-yr)82%82%(2-yr)LRp<.001OSNS

10. Pre-Op vs Post-Op Chemoradiation NSABP R-03 – Low Accrual NSABP R-03 – Low Accrual Treatment-related toxicity similar Treatment-related toxicity similar Sphincter-saving surgery Sphincter-saving surgery Pre-op Group (plan 31% to 50%) Pre-op Group (plan 31% to 50%) Post-op Group (plan 33% vs 33% actual) Post-op Group (plan 33% vs 33% actual) INT-0147 – Low Accrual INT-0147 – Low Accrual German Trial – CAO/ARO/AIO-94 German Trial – CAO/ARO/AIO-94 Results presented ASTRO – Oct. 2003 Results presented ASTRO – Oct. 2003 NSABP R-03 – Low Accrual NSABP R-03 – Low Accrual Treatment-related toxicity similar Treatment-related toxicity similar Sphincter-saving surgery Sphincter-saving surgery Pre-op Group (plan 31% to 50%) Pre-op Group (plan 31% to 50%) Post-op Group (plan 33% vs 33% actual) Post-op Group (plan 33% vs 33% actual) INT-0147 – Low Accrual INT-0147 – Low Accrual German Trial – CAO/ARO/AIO-94 German Trial – CAO/ARO/AIO-94 Results presented ASTRO – Oct. 2003 Results presented ASTRO – Oct. 2003

11. German Trial – CAO/ARO/AIO-94 800+ pts – T3/T4, N+ rectal cancer(CI 5-FU + 50.4 Gy) Pre-OpPost-Opp-value 5-yr Local Recurrence 6%12%p=.02 5-yr Distant Relapse 35%39%p=.52 5-yr DFS 59%55%p=.23 5 –yr Overall Survival 78%73%p=.38 Acute Grade 3/4 Tox 30%30%NS Anastomotic Stenosis 2.7%8.5%p=.001 Sphincter preserved (188 – low lying tumors) 39% (pCR 8%) 19%p=.004 U Penn Oncolink Report on Plenary Session Presentation – ASTRO 45 th Annual Meeting – Oct. 2003 - R. Sauer et al – German Rectal Cancer Group

12. Pathologic Complete Response Mix of Retrospective Series, Prospective Series, and Phase 2 Studies Mix of Retrospective Series, Prospective Series, and Phase 2 Studies Small Studies Small Studies Dependent on pathologic review/QA Dependent on pathologic review/QA Different ChemoRT regimens Different ChemoRT regimens Different Stages (usually T3, N+) Different Stages (usually T3, N+) Range pCR 9% - 24% Range pCR 9% - 24% pCR associated with trends in decreased LR, increased sphincter-preserving surgery pCR associated with trends in decreased LR, increased sphincter-preserving surgery Mix of Retrospective Series, Prospective Series, and Phase 2 Studies Mix of Retrospective Series, Prospective Series, and Phase 2 Studies Small Studies Small Studies Dependent on pathologic review/QA Dependent on pathologic review/QA Different ChemoRT regimens Different ChemoRT regimens Different Stages (usually T3, N+) Different Stages (usually T3, N+) Range pCR 9% - 24% Range pCR 9% - 24% pCR associated with trends in decreased LR, increased sphincter-preserving surgery pCR associated with trends in decreased LR, increased sphincter-preserving surgery

13. Pathologic Assessment: # Lymph Nodes & Outcome Nodal Status # Nodes Analyzed # Pts 5-Yr Relapse- Free Survival 5-Yr Survival Rate Node Negative Pts  0 and < 5  5 and < 9  9 and < 14  14 12713812913337%34%26%19%68%73%72%82% Node Positive Pts  0 and < 6  6 and < 10  10 and < 15  15 27030626429741%49%47%46%61%58%57%61% J. Tepper et al, J Clin Oncol 19:157-163, 2001 Pathology Reports with Information on Circumferential Margin Status <10% in this study US GI Intergroup Adj. Trial INT-0114 (1,664 pts, pT3,T4 or Node+ Rectal Cancer)

14. Future US Phase III Trials: Rectal Cancer NSABP R-04 Pre-Op ChemoRT Activation 2004 5-FU Capecitabine E3201 Post-Op ChemoRT Activated 10/2003 5-FU/LV CPT-11/5-FU/LVOxaliplatin/5-FU/LV NSABP R-04 Pre-Op ChemoRT Activation 2004 5-FU Capecitabine E3201 Post-Op ChemoRT Activated 10/2003 5-FU/LV CPT-11/5-FU/LVOxaliplatin/5-FU/LV

15. DISCUSSION

16. Rectal Cancer Endpoints Neoadjuvant Therapy-Stage II/III Rectal Cancer Proposed Endpoint AdvantagesDisadvantages Local Control Sphincter Preservation Pathologic Complete Response