Introduction

1. An updated analysis of safety and efficacy of oxaliplatin (Ox)/bevacizumab (bev) +/- panitumumab (pmab) for 1st‑line treatment (tx) of metastatic colorectal cancer (mCRC) from a randomized, controlled trial (PACCE) J. Randolph Hecht,1Edith Mitchell,2 Tarek Chidiac,3Carroll Scroggin,4 Christopher Hagenstad,5 David Spigel,6John Marshall,7 Allen Cohn,8 Seta Shahin,9 Thomas Griffin9 1UCLA School of Medicine, Los Angeles, CA; 2Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA; 3Mid Ohio Oncology/Hematology, Inc, Columbus, OH; 4NEA Clinic, Jonesboro, AR; 5Suburban Hematology-Oncology Associates, Lawrenceville, GA; 6Sarah Cannon Research Institute, Nashville, TN;7Georgetown University Hospital, Washington, DC; 8Rocky Mountain Cancer Centers, Denver, CO;9Amgen Inc., Thousand Oaks, CA This study was funded by Amgen Inc.

2. Introduction • Panitumumab, a fully human monoclonal antibody that targets the epidermal growth factor receptor (EGFr), is approved in the US as monotherapy for the treatment of refractory mCRC • Preclinical and preliminary clinical studies have suggested that combining EGFr, VEGF inhibitors, and chemotherapy may improve efficacy over single-agent treatments 1,2 • PACCE was a US, community-based study designed to compare the efficacy and safety of bevacizumab and chemotherapy +/- panitumumab for first-line treatment of mCRC • This interim analysis describes updated data available as of May 31, 2007 on safety and efficacy on the Ox-based cohort from PACCE (trial discontinued only panitumumab therapy in March 2007 after a planned interim analysis of ~231 PFS events in the Ox-CT cohort) 1 Shaheen RM et al. Brit J Cancer 2001;85:584–589 2 Saltz LB et al. J Clin Onc 2007;25:4557–4561.

3. PACCE Study Schema Randomized, Open-Label, Controlled Phase 3b Study Panitumumab 6 mg/kg Q2W + Ox-CT + Bevacizumab Ox-based CT (eg, FOLFOX) N = 800 Investigator choice S C R E E N I N G R A N D O M I Z E 1:1 Ox-CT + Bevacizumab Panitumumab 6 mg/kg Q2W + Iri-CT + Bevacizumab Iri-based CT (eg, FOLFIRI) N = 200 Investigator choice 1:1 Iri-CT + Bevacizumab Stratification Factors: ECOG score, prior adjuvant treatment, disease site,Ox doses/Iri regimen, number of metastatic organs Tumor Assessments: Q12W until disease progression or intolerability

4. Key Eligibility Criteria • Age ³ 18 years old • Measurable mCRC per modified RECIST • ECOG status 0 or 1 • Adequate hematologic, renal, and hepatic function • No prior chemotherapy or biologic therapy for mCRC • No adjuvant chemotherapy within 6 months of randomization • No major surgery within 28 days of randomization or elective and/or planned major surgical procedures during the study • No clinically significant cardiovascular disease within 1 year prior to randomization • No EGFr testing required

5. Study Endpoints and Design Characteristics • Primary endpoint: • Progression-free survival (PFS) by central review in the Ox-CT stratuma • Secondary endpoints included: • Overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), safety profile • Design Characteristics • To detect a 30% improvement in median PFS in the panitumumab plus bevacizumab/Ox-CT treatment group vs bevacizumab/Ox-CT alone • 80% power and a = 0.05 (2-sided) for 462 PFS events (disease progression or death) • Planned interim analysis at ~ 231 Ox-CT PFS events aPowered for oxaliplatin stratum only; descriptive for irinotecan stratum

6. Independent DMC Analyses 1st pt randomized ~231 PFS events 75 pts 500 pts 25pts 150 pts 800 pts Safety Safety SafetyRR Unplanned Safety Efficacy SafetyRR SafetyEfficacy Mar 2005 DMC recommended changes to informed consent DMC recommended continuation without protocol modification Panitumumab dosing was discontinued on Mar 22, 2007 DMC = data monitoring committee

7. Treatment: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff) aOf those patients who received any first-line treatment; bAllowed per protocol; capecitabine was not allowed

8. Demographics and Baseline Characteristics (Interim Analysis, May 2007 Data Cutoff) aOne patient had no metastatic organs

9. Summary of Adverse Events: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff) Based on the safety analysis set (all patients who received ≥ 1 dose of treatment)Graded per NCI CTCAE v 3.0; n/a, not applicable aAs reported by investigator – does not include disease progression (ie, neoplasms)

10. Grade 3 or 4 Adverse Events of Interest: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff) MedDRA v 9.0 preferred terms; graded per NCI CTCAE v 3.0 aSkin toxicity included terms from the skin and subcutaneous and infections system organ class(SOC) bGrade 5 infections occurred in 3 (1%) of pmab + bev/Ox-CT pts and 3 (1%) of bev/Ox-CT pts cGrade 5 pulmonary embolism occurred in 3 (1%) of pmab + bev/Ox-CT pts

11. Deaths (All Causes): Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff) aDeaths at any time including long-term follow-up (post-study treatment). Based on the safety analysis set

12. Overall Tumor Response: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff) aCT scans performed Q12W; responses did not require confirmationbCentral review unable to evaluate clinical disease progression (ie, non-radiographic PD); central review unable to accurately evaluate PD after surgical resectionscIncluded missing and unreadable scans

13. Maximum Percent Change From Baseline in Sum of Longest Diameters by Central Review: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff) Panitumumab +bevacizumab / Ox-CT bevacizumab / Ox-CT Best Overall Response Best Overall Response PR (n = 189) SD (n = 133) PD (n= 16) Unknown (n = 4) PR (n = 187) SD (n = 120) PD (n= 25) Unknown (n = 2)

14. pmab+bev/Ox-CT bev/Ox-CT Progression-Free Survival: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff) Central Reviewa Local Reviewb HR = 1.27 (95% CI: 1.07–1.50)* HR = 1.27 (95% CI: 1.05–1.53)* *Descriptive only *Descriptive only bCensoring based on last day of patient contact or visit Q2W aCensoring based on last available scan read centrally Q12W

15. pmab+bev/Ox-CT bev/Ox-CT Overall Survival: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff) HR = 1.43 (95% CI: 1.11–1.83)a aDescriptive only. Statistical significance is limited by the lack of a prespecified significance boundary. % Surviving Months Panitumumab N 413 334 205 73 1 Censored N 0 34 84 96 55 No Panitumumab N 410 347 221 71 3 Censored N 0 44 75 120 61

16. Treatment Exposure: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff) aBolus 5-FU bInfusional 5-FUN/A=not applicable

17. Reasons for First-Line Treatment Discontinuation: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff) aOf those who discontinued first-line treatment bOther included end of first-line treatment without progression, requirement for alternative therapy, administrative, lost to follow-up, and other

18. Rates of Metastases Intervention For Curative Intent: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff)

19. Summary • Based on this updated interim analysis of the PACCE study, panitumumab + bevacizumab/Ox-CT was associated with shorter PFS time and increased toxicity, indicating that this combination has an unfavorable benefit-to-risk profile in unselected patients with mCRC • Lower-dose intensity was observed in the panitumumab + bevacizumab/Ox-CT arm • Most patients withdrew from the study for non-progressive events (65% in the panitumumab + bevacizumab/Ox-CT arm, 71% in the bevacizumab/Ox-CT arm) • Further data collection and analyses are ongoing, including subset analyses based on biomarkers • Phase 3 studies are currently ongoing to investigate panitumumab with chemotherapy in 1st- and 2nd-line mCRC • Study 20050181 investigates FOLFIRI +/- panitumumab as 2nd-line in mCRC (Peeters et al., Abstract #335, Poster #A56) • PRIME/Study 20050203 investigates FOLFOX +/- panitumumab in first-line mCRC (Douillard et al., Abstract #443, Poster #A63)

20. ACKNOWLEDGEMENTS • Patients who participated in this study and their families • All investigators, co-investigators, and study staffs at 194 sites across the US • The Amgen study team