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 MeetingVenice, Italy

4 November 2006

CTOS 20062

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 malignanciesHerbst R et al. Eur J Cancer. 2005;3(Suppl):1455.

Rosen L et al. Proc ASCO. 2005. Abstract 3013.

N NH

NH

O

NH

N

CTOS 20063

AMG 706 Selectively Targets Multiple Receptor Tyrosine Kinases Involved in Angiogenesis

aStem cell factor

CTOS 20064

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

CTOS 20065

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

CTOS 20066

Study Design and Treatment Regimen

SCREENING

AMG 706 125 mg po daily7 Day

imatinibWashout

Screening /Baseline

CT

Day 1Start

AMG 70618FDG-PET

8 WkCT

FDG-PET

16 WKCT

24 WKCT

32 WKCT

Q 8 WksThereafter

CT

48 wks off studya

Responders andstable diseasemay continueAMG 706 infollow-upprotocol

aAll subjects are followed for survival for up to 2 years following last AMG 706

CTOS 20067

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

CTOS 20068

Baseline Demographics and Clinical Characteristics

All Patients

N = 138

Men, n (%) 84 (61)

Age

Median (min, max), years≥ 65 years, n (%)

61 (25, 90)54 (39)

Karnofsky performance, n (%)

100 90 80 70 60

33 (24)63 (46)22 (16)14 (10)

6 (4)

Prior chemotherapy other than imatinib, n (%)

None1 regimen≥ 2 regimens

117 (85)11 (8)10 (7)

Prior radiotherapy, n (%)

None 132 (96)

CTOS 20069

Prior Imatinib Therapy

All Patients

N = 138

Duration of first imatinib therapy, n (%)

≤ 6 months> 6 months

34 (25)104 (75)

Duration of last imatinib therapy, n (%)

≤ 6 months> 6 months

88 (64)50 (36)

Total duration of imatinib therapy, monthsmedian (min, max) 32.5 (4.1, 57.3)

Best response to most recent imatinib, n (%)

Complete responsePartial responseStable diseaseProgressive disease

4 (3)48 (35) 39 (28)47 (34)

CTOS 200610

Maximal Dose of Prestudy Imatinib

All Patients

N = 138

Highest imatinib dose administered, n (%)

800 mg 108 (78)

600 mg 21 (15)

1000 mg 4 (3)

1200 mg 3 (2)

1100 mg 1 (1)

700 mg 1 (1)

CTOS 200611

Patient Disposition

All Patients

N = 138

Completed planned AMG 706 administration (48 wks), n (%) 10 (7)

Discontinued AMG 706 administration (< 48 wks), n (%)

Disease progressionAdverse eventConsent withdrawnDeathAdministrative decisionProtocol deviationOther

128 (93)

83 (60)31 (22)

6 (4)3 (2)1 (1)1 (1)3 (2)

Weeks of AMG 706 treatment

median (min, max) 16 (0.3, 52.0)

CTOS 200612

Best Tumor Response by RECIST per Independent Review: Per-Protocol Analysis Seta

All Patients

N = 120

Confirmed RECIST response, n (%) 3 (3)

95 % CI 0.5, 7.1

Confirmed complete response (CR), n (%)Confirmed partial response (PR), n (%)

0 (0)3 (3)

Stable disease (SD ≥ 52 days), n (%) 55 (46)

Durable stable disease (SD ≥ 22 weeks), n (%) 29 (24)

Progressive disease (PD), n (%) 39 (33)

Unevaluable, n (%) 5 (4)

Not performed, n (%) 18 (15)

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.

CTOS 200613

Objective Response by 18FDG-PETa at Week 8 per Independent Review: Per-Protocol Analysis Set

Evaluableb

N = 89All Patients

N = 120

Objective response, n (%)

95% CI

27 (30)

21.0, 41.0

27 (23)

15.4, 31.0

Non-response, n (%)

95% CI

62 (70)

59.0, 79.0

93 (78)

69.0, 84.6

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.

CTOS 200614

Objective Response by 18FDG-PET

Screening: 21 June 05 Week 8: 24 August 05

CTOS 200615

Objective Response by Choi Criteriaa at Week 8 per Independent Review: Per-Protocol Analysis Set

Evaluableb

N = 97All Patients

N = 120

Objective response, n (%)

95% CI

39 (40)

30.3, 50.7

39 (33)

24.2, 41.7

Non-response, n (%)

95% CI

58 (60)

49.4, 69.6

81 (68)

58.3, 75.8

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).

CTOS 200616

Objective Response by Choi Criteria at Week 8

Baseline Week 8

HU = 141.4 HU = 89.8

CTOS 200617

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

0

20

-20

40

-40

60

-60

80

-80

100

-100

Max

imu

m P

erce

nt

Ch

ang

e in

SL

D

Change from baseline between -30% and -9%

< 2% change from baseline

RECIST

Choi criteria

Subject

Overall Best Response (RECIST)

Missing Partial ResponseStable Disease Progressive Disease

SLD = sum of longest diameters oftarget tumor lesions

CTOS 200618

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

(N) 120 111 92 60 50 42 34 23 19 14 11 7 6 1 1 0

Kap

lan

-Mei

er P

erce

nt

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Weeks

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

K-M estimate (95% CI) of 26-week PFS: 27% (19%, 36%)K-M median time (95% CI), weeks: 16 (10, 23)Number of PFS events: 90 (75%)

95% confidence intervals of the Kaplan-Meier estimate at Week 16, Week 32 and Week 48 are presented. = Censored observation

CTOS 200619

Survival: Per-Protocol Analysis Set

(N) 120 117 114 107 102 97 93 88 80 77 70 62 60 51 40 31 23 17 11 4 3 3 0

95% confidence intervals of the Kaplan-Meier estimate at Week 16, Week 32 and Week 48 are presented. = Censored observation

Kap

lan

-Mei

er P

erce

nt

0%

10% 20%

30% 40%

50%

60% 70%

80% 90%

100%

Weeks0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88

K-M median time (95% CI), weeks: 59.3 (49.3, NE)Number of deaths: 56 (47%)

CTOS 200620

Pharmacokinetic Profiles (Day 1)

Parameter No GastrectomyPartial or Full Gastrectomy

n Mean (SD) n Mean (SD)

tmax (hr)* 180.5

(0.25, 2.0)8

0.75(0.25, 4.0)

Cmax (ng/mL) 18 572 (175) 8 581 (284)

AUC0-24 (μg•hr/mL) 12 3.03 (1.94) 7 2.81 (1.37)

AUC0- (μg•hr/mL) 12 3.28 (2.23) 7 3.08 (1.47)

t1/2, z (hr) 12 5.80 (1.61) 7 6.77 (2.33)

CL/F (L/hr) 12 54.1 (36.4) 7 59.6 (55.0)

C24 (ng/mL) 12 24.8 (27.6) 7 25.5 (13.6)

• 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).

*Median (range)Time (hr)

0 4 8 12 16 20 24A

MG

70

6 P

las

ma

Co

nc

. (n

g/m

L)

1

10

100

1000

10000

No Gastrectomy (n = 18)Partial or Full Gastrectomy (n = 8)

CTOS 200621

Treatment-Emergent Adverse Events Occurring in at Least 15% of Patients

All PatientsN = 138

Grade 3 Grade 4

Diarrhea 76 (55) 10 (7) 0

Hypertension 66 (48) 31 (22) 1 (1)a

Fatigue 62 (45) 17 (12) 0

Nausea 48 (35) 5 (4) 0

Headache 47 (34) 5 (4) 0

Abdominal Pain 44 (32) 14 (10) 0

Anorexia 42 (30) 10 (7) 0

Vomiting 41 (30) 7 (5) 0

Weight decrease 37 (27) 6 (4) 0

Constipation 33 (24) 2 (1) 0

Dysphonia 27 (20) 0 0

Asthenia 23 (17) 7 (5) 0

Dizziness 22 (16) 2 (1) 0

Insomnia 21 (15) 1 (1) 0

Data are n (%)aReversible posterior leukoencephalopathy syndrome

CTOS 200622

Adverse Events of Interest

All PatientsN = 138

Grade 3 Grade 4 Grade 5

Hemorrhage 14 (10) 5 (4) 1 (1) 0

Thromboembolic eventsa 10 (7) 2 (1) 4 (3) 1 (1)

Cardiac disordersa 5 (4) 1 (1) 2 (1) 1 (1)

Hypothyroidismb 3 (2) 1 (1) 0 0

Impaired wound healing 2 (1) 1 (1) 0 0

Cholecystitis 1 (1) 0 0 0

Pancreatitis 1 (1) 1 (1) 0 0

Data are n (%)aTwo patients experienced both a thromboembolic event and a cardiac disorderbPatients were not monitored with serial TSH levels during the study

CTOS 200623

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.

CTOS 200624

AcknowledgementsAll of the participating patients and their families

To the global network of investigators, research nurses, study coordinators, and operations staff

North America

Europe

Amgen, Inc. (Sponsor)

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)

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

Participating Investigators (Number of Patients Enrolled)