1. www.OncologyEducation.ca Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) Update Authors: Hecht et al at ASCO GI 2008 Date posted: April 3 2008

2. www.OncologyEducation.ca RANDOMIZERANDOMIZE 1:1 Panitumumab + Ox-CT + Bevacizumab REGISTERREGISTER Oxali-based CT Investigator choice N= 823 Iri-based CT Investigator choice N=230 Ox-CT + Bevacizumab Panitumumab + Iri-CT + Bevacizumab Iri-CT + Bevacizumab Primary Outcome : PFS

3. www.OncologyEducation.ca PACCE Trial stopped early after interim analysis suggested excess toxicity and inferior efficacy in oxaliplatin arms Data from oxaliplatin arms presented at World GI 2007 –Summarized in Dr Phil Bedard’s December 2007 GI Update on OncologyEducation.ca:Dr Phil Bedard’s December 2007 GI Update on OncologyEducation.ca –Oxali + Bev + Pmab had increased toxicity and decreased efficacy (PFS)

4. www.OncologyEducation.ca PACCE At ASCO GI 2008: –Oxaliplatin data updated (Mitchell) No substantive differences from previous data –Irinotecan data presented for first time (Hecht)

5. www.OncologyEducation.ca Efficacy - Irinotecan Pmab+Bev/IriBev/Iri Response43%39% CR0% PR43%39% Median PFS (Central Review) 10.1 mos (95% CI 8.2 -13.7) 11.7 mos (95% CI 9.0 -13.2) Median OS20.7 mos20.5 mos

6. www.OncologyEducation.ca Efficacy - Irinotecan Local Review : –PFS : 11 vs 10.7 mos (Bev/Pmab/Iri vs Bev/Iri) Differences in censoring rules; more early censoring in central review and in bev/Iri-CT cohort Central review unable to assess clinical disease progression Central review unable to accurately evaluate PD after surgical resections Investigator bias

7. www.OncologyEducation.ca Toxicity Pmab+ Bev/Iri N=401 Bev/Iri N=392 Gr 3 (%)Gr 4 (%)Gr 3 (%)Gr 4 (%) Skin37000 Diarrhea27190 Dehydration14060 Hypokalemia9240 Hypomagnesemia3201 Neutropenia143174 Neuropathy9<126<1 Nausea10260 Infection12290 DVT13060 PE01105

8. www.OncologyEducation.ca Toxicity Grade 5 toxicities: –5 Bev /Pmab/Iri vs 1 Bev/Iri –2 Infections, 2 GI Perfs, 1 PE

9. www.OncologyEducation.ca STUDY COMMENTARY The results with Irinotecan / Bevacizumab and Panitumumab raise similar concerns as the oxaliplatin results : The triple combination is more toxic and likely less efficacious

10. www.OncologyEducation.ca BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS NCIC – CTG has just activated CRC.5 (North American Intergroup) : Chemo at investigator’s choice +/- Bevacizumab or Cetuximab or Both Should we have similar concerns with this trial with the combination of Chemo + Bev + Monoclonal Ab to EGFR antibody? Need to monitor but Chemo + Bev + Cetuximab does not appear to have the same safety concerns as panitumumab containing regimens Previous randomized phase II trialof Bev/Cetux/Iri vs Bev/Cetux in Iri resistant patients did not raise any concerns re : safety Americans have accrued ~1000 patients with no safety concerns from DSMB Dutch Trial of Capecitabine/Ox/Bev/Cetux vs Capecitabine/Ox/Bev accrued almost 400 patients with no toxicity concerns