KRAS Status in Response to Cetuximab E Idelevich, 2011 KRAS Status in Response to Cetuximab Retrospective analysis of CRYSTAL[1] PFS and ORR benefit of FOLFIRI + cetuximab only observed in mCRC patients with wild-type KRAS Outcome Wild-Type KRAS (n = 348) Mutated KRAS (n = 192) Median PFS, mos FOLFIRI + cetuximab 9.9 7.6 FOLFIRI 8.7 8.1 HR 0.68* 1.07† ORR, % 59.3‡ 36.2 43.2 40.2 FOLFIRI, 5-fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; ORR, overall response rate; PFS, progression-free survival.   A retrospective analysis of the CRYSTAL study that stratified patients by either wild-type or mutated KRAS status was then conducted. This analysis showed that patients with wild-type KRAS were the only ones who derived clinical benefit from the addition of cetuximab, both in terms of median progression-free survival and median overall response rate. Specifically, the response rate with FOLFIRI chemotherapy alone increased from 43% to 60% with the addition of cetuximab. An increase in response rates correlated with an increased ability to undergo surgical resection. *P = .017; †P = .75; ‡P = .0025 1. Van Cutsem E, et al. ASCO 2008. Abstract 2. 1

20060314 FOLFIRI + Panitumumab in 1st-line Treatment of Metastatic CRC E Idelevich, 2011 20060314 FOLFIRI + Panitumumab in 1st-line Treatment of Metastatic CRC S c r e n I g E n r o l m e t E n d o f t r e a t m e n t S a f e t y f o l l o w u p E n d o f s t u d y FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W, on day 1 of each cycle) Metastatic CRC (n=150) Approx. 56 days after end of treatment This was a first-line, single-arm phase 2 study prospectively evaluating the relationship between KRAS status and response to combination therapy with panitumumab and FOLFIRI. Eligible patients received panitumumab (6 mg/kg; intravenous infusion [IV]) on day 1 of a 14-day cycle with the initial dose administered over 60 minutes ± 15 minutes prior to chemotherapy. If the first dose was well tolerated subsequent infusions were given over 30 minutes ± 10 minutes prior to chemotherapy. No panitumumab-specific pre-medication was given before administration. Treatment was to be given until progression or unacceptable toxicity. Study objectives also included the evaluation of patient reported outcomes, healthcare resource utilisation and any integument and eye toxicity management scheme. Secondary endpoints also included disease control rate, duration of response, time to response, time to progression, duration of stable disease, and time to treatment failure All analyses were descriptive Study objectives: To estimate the effect of KRAS mutation status on efficacy and to describe the safety profile Study endpoints: ORR (1°); PFS, Safety Köhne CH, et al. ASCO-GI 2010, #414, poster presentation; www.amgentrials.com; protocol ID: 20060314. ClinicalTrials.gov identifier: NCT00508404. 2

20060314 Best Objective Response E Idelevich, 2011 20060314 Best Objective Response Panitumumab + FOLFIRI* KRAS wt (n=85) KRAS mt (n=58) Objective response, % Complete response 2 Partial response 54 36 Stable disease 34 52 Disease progression 7 Unevaluable Not done CR + PR,% (95% CI) 56.5 (45.3, 67.2) 37.9 (25.5, 51.6) Difference, % 18.54 (0.84, 34.63) Unadjusted common treatment odds ratio (95% CI) 2.12 (1.02, 4.45) *Two patients did not have measurable disease per RECIST guidelines at baseline and were therefore not included in the analysis of response rate. Köhne CH, et al. ASCO-GI 2010, #414, poster presentation. 3

Resection Rates – Patients with Liver Only Disease E Idelevich, 2011 Resection Rates – Patients with Liver Only Disease 20060314 Overall resections 40 KRAS evaluable 35 In the population of patients with liver-only metastases at baseline (n=52), resections were performed in 29% of patients (n=15) in the full analysis set In the KRAS WT and MT groups, resection rates in the primary analysis set (KRAS evaluable patients) were 19% (n=6) versus 6% (n=1), respectively, in patients with liver metastases only. Reference: Hofheinz R, et al. J Clin Oncol 2010, 28:7s, abstract #3545, poster presentation Resection rate (%) 20 13 KRAS wt (n=11/31) KRAS mt (n=2/16) Hofheinz R, et al. ASCO 2010, #3545, poster presentation 4

20060314 Progression-free Survival Primary Analysis Set E Idelevich, 2011 20060314 Progression-free Survival Primary Analysis Set Events n (%) Median (95% CI) months KRAS wt (n=86)______ 44 (51) 8.9 (7.6–14.3) KRAS mt (n=59)______ 48 (81) 7.2 (5.6–7.8) 100 90 70 60 80 50 40 30 20 10 HR = 0.46 (95%CI: 0.31–0.70) Proportion Event-Free (%) Vectibix + FOLFIRI extends PFS to approximately 9 months 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Months Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.

E Idelevich, 2011 20060314 Summary This was the first study to investigate the effect of tumour KRAS status on response to panitumumab plus FOLFIRI in the 1st-line treatment of mCRC KRAS wt tumours were more likely to respond to treatment with panitumumab plus FOLFIRI (56.5%vs 37.9%) PFS was longer in patients with KRAS wt tumours Resection rate was higher in the KRAS wt population Safety was as expected for an anti-EGFR inhibitor plus irinotecan-based chemotherapy in this setting PFS was longer in patients with KRAS wt tumours (HR=0.46; 95% CI: 0.31-0.70) KRAS wt tumours were more likely to respond to treatment with panitumumab plus FOLFIRI (OR 2.12; 95% CI: 1.02–4.45) Resection rate was higher in the KRAS wt population (15%) than in the KRAS mt population (7%) Köhne CH, et al. ASCO-GI 2010, #414, poster presentation; Hofheinz R, et al. J Clin Oncol 2010; 28(15S): #3545, poster presentation. 6

20050181 FOLFIRI ± Panitumumab in 2nd-line Treatment of Metastatic CRC E Idelevich, 2011 20050181 FOLFIRI ± Panitumumab in 2nd-line Treatment of Metastatic CRC L o n g t e r m f o l l o w u p E n d o f t r e a t m e n t FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W) Metastatic CRC (n=1100) R 1:1 FOLFIRI (Q2W) Disease assessment every 8 weeks This was an open-label, randomised, multicentre, phase III trial that compared the efficacy of panitumumab 6.0 mg/kg every 2 weeks (Q2W) plus FOLFIRI versus FOLFIRI alone in patients with previously treated metastatic colorectal cancer. The study was not blinded because of the expected skin toxicity related to panitumumab administration. Study objective: To evaluate the treatment effect of the addition of panitumumab to FOLFIRI on PFS and OS by KRAS status The study was initially estimated to require 1,100 patients unselected for KRAS tumour status. Based on emerging KRAS data from other panitumumab studies, the protocol was amended after completion of enrollment, and the primary objective was changed to incorporate patient stratification for KRAS status. Panitumumab was administered by a 60-minute infusion before chemotherapy; if the first panitumumab dose was well tolerated, subsequent infusions could be administered over 30 minutes. All patients received FOLFIRI: 180 mg/m2 irinotecan and 400 mg/m2 racemic leucovorin (or 200 mg/m2 l-leucovorin) by intravenous (IV) infusion on day 1 and FU 400 mg/m2 IV bolus on day 1, followed by 2,400 mg/m2 continuous infusion administered over days 1 and 2. Patients received study medication until disease progression or intolerability. Tumour response was assessed by the investigator and by an independent central radiology review blinded to treatment and outcomes using a modification of Response Evaluation Criteria in Solid Tumors (RECIST) every 8 weeks until disease progression; responses (complete response or partial response) were confirmed 28 days after the criteria for response were first met. Patients were followed-up for safety for at least 30 days after the last study drug administration and for survival every 3 months until approximately 30 months after the last patient was randomised. Enrollment was from June 2006 to March 2008 Participating countries: Australia, Austria, Belgium, Bulgaria, Czech Republic, Finland, France, Germany, Ireland, Italy, Japan, Lithuania, The Netherlands, Norway, Poland, Portugal, Romania, Russia, Slovakia, Spain, Sweden, Switzerland, Ukraine, United Kingdom, United States Stratification by: ECOG score: 0-1 vs. 2 Prior oxaliplatin exposure for mCRC Prior bevacizumab exposure for mCRC Study endpoints: PFS/OS (co-1°); ORR, Safety, PRO PRO, patient-reported outcomes Peeters M, et al. J Clin Oncol 2010;28:4706-4713; ClinicalTrials.gov identifier: NCT00339183; www.amgentrials.com; protocol ID: 20050181. 7

Objective Response Rate (%) Panitumumab + FOLFIRI (n=297) E Idelevich, 2011 20050181 Objective Response in Patients with KRAS wt Tumours (Central Review) 40 30 35 Objective Response Rate (%) 20 10 10 The response rate in the KRAS wt subpopulation who received panitumumab + FOLFIRI in this study is the highest reported in a randomised, phase 3, 2nd-line study. (Response rates for irinotecan-based regimens in 2nd-line therapy are generally between 4% and 16% in KRAS unselected populations1,2) Similar response rates were observed in the FOLFIRI alone arm (10% and 14% in the KRAS wt and mt subpopulations, respectively), indicating that the patient population in this study was similar to those studied previously. The high response rate seen with panitumumab-FOLFIRI may be of particular value in patients who experience disease progression during first-line therapy with borderline resectable metastases or symptomatic disease. References: Cunningham D, et al. N Engl J Med 2004; 351:337-45; Sobrero AF, et al. J Clin Oncol 2008; 26:2311-9. Response rates by central and investigator review were virtually identical. Central: 35% pmab +FOLFIRI vs 10% FOLFIRI Investigator: 35% pmab +FOLFIRI vs 12% FOLFIRI Unevaluable/not done by central review: 7% pmab vs 10% FOLFIRI Reasons for “not done” included: no scans performed after screening. (Scans performed less than 49 days after screening were considered unevaluable) Panitumumab + FOLFIRI (n=297) FOLFIRI (n=285) More than 3x as many patients responded to panitumumab p < 0.001(descriptive); All responses were confirmed no earlier than 28 days after the response criteria were first met Peeters M, et al. J Clin Oncol 2010;28:4706-4713. 8

Progression-Free Probability E Idelevich, 2011 20050181 Panitumumab Improved Median PFS by 51% in Patients with KRAS wt Tumours Events n (%) Median (95% CI) months Panitumumab + FOLFIRI (n=303)___ 178 (59) 5.9 (5.5–6.7) FOLFIRI (n=294)___ 203 (69) 3.9 (3.7–5.3)  2.0 1.0 0.9 0.8 0.7 HR = 0.73 (95%CI: 0.59–0.90) p = 0.004 0.6 Progression-Free Probability 0.5 0.4 0.3 0.2 A statistically significant improvement in PFS with panitumumab-FOLFIRI versus FOLFIRI was demonstrated (HR 0.73; 95% CI, 0.59 to 0.90; P.0036, stratified log-rank) 0.1 0.0 20 18 16 14 12 10 8 6 4 2 Months Peeters M, et al. J Clin Oncol 2010;28:4706-4713. 9 9

E Idelevich, 2011 20050181 Summary This is the first randomised study prospectively analysed by KRAS status in 2nd-line mCRC In patients with KRAS wt tumours, panitumumab significantly improved PFS when added to FOLFIRI Overall survival was numerically improved (not significant) The response rate was improved by more than 3x (35% vs 10%) Safety was as expected for an anti-EGFR antibody in combination with FOLFIRI Peeters M, et al. J Clin Oncol 2010;28:4706-4713. Peeters M, et al. ASCO-GI 2010, #282, oral presentation 10 10

Metastatic colon cancer patients (100%) Non - resectable 75% Resectable 25% Potentially Down-sizable Non curable 12% 63%

Paul Brousse Experience - 1439 Patients (1988–1999) Adam R et al Ann Surg. 2004;240:644-658

Treatment of Metastatic CRC 1980 1985 1990 1995 2000 2005 RR % MS Months 5Fu 20-25 13 Capecitabine Irinotecan 40- 50 20-22 Oxaliplatin EGFR inhibitors ~ 60 > 24 Bevacizumab

Endpoints for assessment of systemic therapy for potentially resectable disease Systemic therapy is enabling resection - Highest RR maximizes resection rate (Folprecht et al) Endpoints - PFS is primary efficacy endpoint (ECNTG, 2007) - Secondary endpoints * Response Rate * Liver related toxicity * Achievement of R0 resection of all disease Are biological essential? - if acceptable toxicity, higher RR, improved resection rates and ultimately improved PFS are demonstrated (European Journal of Cancer, 43 (2007), 2037-2045)

Response rates: recent phase 3 trials Regimen Response Rate Reference _________________________________________________________________________ FOLFOX 36% NS; FOFOX+cetuximab 46% (OPUS, Bokemeyer) _____________________________________________________________________________________ FOLFIRI 43% p=0.004; FOLFIRI+cetuximab 59% (CRYSTAL,van Cutsem) ______________________________________________________________________________________ FOLFOX 38% NS; FOLFOX+bevacizzumab 38% (XELOX-1/NO16966 Saltz) FOLFOX 47% NS; p=0.06 FOLFOX+panitumumab 55 (PRIME, J-Y Douillard) FOLFIRI 36% p=0.001; FOLFOXIRI 60% (Falcone) FOLFOX+bevacizumab 41% NS; FOLFOX+bevacizumab+cetuximab 39% (PACCE; Hecht) CAPOX+bevacizumab 44% NS; CAPOX+becizumab+cetuximab 44% (CAIRO2; Punt) Standard Doublets ~ 40% Response Rate (RR)

Response rates: recent phase 3 trials Regimen Response Rate Reference ______________________________________________________________________________________ FOLFOX 36% NS; FOFOX+cetuximab 46% (OPUS, Bokemeyer) FOLFIRI 43% p=0.004; FOLFIRI+cetuximab 59% (CRYSTAL,van Cutsem) FOLFOX 38% NS; FOLFOX+bevacizzumab 38% (XELOX-1/NO16966 Saltz) FOLFOX 47% NS; p=0.06 FOLFOX+panitumumab 55% (PRIME, J-Y Douillard) FOLFIRI 36% p=0.001; FOLFOXIRI 60% (Falcone) FOLFOX+bevacizumab 41% NS; FOLFOX+bevacizumab+cetuximab 39% (PACCE; Hecht) CAPOX+bevacizumab 44% NS; CAPOX+becizumab+cetuximab 44% (CAIRO2; Punt) Adding EGFR inhibitors or using triplet chemotherapy increases RR

Response rates: recent phase 3 trials Regimen Response Rate Reference _____________________________________________________________________________________ FOLFOX 36% NS; FOFOX+cetuximab 46% (OPUS, Bokemeyer) FOLFIRI 43% p=0.004; FOLFIRI+cetuximab 59% (CRYSTAL,van Cutsem) ______________________________________________________________________________________ FOLFOX 38% NS; FOLFOX+bevacizzumab 38% (XELOX-1/NO16966 Saltz) FOLFOX 47% NS; p=0.06 FOLFOX+panitumumab 55% (PRIME, J-Y Douillard) FOLFIRI 36% p=0.001; FOLFOXIRI 60% (Falcone) FOLFOX+bevacizumab 41% NS; FOLFOX+bevacizumab+cetuximab 39% (PACCE; Hecht) CAPOX+bevacizumab 44% NS; CAPOX+becizumab+cetuximab 44% (CAIRO2; Punt) Bevacizumab does not increase Response Rate (RR)

Kras-dependent RR in First-Line Trials RR (K-ras w.t.) RR (K-ras mut) __________________________________________________________________ OPUS (Bokemeyer) FOLFOX 37% 49% FOLFOX+erbitux 61% 33% CRYSTAL (van Cutsem) FOLFIRI 43% 40% FOLFIRI+erbitux 59% 38% PRIME (J-Y Douillard) FOLFOX 47% 40% FOLFOX+vectibix 55% 40% 20060314 (Köhne CH) FOLFIRI+vectibix 56,5% 37.9%

In K-ras wild type patients Response Rate In K-ras wild type patients - FOLFOX or FOLFIRI+EGFR inhibitors has shown 55%- 60% response rate FOLFOXIRI - 60% response rate in small phase 3 trial

What is the optimal chemotherapy for the neoadjuvant treatment of unresectable liver metastases?

In patients with K-ras unknown or mutant - FOLFOX remains a standard treatment - FOLFOXIRI is an option (resectability, RR + PFS), but unknown toxicity profile in larger series - FOLFOX + bevacizumab is safe, but neither improves response rates nor resection rates In patients with wildtype K-ras - FOLFOX or FOLFIRI + EGFR inhibitors improve resection rates - FOLFIRI + cetuximab improves resection rate compared FOLFIRI

Treatment of unresectable mCRC Patients needing or desiring an aggressive approach: - patients with potentially resectable metastases - patients with clearly symptomatic disease in whom tumor regression is needed KRAS wild type patients: - CT + panitumumab, CT+cetuximab -evidence for response is greater for cetuximab in neoadjuvant approach KRAS mutant patients: - CT + bevacizumab - FOLFOXIRI may be an option if contraindications for bevacizumab and downsizing is desired Van Cutsem E, et al. WCGIC 2009 Expert Opinion

Treatment of unresectable mCRC Specific issues Treat with biologicals until progression or toxicity, or until metastases become resectable Continue treatment until progression with biologicals, even if one of the cytotoxic partners (oxaliplatin, irinotecan) is stopped No clear evidence to administer biologicals beyond progression Correlation of rash and activity after anti-EGFR antibodies has no immediate practical implications in clinical practice Van Cutsem E, et al. WCGIC 2009 Expert Opinion

Stage IV Colon Cancer Group I Group II Group III Group IV Curable Potentially Symptomatic Asymptomatic disease curable non curable non curable disease disease disease ! Non curable Non curable

First line strategy of metastatic CRC Dose the patient need (or desire) aggressive therapy? Yes ~ 85% No ~ 15% K-RAS 5FU/Cape +/- bev + inh.EGFR(WT) Unavailable WT MUT Doublet + bev Doublet + bev Doublet + EGFR inhibitors Doublet + bevacizumab Van Cutsem E, et al. WCGIC 2009 Expert Opinion

Optimal Chemotherapy for the neoadjuvant treatment of non- resectable liver metastases – Do we have to include biologics in this setting? Conversion Therapy Considerations: Practical Management Role of FOLFOX better established than FOLFIRI - Better toxicity profile, more clinical data FOLFOXIRI attractive … Limit duration of pre-operative therapy to 3-4 months - Don’t treat to best response, but to resectability - Decrease hepatotoxicity Role of biologics is evolving - Bevacizumab is not mandatory! - If Bevacizumab is used, d/c 6 wks before planned surgery EGFR inhibitors could emerge as best option in K-ras wild type CRC

Multi-disciplinary Approach Take-home Messages Aggressive Multi-disciplinary Approach

Thank you!