A Randomized, Phase 1/2 Trial of AMG 102 orAMG 479 in Combination With Panitumumab vs Panitumumab Alone in Patients With Wild‑Type

KRAS Metastatic Colorectal Cancer (mCRC): Safety and Efficacy Results

 Eric Van Cutsem,1 Cathy Eng,2 Josep Tabernero,3 Elzbieta Nowara,4 Anna Świeboda-Sadlej,5

Niall C. Tebbutt,6 Edith P. Mitchell,7 Irina Davidenko,8 Lisa Chen,9 Dominic Smethurst10

1University Hospital Gasthuisberg, Leuven, Belgium; 2The University of Texas M.D. Anderson Cancer Center, Houston, TX; 3Vall d'Hebron University

Hospital, Barcelona, Spain; 4Instytut im. M. Sklodowskiej-Curie, Gliwice, Poland; 5Warszawski Uniwersytet Medyczny, Warszawa, Poland; 6Austin

Health, Heidelberg, VIC, Australia; 7Thomas Jefferson University, Philadelphia, PA; 8Krasnodar City Oncology Center, Krasnodar, Russia;

9Amgen Inc., Thousand Oaks, CA; 10Amgen Ltd., Uxbridge, UK

Disclosures

• Eric Van Cutsem: research funding from Amgen, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis

Introduction

• Panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), has demonstrated efficacy in patients with wild-type KRAS mCRC in clinical trials1-4

• Rilotumumab (AMG 102) and ganitumab (AMG 479) are investigational, fully human monoclonal antibodies against hepatocyte growth factor (HGF; ligand for c-Met receptor) and insulin‑like growth factor 1 receptor (IGF-1R), respectively

• Preclinical studies indicate that there is complex interdependence between the HGF/c-Met and IGF-1R and EGFR pathways5-10

• Combinations of agents that block these receptors are being investigated for their potential to generate additive/synergistic anticancer effects1. Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664.2. Amado RG, et al. J Clin Oncol. 2008;26:1626-1634.3. Peeters M, et al. J Clin Oncol. 2010;28:4706-4713.4. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.5. Lesko E, et al. Front Biosci. 2008;13:1271-1280.

6. Hynes NE, et al. Nat Rev Cancer. 2005;5:341-354.7. Jo M, et al. J Biol Chem. 2000;275:8806-8811.8. Ahmad T, et al. J Biol Chem. 2004;279:1713-1719.9. Roudabush FL, et al. J Biol Chem. 2000;275:22583-22589.10. Swantek JL, et al. Endocrinology. 1999;140:3163-3169.

Rilotumumab and Ganitumab Mechanisms of Action

Ganitumab (AMG 479) targets IGF-1R, inhibiting

downstream signaling through PI3K/AKT and

MAPK pathways

Rilotumumab (AMG 102) targets HGF, inhibiting

downstream c-Met signaling

InvasionMigration

Cell PolarityAdhesion

HGF/SF

Cdc42

Rac1PAK

c-Met

Grb2

Sos

Ras

Gab1

RafShp2

ERK/MAPK

Proliferation

PI3K

AKT/PKB

PIP2

PIP3

Survival

XX

X

AMG 102

This depiction is believed to be the MOA of AMG 102; this compound is investigational.

Rilotumumab( )

Ganitumab (AMG 479) IGF-1

IGF-1R

Ras

Raf

ShcIRS1

PI3K

PTEN AKT/PKB

Grb2SOS

MEK

ERK

EIk-1

IGF-2

Cellproliferation

Survivalmechanisms

Study Schema

Part 1 (Phase 1b)a

Panitumumab+ Rilotumumab

(AMG 102) Q2W

Part 2 (Phase 2)b

RANDOMIZE

Part 3 (Phase 2)c

Rilotumumab(AMG 102) Q2W

Ganitumab(AMG 479) Q2W

RANDOMIZE

aPanitumumab 6 mg/kg Q2W; rilotumumab (AMG 102) 10 mg/kg Q2W with dose de-escalation to 5 mg/kg as necessary; primary endpoint was incidence of dose-limiting toxicities

bPanitumumab 6 mg/kg Q2W; rilotumumab (AMG 102) dose based on phase 1b; ganitumab (AMG 479) 12 mg/kg Q2W; primary endpoint was ORR

cRilotumumab 10 mg/kg Q2W; ganitumab (AMG 479) 12 mg/kg Q2W; primary endpoint was ORRdPatients in the placebo arm of Part 2 with progressive disease or intolerance to treatment were eligible to participate in Part 3DLT, dose-limiting toxicity; ORR, objective response rate; Q2W, every 2 weeks

Panitumumab+ Rilotumumab

(AMG 102) Q2W

Panitumumab+ Ganitumab

(AMG 479) Q2W

Panitumumab+ Placebo Q2Wd

• Amgen Trial 20060447; ClinicalTrials.gov identifier NCT00788957

• Tumor assessments were performed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0

Study Objectives

Primary Objectives (Part 1 and Part 2)

• Part 1: To identify a tolerable dose of rilotumumab (AMG 102) in combination with panitumumab based on the incidence and nature of dose-limiting toxicities (DLTs)

• Part 2: To evaluate the efficacy as measured by the objective response rate (ORR) of rilotumumab (AMG 102) + panitumumab and ganitumab (AMG 479) + panitumumab vs panitumumab + placebo

Other Key Objectives (Part 2)

• Efficacy including progression-free survival (PFS) and overall survival (OS)

• Safety

• Pharmacokinetic analysis

• Biomarker analysis

Key Eligibility Criteria

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

• Histologically or cytologically confirmed wild-type KRAS mCRC by local or central testing

• Progression during or following prior treatment with irinotecan- and/or oxaliplatin-based chemotherapy for mCRC

• Glycosylated hemoglobin ≤ 8%

• No prior treatment with EGFR, c-Met, or IGF-1R inhibitors

Statistical Considerations for Part 2

• Randomization was stratified by prior therapy (oxaliplatin or irinotecan vs both)

• Bayesian analysis of response– This method compares the posterior distribution of the ORR for the experimental arms to

that of the control arm to determine an Odds Ratio

– An ORR prior distribution for panitumumab monotherapy was derived from 4 previous trials (patients had received both prior oxaliplatin and irinotecan)

– The ORR prior distributions for the combination arms were assumed to have the same mean as the panitumumab alone arm

– The ORR posterior distribution for each arm combines the prior distributions with observed ORRs from the study

• It was prespecified that if there was ≥ 90% probability that combination therapy was better than panitumumab alone as evaluated by objective tumor response, the combination was considered promising – If there was between 50% and 90% probability, the combination was considered

indeterminate

– If there was < 50% probability, the combination was considered not promising

Results

Part 1 Results (Phase 1b)

• In Part 1, no DLTs were reported for the first 6 DLT-evaluable patients receiving panitumumab in combination with rilotumumab (AMG 102) 10 mg/kg Q2W– The 10 mg/kg Q2W dose of rilotumumab (AMG 102) was used in

Part 2

Part 2 Results (Phase 2)

• 142 patients enrolled from 37 sites in 11 countries

• The enrollment period was June 9, 2009 throughFebruary 5, 2010

• The date for data cut-off for this analysis was July 23, 2010

• Median follow-up is 6.9 months; follow-up is ongoing

Part 2: Patient Demographics and Disease Characteristics at Baseline

Panitumumab+ Placebo

(n = 48)

Panitumumab+ Rilotumumab

(AMG 102)(n = 48)

Panitumumab+ Ganitumab

(AMG 479)(n = 46)

Men - n (%) 28 (58) 29 (60) 25 (54)

Age - mean years (range) 55.0 (19-75) 62.1 (45-78) 62.0 (33-81)

ECOG status - n (%)01

15 (31)33 (69)

24 (50)23 (48)a

18 (39)28 (61)

Metastatic sites - n (%)Liver onlyLiver + other sites

5 (10)27 (56)

5 (10)32 (67)

4 (9)29 (63)

Prior therapies for mCRC - n (%)First-line therapySecond-line therapyThird-line therapy and later

46 (96)b

31 (65)14 (29)

48 (100)33 (69)16 (33)

46 (100)26 (57)12 (26)

Prior chemotherapies for mCRC - n (%)OxaliplatinIrinotecanOxaliplatin and irinotecan

39 (81)30 (63)23 (48)

42 (88)32 (67)26 (54)

40 (87)26 (57)20 (44)

aOne patient with ECOG performance score of 2 was enrolled in error; data from this patient were included in all efficacy and safety analysesbTwo patients had not received first-line therapy for mCRC; both patients had received oxaliplatin-based chemotherapy for non-metastatic CRC in the adjuvant setting and progressed on therapy before entering the study

Part 2: Primary EndpointOverall Response Rate

Panitumumab+ Placebo

(n = 48)

Panitumumab+ Rilotumumab

(AMG 102)(n = 48)

Panitumumab+ Ganitumab

(AMG 479)(n = 46)

Objective Response - n (%)

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Unevaluable/Not done

10 (21)

0 (0)

10 (21)

17 (35)

16 (33)

5 (10)

15 (31)

0 (0)

15 (31)

19 (40)

11 (23)

3 (6)

10 (22)

0 (0)

10 (22)

18 (39)

15 (33)

3 (6)

Disease control ratea - % (95% CI) 56 (41-71) 71 (56-83) 61 (45-75)

Duration of response - median months (95% CI)

3.7 (3.6-NE) 5.1 (3.7-5.6) 3.7 (3.6-5.8)

Posterior probability of Odds Ratio > 1b 0.93 0.63

aDisease control rate = CR + PR + SDbOR is calculated based on ORR; an OR > 1 favors the combination arm over panitumumab alone NE, not estimable

• Responses were required to be confirmed at least 4 weeks after response criteria were first met

Part 2: Progression-Free Survival

Panitumumab ± Rilotumumab (AMG 102)

Panitumumab ± Ganitumab (AMG 479)

Eventsn/N (%)

Median Months(95% CI)

Panitumumab + Placebo (n = 48) 36/48 (75) 3.7 (2.5-5.3)

Panitumumab + Rilotumumab (n = 48) 41/48 (85) 5.2 (3.6-5.4)

Hazard ratio = 0.96 (95% CI: 0.61-1.51)

Eventsn/N (%)

Median Months(95% CI)

Panitumumab + Placebo (n = 48) 36/48 (75) 3.7 (2.5-5.3)

Panitumumab + Ganitumab (n = 46) 36/46 (78) 5.3 (2.7-5.7)

Hazard ratio = 0.89 (95% CI: 0.56-1.42)Pat

ien

tsw

ith

Pro

gre

ssio

n-F

ree

Su

rviv

al(%

)

Patients at risk:Panitumumab + Placebo: 48 43 30 24 19 19 7 6 3 2 1 1 0

Panitumumab + Ganitumab: 46 44 30 27 24 22 11 8 1 1 1 1 0

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 10 11 12

Months

100

90

80

70

60

50

40

30

20

10

0

Pat

ien

tsw

ith

Pro

gre

ssio

n-F

ree

Su

rviv

al(%

)

Patients at risk:Panitumumab + Placebo: 48 43 30 24 19 19 7 6 3 2 1 1 0

Panitumumab + Rilotumumab: 48 45 35 30 27 26 10 8 4 1 0 0 0

0 1 2 3 4 5 6 7 8 9 10 11 12Months

(AMG 102)

(AMG 479)

(AMG 102)

(AMG 479)

Adverse Events in Part 2(Any Grade in ≥ 20% or Grade 3/4 in ≥ 2 Patients)

Panitumumab+ Placebo

(n = 48)

Panitumumab+ Rilotumumab(AMG 102)

(n = 48)

Panitumumab+ Ganitumab

(AMG 479) (n = 46)

AE (Preferred term) - % Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4

Any AE 94 52 98 71 100 63

Rash 52 8 58 29 48 13

Acneiform dermatitis 33 10 35 15 26 11

Pruritus 25 0 21 0 28 2

Skin fissures 17 0 15 2 26 0

Paronychia 15 2 31 4 20 2

Dry skin 15 0 23 2 22 0

Acne 0 0 8 4 11 0

Skin toxicity 0 0 2 2 4 4

Constipation 25 6 10 0 13 0

Decreased appetite 17 2 21 2 20 2

Abdominal pain 15 6 10 4 9 7

Diarrhea 10 0 15 4 26 2

Hypomagnesemia 21 2 29 4 41 15

Fatigue 21 2 10 4 17 2

Anemia 17 8 4 0 2 0

Asthenia 15 0 8 0 13 4

• There were 9 grade 5 AEs; 1 occurred in the panitumumab alone arm and 4 occurred each in the combination arms― All except 1 were due to disease progression; 1 fatal AE was due to staphylococcal sepsis (panitumumab +

ganitumab [AMG 479] arm)― None were reported to be related to investigational product

AE, adverse event

Conclusions

• This is the first study to show promising evidence of efficacy by an HGF (c-Met pathway) inhibitor (rilotumumab [AMG 102]) when combined with panitumumab in patients with mCRC

• The activity as assessed by ORR for patients receiving rilotumumab (AMG 102) plus panitumumab is promising (per prospectively specified Bayesian criterion)

• Efficacy of ganitumab (AMG 479) plus panitumumab combination therapy as determined by ORR was indeterminate

• The safety profiles of the drug combinations were generally similar to that of panitumumab alone with some exceptions, including a higher rate of grade 3/4 rash with rilotumumab and of hypomagnesemia with ganitumab

• Analyses of biomarkers of response in serum and tissue samples are underway