clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer N016966: Efficacy Results  PFS significantly increased with addition of bevacizumab to chemotherapy, but not RR and OS Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Saltz LB, et al. J Clin Oncol. 2008;26: Mos Proportion of Patients XELOX/FOLFOX4 + bevacizumab (n = 700; 513 events) XELOX/FOLFOX4 + placebo (n = 701; 547 events) HR: 0.83 (97.5% CI: ; P =.0023) E Idelevich, 2011

Active p21K-ras Inactive p21K-ras EGF-R TK Cyclin D Cell replication MAPK Anti-apoptosis Glucose metabolism Energy Protein synthesis Ribosome biosynthesis Enhanced angiogenesis Akt/P KB TK EGF Her2

Inactive p21K-ras EGF-R TK Glucose metabolism Energy Akt/P KB TK EGF Growth arrest Cell replication Active p21K-ras (WT) Cyclin D MAPK ApoptosisAnti-apoptosis No protein synthesis Protein synthesis Ribosome biosynthesis No angiogenesisEnhanced angiogenesis EGFR inhibitors ____ ___

Antibody dependent cellular cytotoxicity=ADCC EGFR NK cell T cell A Apoptosis EGFR inhibitors

EGFR inhibitors induced rash

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer PRIME Study: KRAS Status in Response to Panitumumab  Randomized, global, open-label, phase III trial Douillard JY, et al. J Clin Oncol. 2010;28: Panitumumab 6.0 mg/kg q2w + FOLFOX4 q2w (n = 593) FOLFOX4 q2w (n = 590) Stratified by ECOG PS (0-1 vs 2) and geographic region (Western Europe, Canada, and Australia vs all other locations) Patients with previously untreated mCRC (N = 1183) E Idelevich, 2011

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer PRIME Panitumumab Improved Median PFS by 20% in Patients with KRAS wt Tumours Probability of Progression-Free Survival Months Events n (%) Median PFS (95% CI) months Panitumumab + FOLFOX4 (n=325)____199 (61) 9.6 (9.2–11.1) ____ FOLFOX4 (n=331)____215 (65)8.0 (7.5–9.3)  1.6 HR = 0.80 (95%CI: 0.66–0.97) p = 0.02 Douillard J-Y, et al. J Clin Oncol 2010;28: E Idelevich, 2011

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer PRIME Summary  This is the first randomised study prospectively analysed by KRAS status in 1 st -line mCRC  In patients with KRAS wt tumours, panitumumab significantly improved PFS when added to FOLFOX4  Responses were more frequent in the panitumumab + FOLFOX4 arm (55%)  Overall survival was in favour of panitumumab + FOLFOX4  Safety was as expected for an anti-EGFR antibody in combination with FOLFOX4 Douillard J-Y, et al. J Clin Oncol 2010;28: E Idelevich, 2011

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer KRAS Status in Response to Cetuximab  CRYSTAL: randomized, multicenter phase III trial [1]  Significant improvement in PFS with addition of cetuximab to FOLFIRI vs FOLFIRI alone for first-line mCRC treatment  Retrospective analysis of CRYSTAL [2] –Included only subset of KRAS-evaluable patients (N = 540) 1. Van Cutsem E, et al. N Engl J Med. 2009;360: Van Cutsem E, et al. ASCO Abstract 2. FOLFIRI* 2-wk cycle (n = 609) FOLFIRI* 2-wk cycle + Cetuximab † (n = 609) Stratified by geographic region, ECOG PS EGFR-positive patients with previously untreated mCRC (N = 1218) *FOLFIRI: irinotecan 180 mg/m 2, folinic acid 400 mg/m 2, 5-FU 400 mg/m 2 bolus, 5-FU infusion 2.4 g/m 2 over 46 hrs. † Cetuximab: 400 mg/m 2 on Day 1, then 250 mg/m 2 /wk. E Idelevich, 2011