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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)