An Interim Analysis of Efficacy And Safety From A Randomized Controlled Trial of Panitumumab With Chemotherapy Plus Bevacizumab (Bev) for Metastatic Colorectal Cancer (mCRC)

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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

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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 200185584-589 2Sal
tz LB et al. ASCO 2005. Abstract 3508 (BOND2)
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Study Schema
PACCE Panitumumab Advanced Colorectal Cancer
Evaluation Randomized, Open-Label, Controlled
Phase 3b Trial
Panitumumab 6 mg/kg Q2W Ox-CT Bevacizumab
Ox-based CT (eg, FOLFOX) N 800 Inv choice
R A N D O M I Z E
S C R E E N I N G
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Ox-CT Bevacizumab
Panitumumab 6 mg/kg Q2W Iri-CT Bevacizumab
Iri-basedCT (eg, FOLFIRI) N 200 Inv choice
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Iri-CT Bevacizumab
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
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Key Eligibility Criteria

• Age ³ 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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Study Endpoints and Design Characteristics

• 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 a 0.05 (2-sided) for 462 PFS
  events (disease progression or death)
• Planned interim analysis at 231 PFS events

Powered for oxaliplatin cohort only descriptive
for irinotecan cohort
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Independent DMC Analyses
75 Pts
500 Pts
231 PFS events
1st pt randomized
25 Pts
150 Pts
800 Pts
231 OS
Safety
Safety
SafetyRR
Unplanned Safety Efficacy
SafetyRR
SafetyEfficacy
Q3 07
Mar 2005
DMC recommended changes to informed consent
DMC recommended continuation without protocol
modification
Panitumumab dosing was discontinued
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Baseline Demographics and Characteristics
pmab bev/Ox-CT(N407) bev/Ox-CT(N405) pmab bev/Iri-CT(N68) bev/Iri-CT(N67)
Male, 57 58 49 63
Race, White Black Hispanic 83 8 6 81 10 6 75 18 3 70 19 10
Age, median, years Range 61 28 - 88 62 27 - 89 60.5 37 - 84 57 23 - 80
Age ? 65, 39 43 41 28
Baseline ECOG, 0 1 62 38 59 41 60 40 63 37
Prior Adjuvant Therapy, 19 19 40 37
Metastatic organs, 1 gt1 49 51 49 51 40 60 48 52
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PACCE INTERIM ANALYSISSAFETY
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Summary of Adverse Events (Ox-CT Cohort)
pmab bev/Ox-CT(N401) bev/Ox-CT(N392)
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 Interest(Ox-CT
Cohort)
pmabbev/Ox-CT(N401), pmabbev/Ox-CT(N401), bev/Ox-CT(N392), bev/Ox-CT(N392),
Gr 3 Gr 4 Gr 3 Gr 4
Skin toxicity 33 lt1 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 lt1 10 lt1
Nausea 10 0 4 lt1
Infectionsa 16 2 7 2
Deep venous thrombosis 6 0 7 0
Pulmonary embolismb 0 6 0 4
MedDRA v9.0 preferred terms Graded per NCI CTCAE
v3.0 aGrade 5 infections occurred in 2 (1) pmab
bev/Ox-CT pts and 3 (1) bev/Ox-CT pts bGrade 5
pulmonary embolism occurred in 2 (1) pmab
bev/Ox-CT pts
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Deaths (Ox-CT Cohort)
pmab bev/Ox-CTN401 n () bev/Ox-CTN392 n ()
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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PACCE INTERIM ANALYSISEFFICACY
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Objective Response Rate By Cohort(Central
Review)
pmab bev/Ox-CT(N407) bev/Ox-CT(N405) pmab bev/Iri-CT(N68) bev/Iri-CT(N67)
Best ORR 39 41 38 31
Complete response 0 lt1 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 setIncluded missing and unreadable scans
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Maximum Change in SLD of Target Lesions(Ox-CT
Cohort, Central Review)
Pmab bev/Ox-CT (N305)
Partial Response 39 Stable Disease
31 Progressive Disease 6
bev/Ox-CT(N310)
Complete/Partial Response 41 Stable Disease
33 Progressive Disease 4
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Objective Response Rate By Cohort(Investigator
Review)
pmab bev/Ox-CT(N407) bev/Ox-CT(N405) pmab bev/Iri-CT(N68) bev/Iri-CT (N67)
Best ORR 49 48 54 40
Complete response 4 5 7 4
Partial response 44 42 47 36
Stable disease 29 34 25 37
Progressive disease 7 5 4 10
Not done/Unevaluable 15 13 16 12
ITT setIncluded missing and unreadable scans
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Interim Rates of Metastases Intervention(Ox-CT
Cohort, Oct 2006 Data Cutoff)
pmab bev/Ox-CT(N407) bev/Ox-CT(N405)
Resection or radiofrequency ablation of metastases (ie, liver, lung, other) 27 (7) 12 (3)
ITT setIncluded missing and unreadable scans
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Interim PFS Ox-CT Cohort (Central Review, Oct
2006 Data Cutoff)
PFS events () Median (95CI), mos
147 (36) 8.8 (8.3-9.5)
110 (27) 10.5 (9.4-12.0)
HR1.44 (95 CI 1.13-1.85) p 0.004
ITT set for this planned interim analysis, the
nominal alpha as specified by the Lan-DeMets
alpha spending function and the OBrien-Fleming
stopping boundaries was 0.0053
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Limited Update of PFS Ox-CT Cohort(Central
Review, Apr 2007 Data Cutoff)
PFS events () Median (95CI), mos
206 (50) 9.0 (8.5-10.4)
172 (42) 10.5 (9.7-11.6)
Pmabbev/Ox-CT Bev/Ox-CT
HR 1.29 (95 CI 1.05-1.58)
ITT set
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Unplanned Interim Overall Survival (Ox-CT Cohort)
Oct 2006 Data Cutoff
Apr 2007 Data Cutoff
OS events () Median (95CI), mos
127 (31) 18.6 (16.4- 20.6)
95 (23) NE
OS events () Median (95CI), mos
83 (20) 18.4 (13.8-NE)
58 (14) NE
HR 1.44 (95 CI 1.10-1.88)
HR 1.56 (95 CI 1.11-2.17)
Proportion Alive
Proportion Alive
Interpretation of statistical significance is
limited by the lack of a prespecified
significance boundary
NE not estimable ITT set
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PACCE INTERIM ANALYSISADDITIONAL
ANALYSES(Ox-CT Cohort )
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Exposure-Adjusted Adverse Event Incidence
(Events per month)
No PD
PD
6.9
Alive
5.8
Died
5.0
4.8
3.9
3.9
3.9
3.8
Number of events per month
Pmab Bev/Ox-CT
Bev/Ox-CT
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Overall Survival By Age ( 80 yr vs
gt80)(Exploratory Analysis)
Proportion Surviving
Months
Pmabbev/Ox-CT, lt80 yrs n389
Bev/Ox-CT, lt80 yrs n395
Pmabbev/Ox-CT, gt80 yrs n18
Bev/Ox-CT, gt80 yrs, n10
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Overall Survival By Comorbidities (0 vs
1)(Exploratory Analysis)
Proportion Surviving
Months
Pmabbev/Ox-CT, Comobidity 0 n119
Bev/Ox-CT, Comobidity 0 n104
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Overall Survival of ECOG (0 vs 1)(Exploratory
Analysis)
Proportion Surviving
Months
Pmabbev/Ox-CT, ECOG 0 n254
Bev/Ox-CT, ECOG 0 n237
Pmabbev/Ox-CT, ECOG 1 n153
Bev/Ox-CT, ECOG 1 n168
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Treatment Exposure (Ox-CT Cohort)
Dose Delays Pts Dose Delays Pts Dose Delays Pts Dose Reductions Pts Dose Reductions Pts Relative Dose Intensity (RDI) Relative Dose Intensity (RDI)
  pmab bev/Oxn401 bev/Oxn392 bev/Oxn392 pmab bev/Oxn401 bev/Oxn392 pmab bev/Oxn401 bev/Oxn392
Panitumumab 62 n/a n/a 31 n/a 87 0
Bevacizumab 57 49 49 3 2 92 92
Oxaliplatin 55 46 46 26 25 84 88
5-FU 52a 45a 45a 23a 16a 82b 87b
Pts Pts
Inf 5-FU/Ox/Bev 85 n/a n/a n/a n/a n/a 36 44
aBolus 5-FUbInfusional 5-FU n/anot applicable
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Reasons for First-Line Treatment 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)
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Time to Treatment Failure(Ox-CT Cohort)
Pmabbev/Ox-CT Bev/Ox-CT
HR 1.03 (95 CI 0.87-1.21)
Survival Distribution Function
Patients at risk Pmabbev/Ox-CT Bev/Ox-CT
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SUMMARY

• 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 riskbenefit 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 (cont.)

• In an exploratory, post-hoc analysis, specific
  populations, particularly patients who were
  elderly, had poor performance status, or had
  comorbidities gt 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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ACKNOWLEDGEMENTS

• 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