Safety and Efficacy of Panitumumab
Monotherapy in the Treatment of Metastatic
Colorectal Cancer (mCRC) – Summary of
Results Across Clinical Studies
Jordan Berlin,1 Eric Van Cutsem,2 Marc Peeters,3
J. Randolph Hecht,4 Michael Wolf,5 Rafael Amado,5
Neal J. Meropol6
Abstract #326O
1Vanderbilt
University Medical Center, Nashville, TN; 2University Hospital
Gasthuisberg, Leuven, Belgium; 3Ghent University Hospital, Ghent,
Belgium; 4UCLA School of Medicine, Los Angeles, CA; 5Amgen Inc.,
Thousand Oaks, CA; 6Fox Chase Cancer Center, Philadelphia, PA
Introduction
• Panitumumab is a high-affinity (Kd = 5  10−11 M), fully human IgG2
monoclonal antibody directed against EGFr.1
• Panitumumab inhibits EGFr-mediated activity, including EGFr
tyrosine autophosphorylation, tumor cell growth, and
metastases.1-4
• Panitumumab monotherapy shows clinical activity in patients with
late-stage colorectal cancer whose disease progressed after
standard irinotecan- and/or oxaliplatin-containing chemotherapy
regimens.5
• This summary of five studies presents efficacy data for
panitumumab in a total of 732 patients with mCRC who were
refractory to prior therapy. Two studies are complete, three are
interim.
1Foon
et al. Int J Radiat Oncol Biol Phys. 2004;58:984-990.
et al. Eur J Cancer Suppl. 2004;2:95-96. Abstract 313.
3Freeman et al. Proc Am Assoc Cancer Res. 2005;46:1062. Abstract 4494.
4Lynch and Yang. Semin Oncol. 2002;29(suppl 9):47-50.
5Peeters et al. Proc Am Assoc Cancer Res. 2006;47: Abstract CP-1.
2Freeman
Berlin et al. ESMO 2006
Objectives
•
Assessment of the efficacy of panitumumab in patients with
disease progression during or after prior fluoropyrimidine,
irinotecan, and/or oxaliplatin treatment for mCRC
•
Key objectives of the studies included:
– Objective tumor response
– Progression-free survival
– Duration of response
•
Secondary objectives of the studies included:
– Time to response
– Survival time
– Safety (eg, adverse events, skin toxicities, human anti-human
antibody responses)
Berlin et al. ESMO 2006
Design and Methods
Peeters, et al.
2006a
Berlin, et al.
2006b
Hecht, et al.
2006c
Malik, et al. 2005d
Panitumumab
(N=229)
Crossover
(N=177)
(N=93)
(N=88)
(N=150)
3
3 (ES)
2
2
2
Dose
schedule
6 mg/kg Q2W
6 mg/kg Q2W
6 mg/kg Q2W
6 mg/kg Q2W
2.5 mg/kg QW
Response
assessment
RECIST
Central review
RECIST
Local review
WHO
Central review
WHO
Central review
RECIST
Central review
Assessment
schedule
Wks 8-48 and
Q3M thereafter
until PD
Q8W and at
investigator
discretion
Wks 8-48 and
Q3M thereafter
until PD
Wks 8-48 and
Q3M thereafter
until PD
Q9W and at
investigator
discretion
EGFr
staining by
IHC, central
review
≥ 1% of
evaluated
tumor cells
≥ 1% of
evaluated
tumor cells
≥ 10% of
evaluated
tumor cells
<1% (negative)
or 1 to < 10%
of evaluated
tumor cells
 High EGFr: 2+ or
3+ in ≥ 10% of
tumor cells
 Low EGFr: sum of
1+, 2+, and 3+ in ≥
10%, but 2+ and
3+ in < 10% of
evaluated tumor
cells
Phase
aPeeters
et al. Proc Am Assoc Cancer Res. 2006;47: Abstract CP-1
et al. J Clin Oncol. (Meeting Abstracts). 2006;24:3548
cHecht et al. J Clin Oncol. (Meeting Abstracts). 2006;24:3547
dMalik et al. J Clin Oncol. (Meeting Abstracts). 2005;23:3520
bBerlin
Berlin et al. ESMO 2006
Key Eligibility Criteria
• Age  18 years
• ECOG score of 0 – 2 (4 studies)
0 – 1 (1 study)
• Pathologic diagnosis of CRC
• Radiographic documentation of disease progression during or
within 6 months of most recent chemotherapy of
fluoropyrimidine and
– Irinotecan  65 mg/m2/week for 8 weeks and
– Oxaliplatin  30 mg/m2/week for 6 weeks (4 studies)
• Prior fluoropyrimidine and irinotecan or oxaliplatin, or both, any
exposure; no requirement for documentation of disease
progression (1 study: Malik, et al. 2005)
• Evaluation of tumor cell EGFr membrane staining (by IHC at
central laboratory)
Berlin et al. ESMO 2006
Results
Patient Disposition
All Patients
Patients enrolled, n (%)
739 (100)
Patients who received study drug,a n (%)
732 (99)
Efficacy set, n (%)
617 (84)
Median (min, max) follow-up,b weeks
All-enrolled analysis set
Efficacy analysis set
aSafety
56 (3, 151)
64 (16, 151)
set
bFollow-up
time is calculated from the enrollment date to the date
of the data cut-off
Berlin et al. ESMO 2006
Demographics
Peeters, et al. 2006
Panitumumab Crossover
(N=231)
(N=176)
Sex - n (%)
Men
Median (min, max)
age - years
Race - n(%)
White
Black
Hispanic
Other
ECOG status - n (%)a
0
1
2
aECOG
Berlin, et
al. 2006
Hecht, et
al. 2006
Malik, et
al. 2005
(N=93)
(N=88)
(N=148)
146 (63)
62 (55, 68)
111 (63)
62 (32, 83)
51 (55)
59 (31, 82)
51 (58)
62 (26, 85)
83 (56)
60 (21, 88)
229 (99)
175 (99)
74 (80)
71 (81)
120 (81)
1 (0)
0 (0)
8 (9)
12 (14)
14 (9)
1 (0)
0 (0)
0 (0)
1 (1)
7 (8)
4 (4)
3 (3)
2 (2)
5 (3)
9 (6)
107 (46)
94 (41)
29 (13)
53 (30)
85 (48)
38 (22)
31 (33)
55 (59)
7 (8)
41 (47)
42 (48)
5 (6)
37 (25)
111 (75)
0 (0)
status 3 was reported in 1 panitumumab patient in the phase 3 study
Berlin et al. ESMO 2006
Disease Characteristics
Peeters, et al. 2006
Panitumumab Crossover
(N=231)
(N=176)
Primary diagnosis,
n (%)
Colon cancer
Rectal cancer
Berlin, et
al. 2006
Hecht, et
al. 2006
Malik, et
al. 2005
(N=93)
(N=88)
(N=148)
153 (66)
78 (34)
113 (64)
63 (36)
70 (75)
23 (25)
61 (69)
27 (31)
106 (72)
42 (28)
231 (100)
176 (100)
93 (100)
88 (100)
65a (100)
1
2
1 (0)
146 (63)
0 (0)
114 (66)
0 (0)
2 (2)
0 (0)
13 (15)
0 (0)
24 (37)
≥3
84 (36)
62 (35)
91 (98)
75 (85)
41 (63)
Number of prior lines of
chemotherapy, n (%)
aPrior
chemotherapy is based on a subset of patients who had received fluoropyrimidine, oxaliplatin and
irinotecan.
Berlin et al. ESMO 2006
Best Objective Response
Berlin, et
al. 2006
Hecht, et
al. 2006
Malik, et
al. 2005
(N=39)
Adjud
Prior
Failure
3 (8)c
(N=23)
Adjud
Prior
Failure
3 (13)c
(N=148)
All Enrolled
19 (8)a
Crossover
(N=176)
Modified
Intent-totreat
20 (11)b
All
Enrolled
13 (9)a
64 (28)
83 (36)
113 (49)
58 (33)
78 (44)
65 (37)
8 (21)
11 (28)
20 (51)
7 (30)
10 (43)
10 (43)
43 (29)
55 (37)
59 (40)
Peeters, et al. 2006
Panitumumab
(N=231)
Analysis Set
Overall objective
response (CR or
PR), n (%)
Stable Disease, n (%)
Disease Control
PD, n (%)
aModified
RECIST criteria; blinded central review
RECIST criteria; local review
cModified WHO criteria; blinded central review
All responses were confirmed > 4 weeks after response criteria were first met
Disease control rate is the sum of the objective response and stable disease rates
bModified
Berlin et al. ESMO 2006
Time and Duration of Response
Peeters, et al. 2006
Panitumumab Crossover
(N=231)
(N=176)
Median (range)
time to
response weeksa
Median (range)
duration of
response –
weeks
95% CI
Berlin, et al.
2006
Hecht, et al.
2006
Malik, et al.
2005
(N=39)
(N=23)
(N=148)
7.9 (7, 15)
7.7 (7, 25)
11.0 (8, 11)
11.0 (7, 12)
8.1 (7, 25)
17.0 (8, 25)
16.4 (8, 35)
13.2 (12,14)
16.1 (16, 16)
18.1 (8, 36)
16.4, 25.3
16.0, 23.9
12.4, 14.0
NE, NEb
17.9, 23.3
aObjective
responses were assessed by blinded central review except for Peeters, et al (2006) crossover
study, where the responses were assessed by local review.
bNot estimable
Berlin et al. ESMO 2006
Progression-Free Survival
Proportion with
Progression-free Survival
100%
Median (95% CI) in Weeks
Peeters, et al. (2006): 8.0 (7.9, 8.4)
Peeters, et al. (2006) (ES): 8.1 (8.0, 12.4)
Berlin, et al. (2006): 7.9 (7.4, 11.4)
Hecht, et al. (2006): 8.1 (7.1, 22.9)
Malik, et al. (2005) : 13.6 (8.3, 16.1)
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0
Patients at risk:
Peeters, et al. (2006)
231
Peeters, et al. (2006) (ES) 174
Berlin, et al. (2006)
59
Hecht, et al. (2006)
32
Malik, et al. (2005)
148
4
8
12
16
20
24
Weeks
28
32
36
40
44
209
149
53
32
139
118
83
24
17
94
76
56
18
15
70
49
36
12
8
68
40
22
12
8
43
19
5
4
0
28
13
1
1
0
24
8
0
0
0
18
5
0
0
0
14
2
0
0
0
10
31
17
5
1
41
Berlin et al. ESMO 2006
Progression-Free Survival by Objective
Response in the Phase 3 Trial
1.0
CR/PR 8%
0.9
SD 28%
Event-free Probability
0.8
CR/PR
SD
Other
Other
64%
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
8
16
24
32
40
Weeks from Randomization
Other=Pts with progressive disease, unevaluable assessments, or no assessments; Groups not comparable due
tolead-time bias and lack of randomization. By central review by modified RECIST; responses were confirmed at
48
56
Berlin et al. ESMO 2006
Progression-Free Survival by Objective
Response in the Phase 3 Trial
1.0
CR/PR
8%
0.9
SD
Event-free Probability
0.8
10%
Panitumumab CR/PR
Panitumumab SD
BSC SD
28%
Panitumumab Other
BSC Other
0.7
0.6
Other
0.5
90%
64%
0.4
0.3
0.2
0.1
0.0
0
8
16
24
32
40
48
56
Weeks from Randomization
Other=Pts with progressive disease, unevaluable assessments, or no assessments; Groups not comparable due
to lead-time bias and lack of randomization. By central review by modified RECIST; responses were confirmed at
Berlin et al. ESMO 2006
Adverse Events of Interest
Subjects with any adverse eventa – n (%)
Fatigue
Nausea
Diarrhea
Vomiting
Abdominal Pain
Constipation
Dyspnea
Cough
Edema peripheral
Edema
Pleural effusion
Deep vein thrombosis
Pulmonary embolism
Hypomagnesemia
Hypomagnesemia (Lab)b
Any
(N = 732)
Grade 3-4
(N = 732)
239 (33)
208 (28)
185 (25)
152 (21)
147 (20)
146 (20)
106 (14)
100 (14)
83 (11)
30 (4)
16 (2)
9 (1)
7 (1)
31 (4)
41 (6)
14 (2)
15 (2)
21 (3)
37 (5)
13 (2)
28 (4)
4 (1)
9 (1)
4 (1)
7 (1)
6 (1)
4 (1)
9 (1)
226 (31)
32 (4)
MedDRA v.8 preferred terms; graded using the NCI CTCAE v 2.0, with the exception of some
dermatology/skin adverse events that were graded using the CTCAE v 3.0 with modifications
aSafety analysis set
bCaptured as laboratory values above grade 0
Berlin et al. ESMO 2006
Skin-Related Toxicities Occurring
in  10% of Patients
Any
(N = 732)
Grade 3-4
(N = 732)
669 (91)
382 (52)
379 (52)
95 (13)
36 (5)
13 (2)
Erythema
384 (52)
33 (5)
Rash
Skin exfoliation
Paronychia
263 (36)
145 (20)
142 (19)
20 (3)
10 (1)
8 (1)
Skin fissures
Dry skin
115 (16)
99 (14)
5 (1)
1 (0)
Subjects with any adverse eventa – n (%)
Dermatitis acneiform
Pruritus
MedDRA v.8 preferred terms; graded using the NCI CTCAE v 2.0, with the exception of some
dermatology/skin adverse events that were graded using the CTCAE v 3.0 with modifications
aSafety analysis set
Berlin et al. ESMO 2006
Infusion reactions
• Six of 732 (0.8%) patients had infusion reactions of any grade per
investigator
• Two (0.3%) patients had a grade 3 infusion reaction per
investigator
• One patient discontinued panitumumab per patient decision
Berlin et al. ESMO 2006
Antibodies to Panitumumab
Peeters, et al. 2006
Berlin, et
al. 2006
Hecht, et
al. 2006
Malik, et
al. 2005
Total
Panitumumab
(N=229)
Crossover
(N=176)
(N=91)
(N=88)
(N=148)
(N=732)
224
152
90
88
145
699
Baseline
samples, n (%)
221 (99)
150 (99)
88 (97)
87 (100)
142 (98)
688 (98)
Post-dose
samples, n (%)
185 (83)
71 (47)
66 (73)
66 (76)
107 (74)
495 (71)
Baseline
positive
3 (1)
2 (1)
0 (0)
0 (0)
0 (0)
5 (<1)
Post-dose
positive
0 (0)
2 (1)
0 (0)
0 (0)
0 (0)
2 (<1)
Samples
available for
testing,a n
aAcid
dissociation ELISA assay
Berlin et al. ESMO 2006
Conclusions
• Across all studies, panitumumab had consistent antitumor activity
in patients with mCRC:
– Objective response rates ranged from 8% to 13%
– Disease control rates ranged from 28% to 44%
– Progression-free survival ranged from 8 to 14 weeks
• Panitumumab was well tolerated
– Of 732 patients, 0.3% had grade 4 skin-related toxicities, and
13% had grade 3 skin-related toxicities
– The majority of patients (78%) had grade 1 or 2 skin-related
toxicities
– Grade 3 infusion reaction rate was 0.3% (there were no grade 4
infusion reactions); premedication was not required
– Less than 1% of patients had anti-panitumumab antibodies
Berlin et al. ESMO 2006
Conclusions
• Across all studies, EGFr staining levels were not
associated with panitumumab activity
• There was an association of panitumumab activity with
the incidence of skin toxicity (data not shown)
• Additional studies in mCRC with other agents are
ongoing
Berlin et al. ESMO 2006
Acknowledgements
• We wish to thank the patients who participated in these
studies and their families
• We also wish to acknowledge the investigators and
research teams who enrolled patients
• We acknowledge the assistance of Mee Rhan Kim and
Geoffrey Smith for slide production
Berlin et al. ESMO 2006