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INTRODUCTION

Phase 1b Study of AMG 655 in Combination With Modified FOLFOX6 (mFOLFOX6) and Bevacizumab (B) for the First-Line Treatment of Patients With Metastatic Colorectal Cancer (mCRC).

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INTRODUCTION

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  1. Phase 1b Study of AMG 655 in Combination With Modified FOLFOX6 (mFOLFOX6) and Bevacizumab (B) for the First-Line Treatment of Patients With Metastatic Colorectal Cancer (mCRC) L Saltz,1 J Infante,2 L Schwartzberg,3 J Stephenson,4C Rocha-Lima,5 A Braun,6 K Dillingham,7 M Hsu,6J Wiezorek,6 C Fuchs8 1Memorial Sloan Kettering Cancer Center, New York, NY; 2Sarah Cannon Cancer Center, Nashville, TN; 3West Clinic, Memphis, TN; 4Cancer Center of the Carolinas, Greenville, SC; 5University of Miami, Miami, FL; 6Amgen Inc., Thousand Oaks, CA; 7Amgen Ltd, Cambridge, UK; 8Dana-Farber Cancer Institute, Boston, MA

  2. INTRODUCTION • AMG 655 is an investigational, fully human agonist monoclonal antibody (IgG1) that targets human death receptor 5 (DR5) • Evidence supports the development of AMG 655 in combination with chemotherapy to treat metastatic colorectal cancer (mCRC): • CRC tumors express higher levels of DR5 compared with normal colorectal tissue1 • AMG 655 demonstrated dose-dependent activity against CRC xenografts that was significantly enhanced by combining AMG 655 with 5-FU2 • In the AMG 655 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 weeks3 • Bevacizumab plus FOLFOX is the most commonly used standard first-line regimen in the United States for patients with mCRC • We hypothesize that the addition of AMG 655 to modified (m)FOLFOX-bevacizumab may improve antitumor activity in patients with mCRC

  3. INTRODUCTION: AMG 655 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 • AMG 655 mimics endogenous Apo2L/TRAIL by binding DR5 and activating caspases, thereby inducing apoptosis in sensitive cells

  4. OBJECTIVES • Primary • Determine the maximum tolerated dose (up to a target dose of 10 mg/kg IV administered every 2 weeks [Q2W]) of AMG 655 that can be safely administered in combination with mFOLFOX6/bevacizumab to patients with mCRC • Secondary • Safety and tolerability of escalating doses of AMG 655 in combination with mFOLFOX6/bevacizumab • Parameters of clinical benefit (objective response rate, duration of response, time-to-response, progression-free survival, and overall survival) • Pharmacokinetics (PK) of AMG 655 • Anti-AMG 655 antibody formation

  5. PATIENTS AND METHODS: Study Design • Phase 1b, open-label, dose-escalation study of AMG 655 in combination with mFOLFOX6 and bevacizumab for the first-line treatment of patients with mCRC

  6. PATIENTS AND METHODS: Phase 1b Study Schema

  7. PATIENTS AND METHODS (continued) • Patients were enrolled in sequential dose cohorts (6 per cohort) of AMG 655 (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/m2) and leucovorin (400 mg/m2) administered concurrently as a 2-hour infusion 2. Then 5-FU (400 mg/m2) IV bolus for 2 to 4 minutes 3. Then bevacizumab 5 mg/kg IV for 10 to 30 minutes 4. Then AMG 655 IV for 60 minutes 5. Then 5-FU 2400 mg/m2 by continuous IV infusion over 46 to 48 hours • Patients received treatment until disease progression, drug intolerability, withdrawal of consent, or until 30 months from enrollment • Tumor assessments were performed within 21 days before enrollment, Day 1 of Cycle 5, and every 8 weeks thereafter • All patients were followed for survival

  8. PATIENTS AND METHODS: Endpoints • Primary Endpoint • Incidence of dose-limiting toxicities (DLT) • Secondary Endpoints • Incidence of adverse events (AE, graded according to NCI CTCAE Version 3.0) • Incidence of anti-AMG 655 antibody formation • Pharmacokinetic parameters of AMG 655 • Objective response rate (CR, PR), time-to-response, overall survival, duration of response, progression-free survival

  9. PATIENTS AND METHODS: Key Eligibility Criteria • Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum • ECOG performance status 0 or 1 • ≥ 18 years • Adequate hematologic, cardiac, renal, coagulation, and hepatic function • No prior adjuvant or neoadjuvant chemotherapy for the treatment of advanced or mCRC with the following exceptions: • 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 if completed ≥ 12 months prior to enrollment

  10. 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 toAMG 655 or AMG 655 + mFOLFOX6/bevacizumab • Any other grade ≥ 3 hematologic or non-hematologic toxicity felt to be related to AMG 655 or AMG 655 + mFOLFOX6/bevacizumab

  11. RESULTS • As of 25 September 2008, a total of 12 patients (6 per cohort) were enrolled and received ≥ 1 cycle of treatment

  12. RESULTS: Baseline Demographics and Disease Characteristics

  13. RESULTS: Patient Disposition aPatient underwent resection. bPatient reached maximum clinical benefit according to the investigator.

  14. SAFETY: Incidence of Treatment-Emergent Adverse Eventsa aAEs reported in ≥ 3 patients, both cohorts combined (worst grade). bPatient incidence of either of these events. Other grade 3 AEs:DVT (2 patients),febrile neutropenia (2 patients), hydronephrosis (1 patient), hypokalemia (1 patient), hyponatremia (1 patient). Other grade 4 AEs:pulmonary embolism (2 patients).

  15. SAFETY (continued) • There were no DLTs during the first 28 days of therapy • The following serious AEs were reported: • One patient (10-mg/kg cohort) with grade 4 abdominal pain(Day 3) and grade 4 pulmonary embolism (Day 57) • One patient (10-mg/kg cohort) with grade 4 neutropenia (Day 29) and grade 4 pulmonary embolism (Day 56) • One patient (10-mg/kg cohort) with grade 2 nausea and vomiting and grade 3 diarrhea (Day 37) and febrile neutropenia (Day 39) • Post baseline laboratory parameters grade ≥ 3 • ALT or AST: none • Bilirubin: grade 3 in 1 patient (3-mg/kg cohort) on study Day 281 that resolved by the next cycle (not related to AMG 655 treatment) • 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-AMG 655 antibodies have been detected to date

  16. SAFETY: AMG 655 Pharmacokinetics AMG 655 PK samples were collected before the AMG 655 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 AMG 655 infusion in Cycles 1 and 3. Data shown are for both cohorts combined.EOI, end of infusion.

  17. 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.

  18. 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. Data shown are for the 3-mg/kg cohort only.EOI, end of infusion.

  19. SAFETY: Tumor Response • Median (range) time on AMG 655 treatment: 6.9 (1.6 to 11.4+) months • Time to progression in the 3 patients who progressed: 8, 42, 44 weeks • There were no deaths as of September 2008 *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.

  20. CONCLUSIONS • The addition of AMG 655 does not appear to substantially alter the safety profile of mFOLFOX6-bevacizumab • AMG 655 does not appear to affect the PK of oxaliplatin or bevacizumab • The randomizedphase 2 part of thetrial, mFOLFOX6-Bwith or withoutAMG 655, is inprogress Phase 2 Study Schema

  21. REFERENCES • Amgen data on file. • Amgen data on file. • LoRusso P, et al. J Clin Oncol. 2007;25(18S):abstr 3534. • Ghobrial IM, et al. CA Cancer J Clin. 2005;55:178-194. • Ashkenazi A. Nat Rev Cancer. 2002;2:420-430. • Gan HK, et al. Cancer Chemother Pharmacol. 2006;58:157-164. • Lévi F, et al. Clin Pharmacokinet. 2000;38:1-21. • Lu JF, et al. Cancer Chemother Pharmacol. 2008;62:779-786.

  22. ACKNOWLEDGMENT • We would like to thank Francesco Galimi for his contribution to this study and Kathryn Boorer for writing assistance.

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