Transcript 2007_files/Humblet Pmab skin tox QOL ASCO2007

Association of skin toxicity (ST) severity
with clinical outcomes and health-related
quality of life (HRQoL) with panitumumab
(Pmab)
Yves Humblet,1 Marc Peeters,2 Salvatore Artale,3 Alain Hendlisz,4
Bart Neyns,5 A. Sobrero,6 Michael Wolf,7 Michael Woolley,7
Rafael Amado,7 Eric Van Cutsem8
Abstract #4038
1St-Luc
University Hospital, Brussels, Belgium; 2Ghent University Hospital, Ghent,
Belgium; 3Ospedale Niguarda Ca’ Granda, Milan, Italy; 4Jules Bordet Institute,
Brussels, Belgium; 5AZ Vrije Universiteit Brussel, Brussels, Belgium; 6Ospedale
San Martino, Genoa, Italy; 7Amgen Inc., Thousand Oaks, CA; 8University Hospital
Gasthuisberg, Leuven, Belgium
Humblet ASCO 2007 – Draft CONFIDENTIAL
Introduction
• Skin toxicity severity has been shown to be associated with efficacy
in patients with metastatic colorectal cancer (mCRC) receiving antiepidermal growth factor receptor (EGFr) therapy
• Panitumumab is a fully human monoclonal antibody directed against
the EGFr and is indicated for use in patients with mCRC who
progressed on or following standard chemotherapy1,2
• This phase 3, randomized controlled trial demonstrated that
panitumumab plus best supportive care (BSC) improved
progression-free survival (PFS) compared with BSC alone in
chemorefractory mCRC patients3
• We conducted an exploratory analysis to evaluate the association of
skin toxicity severity with PFS, overall survival (OS), disease-related
symptoms and HRQOL with panitumumab treatment
Humblet ASCO 2007 – Draft CONFIDENTIAL
Study Design
R
A
N
D
O
M
I
Z
E
Panitumumab
6.0 mg/kg Q2W
+ BSC
BSC
PD*
PD*
Follow-up
Optional
Panitumumab
Crossover Study
Follow-up
1:1
*PD= progressive disease
Stratification:
• ECOG score: 0-1 vs. 2
• Geographic region (Western Europe vs. Central
and Eastern Europe vs. the rest of world)
Primary
Endpoint
• Progression-free survival (per blinded central radiology
Secondary
Endpoints
• Overall survival time and best overall objective response
assessment of modified RECIST criteria)
(central radiology; testing prespecified)
• Safety, disease-related symptoms,
and HRQoL
Humblet ASCO 2007 – Draft
CONFIDENTIAL
Key Eligibility Criteria
• Metastatic colorectal adenocarcinoma (mCRC)
• ECOG score 0 to 2
• Radiologic documentation of disease progression after
fluoropyrimidine, irinotecan, and oxaliplatin
– During or within 6 months following most recent chemotherapy
regimen
– 2 or 3 prior regimens
• EGFr membrane staining on ≥ 1% tumor cells (IHC, central laboratory)
• Adequate hematologic, renal, and hepatic function
• No symptomatic brain metastases
• No chemotherapy within 30 days before randomization
• No prior anti-EGFR agent therapy
Humblet ASCO 2007 – Draft CONFIDENTIAL
Assessments
•
•
•
Skin toxicity was measured by:
– CTCAE grading criteria version 3.0 (modified for dermatology toxicities)
and
– Modified Dermatology Life Quality Index (mDLQI) (See Table 1)
CRC symptoms were measured by the NCCN/FACT CRC symptom index
(FCSI) (See Table 1)
HRQoL was measured by the EQ-5D and EORTC QLQ-C30 Global QoL
subscale (See Table 1)
Humblet ASCO 2007 – Draft CONFIDENTIAL
Table 1. Patient Reported Outcomes
PRO Instrument
Measurement
Description
Assessment
Schedule
Modified
Dermatology Life
Quality Index
(mDLQI)
Problems due
to skin
condition
3 items measuring problems and bother with skin
condition. Scores range from 0 to 100 with higher
scores indicating less problems/bother
NCCN/FACT
Colorectal
Symptom Index
(FCSI)
CRC
Symptoms
A brief symptom index comprising of the most
clinically relevant (clinician rated) symptoms for
assessing symptomatic response to treatment for
CRC. Scores range from 0 to 100 with higher
scores indicating less symtomatology
Baseline, Q2W
during treatment,
and at the 30-day
safety follow-up
visit after the last
protocol directed
therapy
EUROQOL (EQ5D)
Health Index
HRQOL
Provides a preference-weighted assessment of
overall QOL across five dimensions: mobility, self–
care, usual activity, pain or discomfort, and anxiety
or depression. Scores range from 0 to 1 (0 = death,
1 = perfect health)
EUROQOL (EQ5D)
Visual Analog
Scale (VAS)
HRQOL
Measures overall health status. Scores range from
0 to 100 with 0 representing worst imaginable
health state and 100 representing best imaginable
health state
EORTC QLQ-C30
Global Health
Status/QOL Scale
HRQOL
2 items of the EORTC QLQ-C30 measuring overall
health status and overall QOL. Scores range from 0
to 100 with higher scores indicating better HRQOL
Baseline, monthly
during treatment,
and at the 30-day
safety follow-up
visit after the last
protocol directed
therapy
Humblet ASCO 2007 – Draft CONFIDENTIAL
Statistical Analyses
Overall Treatment Effect
• PRO Analysis set included all patients who had at least 1 post-baseline
PRO assessment
Association of skin toxicity with efficacy and PROs
• Analyses of skin toxicity by CTCAE grading criteria and mDLQI were
restricted to patients in the panitumumab arm who were progression-free
for at least 28 days to allow for onset of skin toxicity and
– had  grade 1 skin toxicity (for CTCAE) or
– had at least 1 post-baseline PRO assessment (mDLQI)
• Dichotomization of PFS for degree of being bothered was explored using
all possible cut points of mDLQI (based on Cox model)
• Hazard ratios (HR) adjusted for randomization factors and correlation
analyses were used to determine relationships between PFS and OS to
skin toxicity, and skin toxicity to colorectal cancer symptoms and overall
HRQoL
Humblet ASCO 2007 – Draft CONFIDENTIAL
Statistical Analyses (cont.)
Association of skin toxicity with efficacy and PROs (cont.)
• Missing PRO data were imputed using 2 imputation methods:
– The last value carried forward (LVCF) method, in which missing
observations were replaced with the LVCF, or zero value carried
forward at death; and
– The slope method, in which a forward linear interpolation of observed
data was utilized to impute missing data
Humblet ASCO 2007 – Draft CONFIDENTIAL
Results
Disposition and Patient Analysis Sets
Panitumumab
Plus BSC
BSC
Alone
Total Randomized, n
231
232
PRO All Enrolled Analysis Set, n
207
184
Patients Completing EQ-5D, n
Week 4
Week 8
Week 12
Week 16
189
111
91
62
129
47
14
7
Patients Completing FACT CRC Subscale, n
Week 4
Week 8
Week 12
Week 16
190
112
90
62
130
48
14
7
Patients Completing mDLQI Subscale, n
Week 4
Week 8
Week 12
Week 16
189
111
90
62
128
48
13
6
Humblet ASCO 2007 – Draft CONFIDENTIAL
Demographics and Disease Characteristics
PRO All Enrolled Analysis Set
Panitumumab
Plus BSC
(N=207)
BSC Alone
137 (66)
119 (65)
61 (27, 79)
63 (32, 83)
Age Categories – years
< 65
≥ 65
124 (60)
83 (40)
109 (59)
75 (41)
ECOG status – n (%)
0-1
≥ 2a
185 (89)
22 (11)
160 (87)
24 (13)
147 (71)
60 (29)
75 (36)
126 (69)
56 (31)
69 (38)
206 (100)
77 (37)
184 (100)
66 (36)
Sex – n (%)
Men
Median (min, max) age – years
Number of metastatic sites – n (%)
1-2
3-5
Prior adjuvant chemotherapy – n (%)
Prior chemotherapy – n (%)
At least 2 lines
At least 3 lines
aOne
(N=184)
patient had ECOG score of 3
Humblet ASCO 2007 – Draft CONFIDENTIAL
Overall Treatment Effect
The mDLQI-Bother Score Indicated That Panitumumab
Patients Were More Bothered By Their Skin Condition
Panitumumab Plus BSC n= 207
BSC Alone
n= 184
Mean DLQI-bother score
103.0
93.0
83.0
73.0
Mean (+/- SE)
63.0
53.0
43.0
33.0
23.0
Base
5
9
13
17
21
25
29
33
37
41
45
48
Week
Responses range from 0 to 100 with a higher score indicating a better quality of life.
Humblet ASCO 2007 – Draft CONFIDENTIAL
Difference (95% CI) in HRQOL Scores (EQ-5D) at
Prespecified Timepoints for Panitumumab minus BSC
Patients (Primary PRO Analysis)
Difference in EQ-5D Scores (panitumumab- BSC)
Panitumumab N=207
BSC N=184
• LVCF imputation method used for missing PRO data
• The yellow line at -0.08 represents a minimum clinical important difference (MCID) anchored to a ½ point change in ECOG score
• Although panitumumab patients were more bothered by their skin conditions, HRQOL
scores were numerically in favor of panitumumab
Humblet ASCO 2007 – Draft CONFIDENTIAL
Difference (95% CI) in CRC Symptom Scores (FCSI) at
Prespecified Timepoints for Panitumumab minus BSC
Patients (Primary PRO Analysis)
Difference in FCSI scores (panitumumab- BSC)
Panitumumab N=207
BSC N=184
MCID
MCID
• LVCF imputation method used for missing PRO data
• The yellow line at -3.94 represents a minimum clinical important difference (MCID) anchored to a ½ point change in ECOG score
• Although panitumumab patients were more bothered by their skin condition,
disease-related symptom scores were numerically in favor of panitumumab
Humblet ASCO 2007 – Draft CONFIDENTIAL
Time to Onset of Worst Severity Skin
Toxicity
• Among all patients:
– The median time (95% CI) to most severe skin toxicity was 15
(14,16) days (Kaplan-Meier method)
• The worst severity of skin toxicity may occur beyond 28 days,
thus lead-time bias cannot be completely eliminated
Humblet ASCO 2007 – Draft CONFIDENTIAL
Association of Skin Toxicity with Outcomes
Progression-Free Survival by Worst Severity of Skin Toxicity in
Panitumumab Patients (Landmark Analysis)
Median
Events / N (%) in Weeks
121 / 144 ( 84 ) 10.0
53 / 56 ( 95 )
8.0
100%
Grade 2-4
Grade 1
Event-free Probability
90%
80%
hazard ratio (grade 2-4:1)=0.66
70%
p=0.01
60%
50%
40%
30%
20%
10%
0%
0
4
8
12
144
144
87
62
41
32
24
16
11
56
56
28
14
8
8
7
3
2
Patients at risk:
Grade 2-4
Grade 1
16
20
24
28
32
36
Weeks from Randomization
40
44
48
7
4
1
1
1
1
1
0
52
Program: /stat/amg954/onc/20020408/analysis/ectd/stats/post_hoc/ASCO07/Humblet/Skin_g1_234.sas
Output: graphs/PFSc.Tx_sk_g1_234LM.cgm (Date Generated:14MAY07:13:39:35)
Landmark Analysis set included patients who were progression free for ≥ 28 days
• Panitumumab patients with worst grade of 2-4 had better progression free survival
Humblet ASCO 2007 – Draft CONFIDENTIAL
vs those with a worst grade of 1
Overall Survival by Worst Severity of Skin Toxicity
in the Panitumumab Patients (Landmark Analysis)
100%
Grade 2-4
Grade 1
90%
Median
Events / N (%) in Months
113 / 144 ( 78 )
7.9
49 / 56 ( 88 )
5.9
Survival Probability
80%
hazard ratio (grade 2-4:1)=0.68
70%
p=0.03
60%
50%
40%
30%
20%
10%
0%
0
2
4
6
144
134
115
93
66
44
31
19
56
49
33
24
16
10
6
4
Patients at risk:
Grade 2-4
Grade 1
8
10
12
14
16
Months from Randomization
18
20
22
7
3
3
2
2
1
1
0
24
Program: /stat/amg954/onc/20020408/analysis/ectd/stats/post_hoc/ASCO07/Humblet/Skin_g1_234.sas
Output: graphs/OS.Tx_sk_g1_234LM.cgm (Date Generated:14MAY07:13:39:35)
Landmark Analysis set included patients who were progression free for ≥ 28 days
• Panitumumab patients with worst grade of 2-4 had better overall survival vs
those with a worst grade of 1
Humblet ASCO 2007 – Draft CONFIDENTIAL
Progression-Free Survival by Minimum Post-Baseline mDLQI
Score in the Panitumumab Patients (Landmark Analysis)
100%
DLQI <= 66.667
DLQI > 66.667
90%
Median
Events / N (%) in Weeks
127 / 150 ( 85 ) 11.9
38 / 40 ( 95 )
7.7
Event-free Probability
80%
hazard ratio (≤66.667:>66.667)=0.41
70%
p<0.0001
60%
50%
40%
30%
20%
10%
0%
0
4
8
12
DLQI <= 66.667
150
150
94
69
47
38
30
19
13
DLQI > 66.667
40
40
17
6
2
2
1
0
0
Patients at risk:
16
20
24
28
32
36
Weeks from Randomization
40
44
48
8
5
2
1
0
0
0
0
52
Program: /stat/amg954/onc/20020408/analysis/ectd/stats/post_hoc/ASCO07/Humblet/DLQI.sas
Output: graphs/PFS_DLQI_max.cgm (Date Generated:14MAY07:13:39:59)
Landmark Analysis set included patients who were progression free for ≥ 28 days; at least 1 post-baseline PRO
assessment was also required.
mDLQI nadir timing: mean – 30 days, median – 14 days, 75th Percentile – 28 days
• Panitumumab patients with a minimum post-baseline mDLQI score ≤ 66.667 (more
bothered by their skin toxicity) had longer progression free
survival
Humblet
ASCO 2007 – Draft CONFIDENTIAL
Overall Survival by Minimum Post-Baseline mDLQI Score in
the Panitumumab Patients (Landmark Analysis)
Median
Events / N (%) in Months
119 / 150 ( 79 )
8.2
37 / 40 ( 93 )
3.4
100%
DLQI <= 66.667
DLQI > 66.667
Survival Probability
90%
80%
hazard ratio (≤66.667:>66.667)=0.35
70%
p<0.0001
60%
50%
40%
30%
20%
10%
0%
0
2
4
6
DLQI <= 66.667
150
144
127
102
73
49
34
22
DLQI > 66.667
40
30
17
11
5
3
2
0
Patients at risk:
8
10
12
14
16
Months from Randomization
18
20
22
9
4
4
2
0
0
0
0
24
Program: /stat/amg954/onc/20020408/analysis/ectd/stats/post_hoc/ASCO07/Humblet/DLQI.sas
Output: graphs/OS_DLQI_max.cgm (Date Generated:14MAY07:13:39:59)
Landmark Analysis set included patients who were progression free for ≥ 28 days; at least 1 post-baseline PRO
assessment was also required.
mDLQI nadir timing: mean – 30 days, median – 14 days, 75th Percentile – 28 days
• Panitumumab patients with a minimum post-baseline mDLQI score ≤ 66.667 (more
bothered by their skin toxicity) had longer overall survival
Humblet ASCO 2007 – Draft CONFIDENTIAL
Minimum Post-Baseline mDLQI Bother Score Association
with Median Post-Baseline Patient-Reported Outcomes
mDLQI
Bother
EQ-5D index
EQ-5D VAS
EORTC Global
EQ-5D
index
EQ-5D VAS
EORTC
Global
FCSI
-0.24
(p=0.0006)
-0.17
(p=0.01)
-0.08
(p=0.25)
-0.13
(p=0.06)
0.61
(p<.0001)
0.60
(p<.0001)
0.71
(p<.0001)
0.79
(p<.0001)
0.70
(p<.0001)
0.74
(p<.0001)
PRO All Enrolled Analysis set, panitumumab patients only.
Pearson correlation coefficients are shown with p-values in parentheses.
NOTES: Bother = the mDLQI “bother” item; EQ-5D Index = EQ-5D Index; EQ-5D VAS = EQ-5D Visual
Analog Store; EORTC Global = EORTC QLQ-C30 Global Quality of Life Scale; FCSI = FACT/NCCN
Colorectal Cancer Symptom Index
• In the panitumumab patients, lower mDLQI scores (more skin bother) were
associated with higher HRQOL scores (improved HRQoL)
Humblet ASCO 2007 – Draft CONFIDENTIAL
Conclusions
• As expected, panitumumab patients reported being more bothered by
their skin conditions than BSC patients; however, CRC symptoms and
HRQOL scores trended in favor of panitumumab vs BSC
– Based on the minimal clinical important difference, a negative effect
with panitumumab treatment could be excluded
• From this exploratory analysis of data from a phase 3 trial, improved
PFS, overall survival, CRC symptomalogy, and HRQOL were associated
with worse skin toxicity as measured by the CTCAE grading scale and
mDLQI.
• These findings support the role of skin toxicity severity as a
pharmacodynamic marker of on-target activity that appears to be
associated with clinical benefit. Further analyses are being conducted
to explore the predictive value of early onset of skin toxicity severity
(see abstract #4134, poster #P5 by Berlin et al.)
Humblet ASCO 2007 – Draft CONFIDENTIAL
References
1.
Foon KA, Yang X-D, Weiner LM, et al. Preclinical and clinical
evaluations of ABX-EGF, a fully human anti-epidermal growth factor
receptor antibody. Int J Radiat Oncol Biol Phys 2004:58:984-990.
2.
VectibixTM Prescribing Information, Amgen Inc. Thousand Oaks CA;
2006.
3.
Van Cutsem E, Peeters M, Siena S, et al. An open-label, randomized,
phase 3 clinical trial of panitumumab plus best supportive care
versus best supportive care in patients with chemotherapyrefractory metastatic colorectal cancer. J Clin Oncol 2007;25:16581664.
Humblet ASCO 2007 – Draft CONFIDENTIAL