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ASCO/FDA Public Workshop on Clinical Trials Endpoints in Colorectal Cancer Rectal Cancer Endpoints November 12, 2003 Rectal Cancer Endpoints November 12, 2003

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

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

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

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

Post-Op ChemoRT vs Surgery K. Hu and L. Harrison – Semin Surg Oncol 19: , 2000 Trial Treatment Arms LFDMOS GITSG 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) NSABPR pts Surgery Alone Chemo (MOF) RT (46-47 Gy) 25%22%26%26%24%31%43%53%41%(Males: 5-yr OS significant)

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

Short-Term Pre-Op Radiotherapy vs Surgery Alone Local Recurrence OS p- value Swedish Rectal Cancer Trial NEJM ,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 NEJM ,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

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 Results presented ASTRO – Oct 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 Results presented ASTRO – Oct. 2003

German Trial – CAO/ARO/AIO pts – T3/T4, N+ rectal cancer(CI 5-FU 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 R. Sauer et al – German Rectal Cancer Group

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

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  %34%26%19%68%73%72%82% Node Positive Pts  0 and < 6  6 and < 10  10 and < 15  %49%47%46%61%58%57%61% J. Tepper et al, J Clin Oncol 19: , 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)

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

DISCUSSION

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