Hecht WCGIC 2007

An Interim Analysis of Efficacy And Safety From A Randomized Controlled Trial of Panitumumab With Chemotherapy Plus

Bevacizumab (Bev) for Metastatic Colorectal Cancer (mCRC)

J. Randolph Hecht,1 Tarek Chidiac,2 Edith Mitchell,3 Philip Stella,4 Allen Cohn,5 David McCollum,6 Mansoor Saleh,7 John Marshall,8

Seta Shahin,9 Robert Deeter9

1UCLA School of Medicine, Los Angeles, CA; 2Mid Ohio Oncology/Hematology, Inc, Columbus, OH; 3Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA; 4St. Joseph Mercy Hospital, Ann Arbor, MI; 5Rocky Mountain Cancer Centers, Denver, CO;

6Baylor-Sammons Cancer Center, Dallas, TX; 7Georgia Cancer Specialists, Atlanta, GA; 8Georgetown University Hospital, Washington, DC; 9Amgen Inc., Thousand Oaks, CA

Hecht WCGIC 20072

Introduction

Panitumumab is a fully human monoclonal antibody that targets the epidermal growth factor receptor (EGFr) and is approved in the US for the treatment of refractory mCRC

The US standard of care for first-line treatment of mCRC is the combination of bevacizumab plus oxaliplatin- or irinotecan-based chemotherapy (Ox-CT or Iri-CT)

Preclinical and preliminary clinical studies have suggested that combining EGFr, VEGF inhibitors, and chemotherapy may improve efficacy1,2

The PACCE study was designed to compare the efficacy and safety of bevacizumab and chemotherapy +/- panitumumab for first-line treatment of mCRC

1Shaheen et al. Brit J Cancer 2001;85:584-5892Saltz LB et al. ASCO 2005. Abstract #3508 (BOND2)

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Study SchemaPACCE: Panitumumab Advanced Colorectal Cancer Evaluation

Randomized, Open-Label, Controlled Phase 3b Trial

Stratification Factors: ECOG score, prior adjuvant tx, disease site,Ox doses/Iri regimen, number of metastatic organs

Tumor assessments: Q12W until disease progression or intolerability

Panitumumab 6 mg/kg Q2W

Ox-CTBevacizumab

Ox-based CT(eg, FOLFOX)

N = 800Inv choice

Iri-basedCT(eg, FOLFIRI)

N = 200Inv choice

Ox-CTBevacizumab

Panitumumab Panitumumab 6 mg/kg Q2W6 mg/kg Q2W

Iri-CTIri-CTBevacizumabBevacizumab

Iri-CTIri-CTBevacizumabBevacizumab

RANDOMIZE

1:1

1:1

SCREENING

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Key Eligibility CriteriaKey Eligibility Criteria

Age 18 years old

Measurable mCRC per modified RECIST criteria

ECOG status 0 or 1

Adequate hematologic, renal, and hepatic function

No prior chemotherapy or biologic therapy for mCRC

No adjuvant chemotherapy within 6 months

No major surgery within 28 days of randomization or elective and/or planned major surgical procedures during the trial

No clinically significant cardiovascular disease within 1 year prior to randomization

No EGFr testing required

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Primary endpoint:*– Progression-free survival (PFS) by central review in the Ox-CT cohort

Secondary endpoints:– Objective response rate by central review– Time to treatment failure (TTF)– Overall survival (OS) – Safety profile

Design Characteristics

– To detect a 30% improvement in median PFS in the panitumumab plus bev/Ox-CT vs the bev/Ox-CT

• 80% power and = 0.05 (2-sided) for 462 PFS events (disease progression or death)

• Planned interim analysis at ~231 PFS events

Study Endpoints and Design Characteristics

*Powered for oxaliplatin cohort only; descriptive for irinotecan cohort

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Independent DMC AnalysesIndependent DMC Analyses

25 Pts

Safety

75 Pts150 Pts

Safety SafetyRR

Unplanned Safety

Efficacy

SafetyRR

SafetyEfficacy

500 Pts800 Pts

~231 PFS events ~231 OS

Q3 07

DMC recommended continuation without protocol modification

Mar 2005

Panitumumab dosing was discontinued

DMC recommended

changes to informed consent

1st pt randomized

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Baseline Demographics and CharacteristicsBaseline Demographics and Characteristics

pmab+ bev/Ox-CT

(N=407)bev/Ox-CT

(N=405)

pmab+ bev/Iri-CT

(N=68)bev/Iri-CT

(N=67)

Male, % 57 58 49 63

Race, % White Black Hispanic

8386

81106

75183

701910

Age, median, years Range

6128 - 88

6227 - 89

60.537 - 84

5723 - 80

Age 65, % 39 43 41 28

Baseline ECOG, % 0 1

6238

5941

6040

6337

Prior Adjuvant Therapy, % 19 19 40 37

Metastatic organs, % 1 >1

4951

4951

4060

4852

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Summary of Adverse Events (Ox-CT Cohort)Summary of Adverse Events (Ox-CT Cohort)

pmab+ bev/Ox-CT

(N=401)bev/Ox-CT

(N=392)

Any event, % 100 100

Grade 3 53 52

Grade 4 28 18

Grade 5* 4 3

Any serious (SAE), % 56 37

Ended first-line treatment due to AE, %

19 20

Ended panitumumab treatment due to AE, %

26 n/a

Panitumumab treatment-related SAE, %

19 n/a

Safety set included all patients who were dosed. Graded per NCI CTCAE v3.0*Not including disease progression (ie, neoplasms)n/a= not applicable

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Grade 3 or 4 Adverse Events of InterestGrade 3 or 4 Adverse Events of Interest(Ox-CT Cohort)(Ox-CT Cohort)

pmab+bev/Ox-CT(N=401), %

bev/Ox-CT(N=392), %

Gr 3 Gr 4 Gr 3 Gr 4

Skin toxicity 33 <1 1 0

Diarrhea 21 2 12 1

Dehydration 14 2 4 1

Hypokalemia 8 2 3 1

Hypomagnesemia 3 1 0 0

Neutropenia 12 10 17 7

Neuropathy 9 <1 10 <1

Nausea 10 0 4 <1

Infectionsa 16 2 7 2

Deep venous thrombosis 6 0 7 0

Pulmonary embolismb 0 6 0 4MedDRA v9.0 preferred terms; Graded per NCI CTCAE v3.0aGrade 5 infections occurred in 2 (1%) pmab + bev/Ox-CT pts and 3 (1%) bev/Ox-CT ptsbGrade 5 pulmonary embolism occurred in 2 (1%) pmab + bev/Ox-CT pts

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Deaths (Ox-CT Cohort)Deaths (Ox-CT Cohort)

pmab+ bev/Ox-CT

N=401n (%)

bev/Ox-CTN=392n (%)

Deaths on study 83 (20) 58 (15)

All cause deaths within 60 days of first dose

10 (2) 6 (2)

All cause deaths within 30 days of last dose of 1st line tx

26 (6) 13 (3)

Safety set included all patients who were dosed

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Objective Response RateObjective Response Rate By Cohort By Cohort(Central Review) (Central Review)

pmab+ bev/Ox-CT

(N=407)%

bev/Ox-CT(N=405)

%

pmab+ bev/Iri-CT

(N=68)%

bev/Iri-CT(N=67)

%

Best ORR 39 41 38 31

Complete response 0 <1 0 0

Partial response 39 40 38 31

Stable disease 31 33 26 37

Progressive disease 6 4 9 4

Not done/Unevaluable* 24 22 26 27

ITT set*Included missing and unreadable scans

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Partial Response 39%

Stable Disease 31%

Progressive Disease 6%

Pmab+ bev/Ox-CT (N=305)

-100%

-75%

-50%

-25%

0%

25%

50%

75%

100%

Ma

x %

Ch

an

ge

in S

um

of

Lo

ng

est

Dia

me

ters

bev/Ox-CT(N=310)

-100%

-75%

-50%

-25%

0%

25%

50%

75%

100%

Ma

x %

Ch

an

ge

in S

um

of

Lo

ng

est

Dia

me

ters

Maximum % Change in SLD of Target LesionsMaximum % Change in SLD of Target Lesions(Ox-CT Cohort, Central Review)(Ox-CT Cohort, Central Review)

Complete/Partial Response 41%

Stable Disease 33%

Progressive Disease 4%

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Interim Rates of Metastases InterventionInterim Rates of Metastases Intervention(Ox-CT Cohort, Oct 2006 Data Cutoff) (Ox-CT Cohort, Oct 2006 Data Cutoff)

pmab+ bev/Ox-CT

(N=407)bev/Ox-CT

(N=405)

Resection or radiofrequency ablation of metastases(ie, liver, lung, other)

27 (7%) 12 (3%)

ITT set*Included missing and unreadable scans

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Months

407 228 111 23 3 0

405 237 113 23 2 0

0 4 8 12 16 20

Pmab+bev/Ox-CT N

bev/Ox-CT N

Patients at risk:

Interim PFS – Ox-CT Cohort Interim PFS – Ox-CT Cohort (Central Review, Oct 2006 Data Cutoff)(Central Review, Oct 2006 Data Cutoff)

# PFS events (%)

Median (95%CI), mos

147 (36) 8.8 (8.3-9.5)

110 (27) 10.5 (9.4-12.0)

HR=1.44 (95% CI: 1.13-1.85)p =0.004

Pmab+bev/Ox-CT

Bev/Ox-CT

Pro

po

rtio

n P

rog

ress

ion

-Fre

e 100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

ITT set; for this planned interim analysis, the nominal alpha as specified by the Lan-DeMets alpha spending function and the O’Brien-Fleming stopping boundaries was 0.0053

Hecht WCGIC 200718

Months

413 267 92 21 3

410 298 96 21 1

0 5 10 15 20

Pmab+bev/Ox-CT Nbev/Ox-CT N

Patients at risk:

Limited Update of PFS – Ox-CT CohortLimited Update of PFS – Ox-CT Cohort(Central Review, Apr 2007 Data Cutoff)(Central Review, Apr 2007 Data Cutoff)

# PFS events (%)

Median (95%CI), mos

206 (50) 9.0 (8.5-10.4)

172 (42) 10.5 (9.7-11.6)

Pmab+bev/Ox-CT

Bev/Ox-CT

HR= 1.29 (95% CI: 1.05-1.58)

Pro

po

rtio

n P

rog

ress

ion

-Fre

e 100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

ITT set

Hecht WCGIC 200719

73 10 0

76 6 0

407 318 194

405 333 184

Months

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 4 8 12 16 20

Pmab+bev/Ox-CT

bev/Ox-CT

Pts at risk:

413 342 224 85 9 0

410 357 234 96 6 0

Pmab+bev/Ox-CT

bev/Ox-CT

Months

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25Pts at risk:

Unplanned Interim Overall Survival (Ox-CT Cohort)Unplanned Interim Overall Survival (Ox-CT Cohort)

# OS events (%)

Median(95%CI), mos

127 (31) 18.6 (16.4- 20.6)

95 (23) NE

Pro

po

rtio

n A

liv

e

HR= 1.44 (95% CI: 1.10-1.88)

*Interpretation of statistical significance is limited by the lack of a prespecified significance boundary

Pmab+bev/Ox-CT

Bev/Ox-CT

HR= 1.56 (95% CI: 1.11-2.17)

Oct 2006 Data Cutoff* Apr 2007 Data Cutoff # OS

events (%)Median

(95%CI), mos

83 (20) 18.4 (13.8-NE)

58 (14) NE

Pro

po

rtio

n A

liv

e

Pmab+bev/Ox-CT

Bev/Ox-CT

NE = not estimable; ITT set

Hecht WCGIC 200721

No PD

PD

Alive

Died

Exposure-Adjusted Adverse Event Incidence Exposure-Adjusted Adverse Event Incidence (Events per month)(Events per month)

0

1

2

3

4

5

6

7

8

Bev/Ox-CTPmab + Bev/Ox-CT

4.8

5.85.0

6.9

3.9 3.9 3.9 3.8

Nu

mb

er o

f ev

ents

per

mo

nth

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0 4 8 12 16

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Overall Survival of ECOG (0 vs 1)Overall Survival of ECOG (0 vs 1)(Exploratory Analysis)(Exploratory Analysis)

Pmab+bev/Ox-CT, ECOG 0 n=254Bev/Ox-CT, ECOG 0 n=237

Pmab+bev/Ox-CT, ECOG 1 n=153Bev/Ox-CT, ECOG 1 n=168

Months

Pro

po

rtio

n S

urv

ivin

g

Hecht WCGIC 200725

Treatment Exposure (Ox-CT Cohort) Treatment Exposure (Ox-CT Cohort)

Dose Delays% Pts

Dose Reductions% Pts

Relative Dose Intensity(RDI) %

 pmab+ bev/Oxn=401

bev/Oxn=392

pmab+ bev/Oxn=401

bev/Oxn=392

pmab+ bev/Oxn=401

bev/Oxn=392

Panitumumab 62 n/a 31 n/a 87 0

Bevacizumab 57 49 3 2 92 92

Oxaliplatin 55 46 26 25 84 88

5-FU 52a 45a 23a 16a 82b 87b

% Pts % Pts

Inf 5-FU/Ox/Bev ≥ 85%

n/a n/a n/a n/a 36 44

aBolus 5-FUbInfusional 5-FU n/a=not applicable

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Reasons for First-Line Treatment Reasons for First-Line Treatment Discontinuation (Ox-CT Cohort)Discontinuation (Ox-CT Cohort)

Patients discontinued first-line tx, n/ N total

pmab + bev/Ox-CT(300/407)

bev/Ox-CT(293/405)

Progressive events, n (%) 108 (36) 79 (27)

Disease progression 91 (30) 68 (23)

Deaths 17 (6) 11 (4)

Non-progressive events, n (%) 192 (64) 214 (73)

Adverse events 69 (23) 76 (26)

Protocol violation 9 (3) 5 (2)

Refused treatment 47 (16) 55 (19)

Other 67 (22) 78 (27)

Hecht WCGIC 200727

Months

407 263 90 2 0405 282 74 3 0

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 4 8 12 16 20

1816

Time to Treatment FailureTime to Treatment Failure(Ox-CT Cohort)(Ox-CT Cohort)

HR = 1.03 (95% CI: 0.87-1.21)

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

Pmab+bev/Ox-CTBev/Ox-CT

Patients at risk:Pmab+bev/Ox-CT

Bev/Ox-CT

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SUMMARYSUMMARY

This phase 3b open-label, US community-based study investigated the potential benefit of adding an anti-EGFr antibody (panitumumab) to an anti-VEGF-A antibody (bevacizumab) and chemotherapy for first-line mCRC

A planned interim analysis on the Ox cohort demonstrated an unfavorable risk:benefit profile for panitumumab+ bev/Ox-CT based on reduced PFS time and additional toxicity

These efficacy data suggest that there is a lack of biological synergy between panitumumab and bevacizumab in combination with Ox-CT

Additional toxicity was observed in the panitumumab + bev/Ox-CT arm

– Dual pathway inhibition may have potentiated toxicity

Lower dose intensity was observed in the panitumumab + bev/Ox-CT arm

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SUMMARY (SUMMARY (cont.cont.))

In an exploratory, post-hoc analysis, specific populations, particularly patients who were elderly, had poor performance status, or had comorbidities > 1, had worse outcomes

Most patients withdrew due to non-progressive events (64% on panitumumab + bev/Ox-CT arm, 73% on bev/Ox-CT arm)

Further data collection and analyses are ongoing, including subset analyses based on biomarkers

Phase 3 registrational studies are currently ongoing to investigate panitumumab with chemotherapy alone in first- and second-line mCRC

– Independent data monitoring committees for these studies have recommended continuation without protocol modification

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ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Patients who participated in this study and their families

All investigators, co-investigators, and study staffs at 194 sites across the US

The Amgen study team