1. ASCO 2009 Safety and Efficacy of AMG 655 Plus Modified FOLFOX6 (mFOLFOX6) and Bevacizumab (B) for the First-line Treatment of Patients (Pts) With Metastatic Colorectal Cancer (mCRC) L Saltz, 1 J Infante, 2 L Schwartzberg, 3 J Stephenson, 4 C Rocha-Lima, 5 F Galimi, 6 T Sabin, 7 M Hsu, 6 J Wiezorek, 6 C Fuchs 8 1 Memorial Sloan Kettering Cancer Center, New York, NY 2 Sarah Cannon Cancer Center, Nashville, TN 3 West Clinic, Memphis, TN 4 Cancer Center of the Carolinas, Greenville, SC 5 University of Miami, Miami, FL 6 Amgen Inc., Thousand Oaks, CA 7 Amgen Ltd, Cambridge, UK 8 Dana-Farber Cancer Institute, Boston, MA Abstract #4079

2. ASCO 2009 INTRODUCTION Conatumumab (AMG 655) is an investigational, fully human agonist IgG1 monoclonal antibody to human death receptor 5 (DR5) Evidence supporting the combination of conatumumab and chemotherapy to treat mCRC: –Higher levels of DR5 in CRC versus normal colorectal tissue 1 –Combination of conatumumab and 5-FU enhanced activity in CRC xenografts 2 –In the conatumumab first in human (FIH) study, 1 patient with mCRC had a metabolic partial response (35% reduction in maximum standardized uptake value measured using FDG-PET) and a 24% decrease in tumor size (measured by RECIST); 4 patients with mCRC had stable disease > 12 weeks 3 Bevacizumab plus FOLFOX is the most commonly used standard first-line regimen in the United States for patients with mCRC The combination of conatumumab and modified (m)FOLFOX- bevacizumab may improve antitumor activity in patients with mCRC

3. ASCO 2009 Conatumumab Mechanism of Action The TRAIL receptor family is comprised of 2 death receptors (DR4 and DR5) and 2 decoy receptors (DcR1 and DcR2) 4,5 Conatumumab mimics endogenous Apo2L/TRAIL by binding DR5 and activating caspases, thereby inducing apoptosis in sensitive cells

4. ASCO 2009 OBJECTIVES Primary Determine the maximum tolerated dose (up to a target dose of 10 mg/kg IV administered every 2 weeks [Q2W]) of conatumumab that can be safely administered in combination with mFOLFOX6/bevacizumab to patients with mCRC Secondary Safety and tolerability Parameters of clinical benefit (objective response rate, duration of response, time-to-response, progression-free survival, and overall survival) Pharmacokinetics (PK) of conatumumab Anti-conatumumab antibody formation

5. ASCO 2009 PATIENTS AND METHODS Study Design Phase 1b, open-label, dose-escalation study of the combination of conatumumab plus mFOLFOX6 and bevacizumab for the first-line treatment of patients with mCRC

6. ASCO 2009 PATIENTS AND METHODS Phase 1b Study Schema a May have received adjuvant or neo-adjuvant chemotherapy, including bevacizumab and EGFR inhibitors, if disease recurrence was documented ≥ 12 months after completion of chemotherapy. May have received prior fluoropyrimidine therapy if administered solely for the purpose of radiosensitization and if completed ≥ 12 months prior to enrollment. ORR, overall response rate; PFS, progression-free survival; OS, overall survival; TTR, time to tumor response.

7. ASCO 2009 PATIENTS AND METHODS (continued) Patients enrolled in sequential dose cohorts (6 per cohort) of conatumumab (3 or 10 mg/kg) administered IV on Day 1 of each 14-day mFOLFOX6/bevacizumab cycle Treatment regimen (Day 1 to 3): 1.Oxaliplatin (85 mg/m 2 ) and leucovorin (400 mg/m 2 ), 2-hour infusion 2.Then 5-FU (400 mg/m 2 ), IV bolus for 2 to 4 minutes 3.Then bevacizumab (5 mg/kg), IV for 10 to 30 minutes 4.Then conatumumab, IV for 60 minutes 5.Then 5-FU (2400 mg/m 2 ), continuous IV infusion over 46 to 48 hours Treatment continued until disease progression, drug intolerability, withdrawal of consent, or until 30 months from enrollment Tumor assessments were done within 21 days before enrollment, Day 1 of Cycle 5, and every 8 weeks thereafter All patients were followed for survival

8. ASCO 2009 PATIENTS AND METHODS Definition of DLT Grade 4 fatigue or grade 3 fatigue > 7 days; grade 3 or 4 nausea, diarrhea, or vomiting (despite best supportive care); grade 3 or 4 neutropenia with fever > 38.5°C; grade 4 neutropenia or thrombocytopenia > 7 days; elevated ALT or AST > 10 x ULN; and grade 4 elevation in amylase or lipase > 7 days felt to be related to conatumumab or conatumumab + mFOLFOX6/bevacizumab Any other grade ≥ 3 hematologic or non-hematologic toxicity felt to be related to conatumumab or conatumumab + mFOLFOX6/bevacizumab

9. ASCO 2009 RESULTS Baseline Demographics and Disease Characteristics

10. ASCO 2009 RESULTS Patient Disposition a According to the investigator.

11. ASCO 2009 SAFETY Incidence of Treatment-Emergent Adverse Events a a AEs reported in ≥ 3 patients, both cohorts combined (worst grade) b Patient incidence of either of these events. Other grade 3 AEs: DVT (2 patients), febrile neutropenia (2 patients), elevated ALT/AST (1 patient), hydronephrosis (1 patient), hypokalemia (1 patient), hyponatremia (1 patient). Other grade 4 AEs: Pulmonary embolism (2 patients).

12. ASCO 2009 SAFETY (continued) There were no DLTs during the first 28 days of therapy Post-baseline laboratory values of interest grade ≥ 3 –ALT/AST: grade 3 in 1 patient (10-mg/kg cohort) on study Day 232 that resolved by the next cycle (not related to conatumumab) –Bilirubin: grade 3 in 1 patient (3-mg/kg cohort) on study Day 281 that resolved by the next cycle (not related to conatumumab) –Lipase: grade 3 in 3 patients (1 in the 3-mg/kg cohort; 2 in the 10-mg/kg cohort; elevations were asymptomatic) No anti-conatumumab antibodies have been detected to date

13. ASCO 2009 SAFETY Conatumumab Pharmacokinetics Conatumumab PK samples were collected before the conatumumab infusion in Cycles 1, 2, 3, 5, and every 8 Cycles thereafter. They were also collected within 5 minutes before EOI and 48 h after the start of the conatumumab infusion in Cycles 1 and 3. Concentration data at selected time points are presented. Data shown are for both cohorts combined. EOI, end of infusion.

14. ASCO 2009 SAFETY Oxaliplatin Pharmacokinetics Oxaliplatin PK samples were collected on Day 1 of Cycles 1 and 3 before each infusion and within 5 minutes before the end of the oxaliplatin infusion. Data shown are for the 3-mg/kg cohort only. EOI, end of infusion.

15. ASCO 2009 SAFETY Bevacizumab Pharmacokinetics Bevacizumab PK samples were collected on Day 1 of Cycles 1 and 3 before each infusion and within 5 minutes before the end of the bevacizumab infusion.

16. ASCO 2009 SAFETY Tumor Response *Unconfirmed partial response: patients underwent surgical resection prior to confirmation of response. One patient in the 10-mg/kg cohort had no measurable disease at baseline. A best response of stable disease required a radiologically determined response of stable disease or better no earlier than Study Day 49. SLD, sum of longest diameter.

17. ASCO 2009 SAFETY (continued) Median (range) time on conatumumab treatment: 7.2 (1.6 to 10.2+) months Time to progression in the 4 patients who progressed: 8, 26, 32, 42 weeks There were no deaths as of February 2009

18. ASCO 2009 CONCLUSIONS The addition of conatumumab does not appear to substantially alter the safety profile of mFOLFOX6- bevacizumab Conatumumab does not appear to affect the PK of oxaliplatin or bevacizumab There was no apparent impact of mFOLFOX6 and bevacizumab on conatumumab PK exposures The randomized phase 2 part of the trial, mFOLFOX6- bevacizumab with or without conatumumab, is in progress

19. ASCO 2009 CONCLUSIONS Phase 2 Study Schema

20. ASCO 2009 ACKNOWLEDGMENT This study was sponsored by Amgen Inc. (ClinicalTrials.gov identifier: NCT00625651) We would like to thank Kathryn Boorer for writing assistance.