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CTOS Meeting Venice, Italy 4 November 2006

Initial Results of a Multicenter, Single-Arm Phase 2 Study of AMG 706, an Oral Multikinase Inhibitor, for the Treatment of Advanced Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST).

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CTOS Meeting Venice, Italy 4 November 2006

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  1. Initial Results of a Multicenter, Single-Arm Phase 2 Study of AMG 706, an Oral Multikinase Inhibitor, for the Treatment of Advanced Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST) Robert Benjamin, Patrick Schöffski, Jörg Thomas Hartmann, Binh Nguyen Bui, Justus Duyster, Scott Schuetze, Jean-Yves Blay, Peter Reichardt, Lee Rosen, Keith Skubitz, Michael Eschenberg, Daniel Stepan, and Laurence Baker On behalf of the study investigators CTOS Meeting Venice, Italy 4 November 2006

  2. AMG 706: An Oral Multi-targeted Kinase Inhibitor • A novel, orally bioavailable, small-molecule multikinase inhibitor • Has shown both antiangiogenic and direct antitumor activity in a phase 1 clinical trial in patients with advanced solid tumor malignancies Herbst R et al. Eur J Cancer. 2005;3(Suppl):1455. Rosen L et al. Proc ASCO. 2005. Abstract 3013.

  3. AMG 706 Selectively Targets Multiple Receptor Tyrosine Kinases Involved in Angiogenesis aStem cell factor

  4. Study Objectives Primary Evaluate the effect of treatment with AMG 706 on the objective response rate (by RECIST) in patients with advanced GIST who developed progressive disease or relapsed while receiving imatinib • Secondary • Assess effect of AMG 706 on duration of response, progression-free survival, time to progression, survival, and adverse events • Explore the utility of 18FDG-PET and target tumor size/density changes (Choi criteria) for predicting tumor response • Assess the pharmacokinetic profiles of AMG 706

  5. Main Eligibility Criteria • Histologically confirmed GIST expressing CD117 • Documented failure of prior treatment with imatinib • At least 600 mg daily for at least 8 weeks • Disease progression per 2 independently assessed pre-study radiographic scans within 6 months of study day 1 • Imatinib treatment terminated at least 7 days before study day 1 • Presence of at least one measurable (per RECIST) and progressing tumor lesion not previously treated with radiotherapy or embolization and evaluable by CT or MRI • Adequate organ function

  6. Study Design and Treatment Regimen

  7. Study Execution • International, multicenter study at 29 sitesa • Participating countries (number of patients) • USA (64) • Germany (34) • France (20) • Belgium (10) • Canada (6) • Italy (2) • United Kingdom (2) • Study accrued 138 patients within 10 months • October 2004 to July 2005 aScreened one or more patients

  8. Baseline Demographics and Clinical Characteristics

  9. Prior Imatinib Therapy

  10. Maximal Dose of Prestudy Imatinib

  11. Patient Disposition

  12. Best Tumor Response by RECIST per Independent Review: Per-Protocol Analysis Seta aIncludes all subjects who received at least one administration of AMG 706 and who were classified as having pre-study disease progression (per RECIST) per independent review.

  13. Objective Response by 18FDG-PETa at Week 8 per Independent Review: Per-Protocol Analysis Set aDefined as > 25% decrease in average standardized uptake value (SUVmax) in all RECIST target lesions compared with the average SUVmax in all RECIST target lesions at baseline as measured by the independent reviewer. bAll patients with a baseline and week 8 18FDG-PET scan. Does not include patients who discontinue study prior to week 8, even if discontinuation is due to clinical progression.

  14. Objective Response by 18FDG-PET Screening: 21 June 05 Week 8: 24 August 05

  15. Objective Response by Choi Criteriaa at Week 8 per Independent Review: Per-Protocol Analysis Set aDefined as ≥ 10% decrease in the sum of the longest diameter of the target lesions (identified by RECIST) and/or ≥ 15% decrease in the average target tumor density (in Hounsfield units, HU) using the RECIST target lesions compared with the average baseline density based on CT scans. bAll patients with both baseline and week 8 measures of the sum of the longest diameters (SLD) or tumor density (in HU).

  16. Objective Response by Choi Criteria at Week 8 HU = 141.4 HU = 89.8 Baseline Week 8

  17. Best Response in Tumor Measurement by CT (per RECIST) per Independent Review: Per-Protocol Analysis Set

  18. Progression-Free Survival (PFS) per Independent Review: Per-Protocol Analysis Set

  19. Survival: Per-Protocol Analysis Set

  20. Pharmacokinetic Profiles (Day 1) *Median (range) • Day 1 PK profiles of AMG 706 were similar in patients with partial or full gastrectomy and • in patients without gastrectomy. • PK profiles of AMG 706 were similar in patients with GIST and in patients with solid tumors (first-in-human study).

  21. Treatment-Emergent Adverse Events Occurring in at Least 15% of Patients Data are n (%) aReversible posterior leukoencephalopathy syndrome

  22. Adverse Events of Interest Data are n (%) aTwo patients experienced both a thromboembolic event and a cardiac disorder bPatients were not monitored with serial TSH levels during the study

  23. Conclusions • AMG 706 demonstrated an encouraging clinical benefit rate in study patients with advanced high-dose imatinib-resistant GIST: • Choi response rate of 33% (40% of evaluable patients) • PET response rate of 23% (30% of evaluable patients) • PR (3%) + durable SD ≥ 22 weeks (24%) of 27% • Median progression-free survival of 16 weeks • 26-week progression-free survival of 27% • Median survival of 59% • AMG 706 was reasonably well tolerated with rare incidence of grade 3/4 adverse events except hypertension. • Further studies of AMG 706 in GIST appear warranted.

  24. AcknowledgementsAll of the participating patients and their families To the global network of investigators, research nurses, study coordinators, and operations staff Participating Investigators (Number of Patients Enrolled) North America Europe B Benjamin (14), S Schuetze and L Baker (10), L Rosen (7), K Skubitz (6), D Mahadevan (5), M Fanucchi (5), R Tozer (4), EG Chiorean (3), E Borden (3), A Staddon (2),A Evens (2), R Taub (2), M von Mehran (2), K Mulder (2), B Brockstein (1), A Elias (1), S Chawla (1) JT Hartmann (12),P Schöffski and AT van Oosterom (10), BN Bui (10), J Duyster (10), JY Blay (7), P Reichardt (7), M Flasshove and T Ebeling (5), A Le Cesne (3), I Judson (2), P Casali (1), M Marangolo (1) Amgen, Inc. (Sponsor) D Stepan, D Reese, M Eschenberg, Y-N Sun, A Koutsoukos, M MacDonald, W Lovelace, K Aitchison, C Puzo, S Creamer, J Wright, T Juan Radiology Review RadPharm

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