Hecht ASCO GI 2008

An updated analysis of safety and efficacy of oxaliplatin (Ox)/bevacizumab (bev) +/-

panitumumab (pmab) for 1st‑line treatment (tx) of metastatic colorectal cancer (mCRC) from a

randomized, controlled trial (PACCE)

J. Randolph Hecht,1 Edith Mitchell,2 Tarek Chidiac,3 Carroll Scroggin,4 Christopher Hagenstad,5 David Spigel,6 John Marshall,7 Allen Cohn,8 Seta Shahin,9 Thomas Griffin9

1UCLA School of Medicine, Los Angeles, CA; 2Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA; 3Mid Ohio Oncology/Hematology, Inc, Columbus, OH;

4NEA Clinic, Jonesboro, AR; 5Suburban Hematology-Oncology Associates, Lawrenceville, GA; 6Sarah Cannon Research Institute, Nashville, TN; 7Georgetown University Hospital,

Washington, DC; 8Rocky Mountain Cancer Centers, Denver, CO; 9Amgen Inc., Thousand Oaks, CA

This study was funded by Amgen Inc.

Introduction

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

Preclinical and preliminary clinical studies have suggested that combining EGFr, VEGF inhibitors, and chemotherapy may improve efficacy over single-agent treatments 1,2

PACCE was a US, community-based study designed to compare the efficacy and safety of bevacizumab and chemotherapy +/- panitumumab for first-line treatment of mCRC

This interim analysis describes updated data available as of May 31, 2007 on safety and efficacy on the Ox-based cohort from PACCE (trial discontinued only panitumumab therapy in March 2007 after a planned interim analysis of ~231 PFS events in the Ox-CT cohort)

1 Shaheen RM et al. Brit J Cancer 2001;85:584–5892 Saltz LB et al. J Clin Onc 2007;25:4557–4561.

PACCE Study SchemaRandomized, Open-Label, Controlled Phase 3b Study

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

Panitumumab 6 mg/kg Q2W

+ Ox-CT + Bevacizumab

Ox-based CT(eg, FOLFOX)

N = 800Investigator choice

Iri-based CT(eg, FOLFIRI)

N = 200Investigator choice

Ox-CT+ Bevacizumab

Panitumumab 6 mg/kg Q2W

+ Iri-CT + Bevacizumab

Iri-CT+ Bevacizumab

RANDOMIZE

1:1

1:1

SCREENING

Tumor Assessments: Q12W until disease progression or intolerability

Key Eligibility Criteria

Age 18 years old

Measurable mCRC per modified RECIST

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 of randomization

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

No clinically significant cardiovascular disease within 1 year prior to randomization

No EGFr testing required

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

Secondary endpoints included:– Overall response rate (ORR), time to treatment failure (TTF), overall survival

(OS), safety profile

Design Characteristics

– To detect a 30% improvement in median PFS in the panitumumab plus bevacizumab/Ox-CT treatment group vs bevacizumab/Ox-CT alone

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

• Planned interim analysis at ~ 231 Ox-CT PFS events

Study Endpoints and Design Characteristics

aPowered for oxaliplatin stratum only; descriptive for irinotecan stratum

Independent DMC AnalysesIndependent DMC Analyses

25 pts

Safety

75 pts

150 pts

Safety SafetyRR

Unplanned Safety

Efficacy

SafetyRR

SafetyEfficacy

500 pts

800 pts

~231 PFS events

DMC recommended continuation without protocol modification

Mar 2005

Panitumumab dosing was discontinued on Mar 22, 2007

DMC recommended

changes to informed consent

1st pt randomized

DMC = data monitoring committee

Treatment: Ox-CT CohortTreatment: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff)

pmab+ bev/Ox-CT(N = 413)

bev/Ox-CT(N = 410)

Patients randomized, n (%) 413 (100) 410 (100)

Patients who received any first-line treatment, n (%)

406 (98) 398 (97)

Median follow-up, weeks Range

53 1-114

552-106

Chemotherapy regimen received on week 1, n (%)a

FOLFOX4 97 (24) 102 (26)

FOLFOX5 2 ( < 1) 1 ( < 1)

FOLFOX6 66 (16) 71 (18)

Modified FOLFOX6 189 (47) 189 (47)

FOLFOX7 7 ( 2) 4 ( 1)

bFOL 5 ( 1) 5 ( 1)

Other Ox-based Q2W CTb 40 (10) 26 (7)

aOf those patients who received any first-line treatment; bAllowed per protocol; capecitabine was not allowed

Demographics and Baseline Characteristics (Interim Analysis, May 2007 Data Cutoff)

pmab + bev / Ox-CT(N = 413)

bev / Ox-CT(N = 410)

Male, % 56 58

Race, % White Black Hispanic

Other

83862

801063

Median age, years (range) 61 (28–88) 62 (22–89)

Age 65, % 39 43

Baseline ECOG, % 0 1

6139

5842

Prior adjuvant therapy for mCRC, % 19 19

Metastatic organs, % 1 > 1

49a

504951

aOne patient had no metastatic organs

Summary of Adverse Events: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff)

pmab + bev/Ox-CT(N = 407)

bev / Ox-CT(N = 397)

Any adverse event (AE), % 100 100

Grade 3 52 53

Grade 4 28 19

Grade 5a 6 3

Pmab-related grade 5 1 N/A

Any serious AE, % 60 38

Panitumumab treatment-related serious AE, %

19 N/A

Ended panitumumab treatment due to AE, %

27 N/A

Based on the safety analysis set (all patients who received ≥ 1 dose of treatment)Graded per NCI CTCAE v 3.0; n/a, not applicableaAs reported by investigator – does not include disease progression (ie, neoplasms)

Grade 3 or 4 Adverse Events of Interest: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff)

pmab + bev / Ox-CT(N = 407)

bev / Ox-CT(N = 397)

Adverse event Gr 3 % Gr 4 % Gr 3 % Gr 4 %

Skin toxicitya 35 1 1 0

Diarrhea 22 2 12 1

Infectionsb 16 2 8 2

Dehydration 15 2 5 < 1

Neutropenia 14 10 17 7

Nausea 11 0 5 < 1

Hypokalemia 8 2 3 1

Hypomagnesemia 3 1 0 0

Neuropathy 3 <1 7 0 Paronychia 1 0 0 0

Deep venous thrombosis 7 0 8 0

Pulmonary embolismc 0 6 0 4MedDRA v 9.0 preferred terms; graded per NCI CTCAE v 3.0aSkin toxicity included terms from the skin and subcutaneous and infections system organ class(SOC)bGrade 5 infections occurred in 3 (1%) of pmab + bev/Ox-CT pts and 3 (1%) of bev/Ox-CT ptscGrade 5 pulmonary embolism occurred in 3 (1%) of pmab + bev/Ox-CT pts

Deaths (All Causes): Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff)

pmab + bev/Ox-CT(N = 407)

bev / Ox-CT(N = 397)

Deaths (all causes), n (%)a 143 (35) 107 (27)

All-cause deaths within 60 days of first dose

10 (2) 6 (2)

All-cause deaths within 30 days of last dose of first- line treatment

33 (8) 14 (4)

aDeaths at any time including long-term follow-up (post-study treatment). Based on the safety analysis set

Overall Tumor Response: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff)

Central Reviewa Local Reviewa

Tumor Response, n (%)

pmab + bev / Ox-CT

(N = 413)bev / Ox-CT

(N = 410)

pmab + bev / Ox-CT

(N = 413)bev / Ox-CT

(N = 410)

Best ORR 187 (45) 189 (46) 210 (51) 203 (50)

Complete response 0 (0) 2 (< 1) 22 (5) 27 (7)

Partial response 187 (45) 189 (46) 188 (46) 176 (43)

Stable disease 121 (29) 138 (34) 114 (28) 134 (33)

Progressive diseaseb 28 (7) 17 (4) 29 (7) 21 (5)

Not done or unevaluablec 78 (19) 64 (16) 60 (15) 52 (13)

aCT scans performed Q12W; responses did not require confirmationbCentral review unable to evaluate clinical disease progression (ie, non-radiographic PD); central review unable to accurately evaluate PD after surgical resections cIncluded missing and unreadable scans

-100

-75

-50

-25

0

25

50

75

100

Patients (N = 334)

Ma

xim

um

Chan

ge(%

)

-100

-75

-50

-25

0

25

50

75

100

-

-

-

-

-100

-75

-50

-25

0

25

50

75

100

Patients (N = 343)

Ma

xim

um

Chan

ge(%

)

-100

-75

-50

-25

0

25

50

75

100

-

-

-

-

Maximum Percent Change From Baseline in Sum of Longest Diameters by Central Review: Ox-CT Cohort

(Interim Analysis, May 2007 Data Cutoff)

Panitumumab +bevacizumab / Ox-CT bevacizumab / Ox-CT

PR (n = 189) SD (n = 133)

PD (n= 16) Unknown (n = 4)

Best Overall ResponseBest Overall Response

PR (n = 187) SD (n = 120)

PD (n= 25) Unknown (n = 2)

Progression-Free Survival: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff)

# PFS events (%)

Median (95%CI), mos

59 9.6 (8.8-10.9)

52 11.1 (10.3-11.9)

pmab+bev/Ox-CT

bev/Ox-CT

HR = 1.27 (95% CI: 1.05–1.53)*

# PFS events (%)

Median(95% CI), mos

70 9.6 (8.8-10.7)

64 11.0 (10.2-11.8)

HR = 1.27 (95% CI: 1.07–1.50)*

Central Reviewa Local Reviewb

aCensoring based on last available scan read centrally Q12W bCensoring based on last day of patient contact or visit Q2W

*Descriptive only*Descriptive only

Months

Panitumumab NCensored

4130

28157

12860

3838

813

03

No Panitumumab NCensored

4100

31063

14276

4040

615

03

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25Months

Panitumumab NCensored

4130

30927

16027

5240

925

04

No Panitumumab NCensored

4100

33134

18731

5949

1023

010

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25

aDescriptive only. Statistical significance is limited by the lack of a prespecified significance boundary.

Overall Survival: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff)

pmab+bev/Ox-CT

bev/Ox-CT

Death events (%)

Median (95%CI), mos

143 (35) 19.4 (18.4- 20.8)

108 (26) NE

HR = 1.43 (95% CI: 1.11–1.83)a

Months

Panitumumab NCensored N

4130

33434

20584

7396

155

No Panitumumab NCensored N

4100

34744

22175

71120

361

% S

urv

ivin

g

0 6 12 18 24

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

100%

Treatment Exposure: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff)

Dose Delays% Patients

Dose Reductions% Patients

Relative Dose Intensity (RDI) %

pmab + bev/Ox(N=413)

bev/Ox(N=410)

pmab + bev/Ox(N=413)

bev/Ox(N=410)

pmab + bev/Ox(N=413)

bev/Ox(N=410)

Panitumumab 64 N/A 33 N/A 86 N/A

Bevacizumab 60 54 3 3 91 92

Oxaliplatin 57 49 28 27 83 87

5-FU 56a 49a 24a 17a 82b 86b

% Patients

Inf 5-FU/Ox/bev ≥ 85%

N/A N/A N/A N/A 33 42

aBolus 5-FU bInfusional 5-FUN/A=not applicable

Reasons for First-Line Treatment Discontinuation: Ox-CT Cohort

(Interim Analysis, May 2007 Data Cutoff)

pmab + bev / Ox-CT

(413)bev / Ox-CT

(410)

Patients who discontinued first-line treatment, n (%)

396 (96) 380 (93)

Progressive events, n (%)a 137 (35) 111 (29)

Disease progression 115 (29) 100 (26)

Deaths 22 (6) 11 (3)

Non-progressive events, n (%)a 259 (65) 269 (71)

Adverse events 89 (22) 90 (24)

Protocol violation 14 (4) 7 (2)

Consent withdrawn/ refused treatment 63 (16) 78 (21)

Otherb 93 (23) 94 (25)

aOf those who discontinued first-line treatmentbOther included end of first-line treatment without progression, requirement for alternative therapy, administrative, lost to follow-up, and other

Rates of Metastases Intervention For Curative Intent: Ox-CT Cohort

(Interim Analysis, May 2007 Data Cutoff)

pmab + bev / Ox-CT

(N = 413)bev / Ox-CT

(N = 410)

Resection or radiofrequency ablation of metastases(i.e., liver, lung, other), n (%)

40 (10) 26 (6)

SummarySummary Based on this updated interim analysis of the PACCE study, panitumumab +

bevacizumab/Ox-CT was associated with shorter PFS time and increased toxicity, indicating that this combination has an unfavorable benefit-to-risk profile in unselected patients with mCRC

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

Most patients withdrew from the study for non-progressive events (65% in the panitumumab + bevacizumab/Ox-CT arm, 71% in the bevacizumab/Ox-CT arm)

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

Phase 3 studies are currently ongoing to investigate panitumumab with chemotherapy in 1st- and 2nd-line mCRC

– Study 20050181 investigates FOLFIRI +/- panitumumab as 2nd-line in mCRC (Peeters et al., Abstract #335, Poster #A56)

– PRIME/Study 20050203 investigates FOLFOX +/- panitumumab in first-line mCRC (Douillard et al., Abstract #443, Poster #A63)

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