hecht wcgic 2007 an interim analysis of efficacy and safety from a randomized controlled trial of...
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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)
Hecht WCGIC 20073
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
Hecht WCGIC 20074
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
Hecht WCGIC 20075
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
Hecht WCGIC 20076
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
Hecht WCGIC 20077
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
Hecht WCGIC 20079
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
Hecht WCGIC 200710
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
Hecht WCGIC 200711
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
Hecht WCGIC 200713
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
Hecht WCGIC 200714
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%
Hecht WCGIC 200716
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
Hecht WCGIC 200717
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
Hecht WCGIC 200724
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
Hecht WCGIC 200726
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
Hecht WCGIC 200728
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
Hecht WCGIC 200729
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
Hecht WCGIC 200730
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