1. Hecht WCGIC 2007 An Interim Analysis of Efficacy And Safety From A Randomized Controlled Trial of Panitumumab With Chemotherapy Plus Bevacizumab (Bev) for Metastatic Colorectal Cancer (mCRC) J. Randolph Hecht, 1 Tarek Chidiac, 2 Edith Mitchell, 3 Philip Stella, 4 Allen Cohn, 5 David McCollum, 6 Mansoor Saleh, 7 John Marshall, 8 Seta Shahin, 9 Robert Deeter 9 1 UCLA School of Medicine, Los Angeles, CA; 2 Mid Ohio Oncology/Hematology, Inc, Columbus, OH; 3 Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA; 4 St. Joseph Mercy Hospital, Ann Arbor, MI; 5 Rocky Mountain Cancer Centers, Denver, CO; 6 Baylor-Sammons Cancer Center, Dallas, TX; 7 Georgia Cancer Specialists, Atlanta, GA; 8 Georgetown University Hospital, Washington, DC; 9 Amgen Inc., Thousand Oaks, CA

2. Hecht WCGIC 2007 2 Introduction  Panitumumab is a fully human monoclonal antibody that targets the epidermal growth factor receptor (EGFr) and is approved in the US for the treatment of refractory mCRC  The US standard of care for first-line treatment of mCRC is the combination of bevacizumab plus oxaliplatin- or irinotecan- based chemotherapy (Ox-CT or Iri-CT)  Preclinical and preliminary clinical studies have suggested that combining EGFr, VEGF inhibitors, and chemotherapy may improve efficacy 1,2  The PACCE study was designed to compare the efficacy and safety of bevacizumab and chemotherapy +/- panitumumab for first-line treatment of mCRC 1 Shaheen et al. Brit J Cancer 2001;85:584-589 2 Saltz LB et al. ASCO 2005. Abstract #3508 (BOND2)

3. Hecht WCGIC 2007 3 Study Schema PACCE: Panitumumab Advanced Colorectal Cancer Evaluation Randomized, Open-Label, Controlled Phase 3b Trial Stratification Factors: ECOG score, prior adjuvant tx, disease site, Ox doses/Iri regimen, number of metastatic organs Tumor assessments: Q12W until disease progression or intolerability Panitumumab 6 mg/kg Q2W Ox-CT Bevacizumab Ox-based CT (eg, FOLFOX) N = 800 Inv choice Iri-basedCT (eg, FOLFIRI) N = 200 Inv choice Ox-CT Bevacizumab Panitumumab 6 mg/kg Q2W Iri-CTBevacizumab Iri-CTBevacizumab RANDOMIZERANDOMIZE 1:1 SCREENINGSCREENING

4. Hecht WCGIC 2007 4 Key Eligibility Criteria  Age  18 years old  Measurable mCRC per modified RECIST criteria  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  No major surgery within 28 days of randomization or elective and/or planned major surgical procedures during the trial  No clinically significant cardiovascular disease within 1 year prior to randomization  No EGFr testing required

5. Hecht WCGIC 2007 5  Primary endpoint:* –Progression-free survival (PFS) by central review in the Ox-CT cohort  Secondary endpoints: –Objective response rate by central review –Time to treatment failure (TTF) –Overall survival (OS) –Safety profile  Design Characteristics –To detect a 30% improvement in median PFS in the panitumumab plus bev/Ox-CT vs the bev/Ox-CT 80% power and  = 0.05 (2-sided) for 462 PFS events (disease progression or death) Planned interim analysis at ~231 PFS events Study Endpoints and Design Characteristics *Powered for oxaliplatin cohort only; descriptive for irinotecan cohort

6. Hecht WCGIC 2007 6 Independent DMC Analyses 25 Pts Safety 75 Pts 150 Pts SafetySafety RR Unplanned Safety Efficacy Safety RR Safety Efficacy 500 Pts 800 Pts ~231 PFS events ~231 OS Q3 07 DMC recommended continuation without protocol modification Mar 2005 Panitumumab dosing was discontinued DMC recommended changes to informed consent 1 st pt randomized

7. Hecht WCGIC 2007 7 Baseline Demographics and Characteristics pmab+ bev/Ox-CT (N=407) bev/Ox-CT (N=405) pmab+ bev/Iri-CT (N=68) bev/Iri-CT (N=67) Male, %57584963 Race, % White Black Hispanic 83 8 6 81 10 6 75 18 3 70 19 10 Age, median, years Range 61 28 - 88 62 27 - 89 60.5 37 - 84 57 23 - 80 Age  65, % 39434128 Baseline ECOG, % 0 1 62 38 59 41 60 40 63 37 Prior Adjuvant Therapy, %19 4037 Metastatic organs, % 1 >1 49 51 49 51 40 60 48 52

8. Hecht WCGIC 2007 8 PACCE INTERIM ANALYSIS: SAFETY

9. Hecht WCGIC 2007 9 Summary of Adverse Events (Ox-CT Cohort) pmab+ bev/Ox-CT (N=401) bev/Ox-CT (N=392) Any event, %100 Grade 35352 Grade 42818 Grade 5* 43 Any serious (SAE), %5637 Ended first-line treatment due to AE, % 1920 Ended panitumumab treatment due to AE, % 26n/a Panitumumab treatment- related SAE, % 19n/a Safety set included all patients who were dosed. Graded per NCI CTCAE v3.0 *Not including disease progression (ie, neoplasms) n/a= not applicable

10. Hecht WCGIC 2007 10 Grade 3 or 4 Adverse Events of Interest (Ox-CT Cohort) pmab+ bev/Ox-CT (N=401), % bev/Ox-CT (N=392), % Gr 3Gr 4Gr 3Gr 4 Skin toxicity33<110 Diarrhea212121 Dehydration14241 Hypokalemia8231 Hypomagnesemia3100 Neutropenia1210177 Neuropathy9<110<1 Nausea1004<1 Infections a 16272 Deep venous thrombosis6070 Pulmonary embolism b 0604 MedDRA v9.0 preferred terms; Graded per NCI CTCAE v3.0 a Grade 5 infections occurred in 2 (1%) pmab + bev/Ox-CT pts and 3 (1%) bev/Ox-CT pts b Grade 5 pulmonary embolism occurred in 2 (1%) pmab + bev/Ox-CT pts

11. Hecht WCGIC 2007 11 Deaths (Ox-CT Cohort) pmab+ bev/Ox-CT N=401 n (%) bev/Ox-CT N=392 n (%) Deaths on study83 (20)58 (15) All cause deaths within 60 days of first dose 10 (2)6 (2) All cause deaths within 30 days of last dose of 1 st line tx 26 (6)13 (3) Safety set included all patients who were dosed

12. Hecht WCGIC 2007 12 PACCE INTERIM ANALYSIS: EFFICACY

13. Hecht WCGIC 2007 13 Objective Response Rate By Cohort (Central Review) pmab+ bev/Ox-CT (N=407) % bev/Ox-CT (N=405) % pmab+ bev/Iri-CT (N=68) % bev/Iri-CT (N=67) % Best ORR39413831 Complete response 0<100 Partial response39403831 Stable disease31332637 Progressive disease6494 Not done/Unevaluable*24222627 ITT set *Included missing and unreadable scans

14. Hecht WCGIC 2007 14 Partial Response 39% Stable Disease 31% Progressive Disease 6% Pmab+ bev/Ox-CT (N=305) Max % Change in Sum of Longest Diameters bev/Ox-CT (N=310) Max % Change in Sum of Longest Diameters Maximum % Change in SLD of Target Lesions (Ox-CT Cohort, Central Review) Complete/Partial Response 41% Stable Disease 33% Progressive Disease 4%

15. Hecht WCGIC 2007 15 Objective Response Rate By Cohort (Investigator Review) pmab+ bev/Ox-CT (N=407) % bev/Ox-CT (N=405) % pmab+ bev/Iri-CT (N=68) % bev/Iri-CT (N=67) % Best ORR49485440 Complete response 4574 Partial response44424736 Stable disease29342537 Progressive disease75410 Not done/Unevaluable*15131612 ITT set *Included missing and unreadable scans

16. Hecht WCGIC 2007 16 Interim Rates of Metastases Intervention (Ox-CT Cohort, Oct 2006 Data Cutoff) pmab+ bev/Ox-CT (N=407) bev/Ox-CT (N=405) Resection or radiofrequency ablation of metastases (ie, liver, lung, other) 27 (7%)12 (3%) ITT set *Included missing and unreadable scans

17. Hecht WCGIC 2007 17 Interim PFS – Ox-CT Cohort (Central Review, Oct 2006 Data Cutoff) # PFS events (%) Median (95%CI), mos 147 (36)8.8 (8.3-9.5) 110 (27)10.5 (9.4-12.0) HR=1.44 (95% CI: 1.13-1.85) p =0.004 Pmab+bev/Ox-CT Bev/Ox-CT Proportion Progression-Free 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ITT set; for this planned interim analysis, the nominal alpha as specified by the Lan-DeMets alpha spending function and the O’Brien-Fleming stopping boundaries was 0.0053

18. Hecht WCGIC 2007 18 Limited Update of PFS – Ox-CT Cohort (Central Review, Apr 2007 Data Cutoff) # PFS events (%) Median (95%CI), mos 206 (50)9.0 (8.5-10.4) 172 (42)10.5 (9.7-11.6) Pmab+bev/Ox-CT Bev/Ox-CT HR= 1.29 (95% CI: 1.05-1.58) Proportion Progression-Free 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ITT set

19. Hecht WCGIC 2007 19 Unplanned Interim Overall Survival (Ox-CT Cohort) # OS events (%) Median (95%CI), mos 127 (31)18.6 (16.4- 20.6) 95 (23)NE Proportion Alive HR= 1.44 (95% CI: 1.10-1.88) *Interpretation of statistical significance is limited by the lack of a prespecified significance boundary Pmab+bev/Ox-CT Bev/Ox-CT HR= 1.56 (95% CI: 1.11-2.17) Oct 2006 Data Cutoff*Apr 2007 Data Cutoff # OS events (%) Median (95%CI), mos 83 (20)18.4 (13.8-NE) 58 (14)NE Proportion Alive Pmab+bev/Ox-CT Bev/Ox-CT NE = not estimable; ITT set

20. Hecht WCGIC 2007 20 PACCE INTERIM ANALYSIS: ADDITIONAL ANALYSES (Ox-CT Cohort )

21. Hecht WCGIC 2007 21 No PD PD Alive Died Exposure-Adjusted Adverse Event Incidence (Events per month) 0 1 2 3 4 5 6 7 8 Bev/Ox-CT Pmab + Bev/Ox-CT 4.8 5.8 5.0 6.9 3.9 3.8 Number of events per month

22. Hecht WCGIC 2007 22 Overall Survival By Age (  80 yr vs >80) (Exploratory Analysis) Pmab+bev/Ox-CT, <80 yrs n=389Bev/Ox-CT, <80 yrs n=395 Months Pmab+bev/Ox-CT, >80 yrs n=18Bev/Ox-CT, >80 yrs, n=10 Proportion Surviving

23. Hecht WCGIC 2007 23 Overall Survival By Comorbidities (0 vs 1+) (Exploratory Analysis) Pmab+bev/Ox-CT, Comobidity 0 n=119Bev/Ox-CT, Comobidity 0 n=104 Pmab+bev/Ox-CT, Comorbidity 1+ n=288Bev/Ox-CT, Comorbidity 1+ n=301 Proportion Surviving Months

24. Hecht WCGIC 2007 24 Overall Survival of ECOG (0 vs 1) (Exploratory Analysis) Pmab+bev/Ox-CT, ECOG 0 n=254Bev/Ox-CT, ECOG 0 n=237 Pmab+bev/Ox-CT, ECOG 1 n=153Bev/Ox-CT, ECOG 1 n=168 Months Proportion Surviving

25. Hecht WCGIC 2007 25 Treatment Exposure (Ox-CT Cohort) Dose Delays % Pts Dose Reductions % Pts Relative Dose Intensity (RDI) % pmab+ bev/Ox n=401 bev/Ox n=392 pmab+ bev/Ox n=401 bev/Ox n=392 pmab+ bev/Ox n=401 bev/Ox n=392 Panitumumab62n/a31n/a870 Bevacizumab57493292 Oxaliplatin554626258488 5-FU52 a 45 a 23 a 16 a 82 b 87 b % Pts Inf 5-FU/ Ox/Bev ≥ 85% n/a 3644 a Bolus 5-FU b Infusional 5-FU n/a=not applicable

26. Hecht WCGIC 2007 26 Reasons for First-Line Treatment Discontinuation (Ox-CT Cohort) Patients discontinued first-line tx, n/ N total pmab + bev/Ox-CT (300/407) bev/Ox-CT (293/405) Progressive events, n (%)108 (36)79 (27) Disease progression91 (30)68 (23) Deaths17 (6)11 (4) Non-progressive events, n (%)192 (64)214 (73) Adverse events69 (23)76 (26) Protocol violation9 (3)5 (2) Refused treatment47 (16)55 (19) Other67 (22)78 (27)

27. Hecht WCGIC 2007 27 Time to Treatment Failure (Ox-CT Cohort) HR = 1.03 (95% CI: 0.87-1.21) Survival Distribution Function Pmab+bev/Ox-CT Bev/Ox-CT Patients at risk: Pmab+bev/Ox-CT Bev/Ox-CT

28. Hecht WCGIC 2007 28 SUMMARY  This phase 3b open-label, US community-based study investigated the potential benefit of adding an anti-EGFr antibody (panitumumab) to an anti-VEGF-A antibody (bevacizumab) and chemotherapy for first-line mCRC  A planned interim analysis on the Ox cohort demonstrated an unfavorable risk:benefit profile for panitumumab+ bev/Ox-CT based on reduced PFS time and additional toxicity  These efficacy data suggest that there is a lack of biological synergy between panitumumab and bevacizumab in combination with Ox-CT  Additional toxicity was observed in the panitumumab + bev/Ox-CT arm –Dual pathway inhibition may have potentiated toxicity  Lower dose intensity was observed in the panitumumab + bev/Ox- CT arm

29. Hecht WCGIC 2007 29 SUMMARY (cont.)  In an exploratory, post-hoc analysis, specific populations, particularly patients who were elderly, had poor performance status, or had comorbidities > 1, had worse outcomes  Most patients withdrew due to non-progressive events (64% on panitumumab + bev/Ox-CT arm, 73% on bev/Ox-CT arm)  Further data collection and analyses are ongoing, including subset analyses based on biomarkers  Phase 3 registrational studies are currently ongoing to investigate panitumumab with chemotherapy alone in first- and second-line mCRC –Independent data monitoring committees for these studies have recommended continuation without protocol modification

30. Hecht WCGIC 2007 30 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