A Phase 2 Clinical Trial of Panitumumab Monotherapy in Japanese
Patients with Metastatic Colorectal Cancer
Kei Muro1, Takayuki Yoshino2,3, Toshihiko Doi3, Kuniaki Shirao4, Hiroya Takiuchi5, Yasuo Hamamoto6,
Hiroyuki Watanabe7, Bing-Bing Yang8and Daisuke Asahi7
1Aichi Cancer Center Hospital, Nagoya,2Shizuoka Cancer Center, Shizuoka,3National Cancer Center Hospital
East, Chiba,4National Cancer Center Hospital, Tokyo,5Osaka Medical College, Osaka,6Tochigi Cancer Center,
Utsunomiya,7Takeda Bio Development Center Ltd, Tokyo, Japan and8Amgen Inc., Thousand Oaks, CA, USA
Received October 17, 2008; accepted February 9, 2009; published online March 14, 2009
Objective: Panitumumab, a fully human monoclonal antibody targeting epidermal growth
factor receptor (EGFR), has antitumor activity and an acceptable safety profile in patients
with metastatic colorectal cancer (mCRC). This Phase 2 study evaluated efficacy, pharmaco-
kinetics and safety of panitumumab in Japanese patients with mCRC who developed pro-
gressive disease during or after fluoropyrimidine, irinotecan and oxaliplatin chemotherapy.
Methods: Eligible patients had histologically proven colorectal adenocarcinoma and EGFR
tumor expression in ?1% of tumor cells by immunohistochemistry. Patients received panitu-
mumab 6 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The
primary endpoint was objective response rate (ORR) per modified Response Evaluation
Criteria in Solid Tumors (RECIST) by independent central review. Secondary endpoints
included progression-free survival (PFS), overall survival (OS), pharmacokinetic parameters
and incidence of adverse events.
Results: Fifty-two patients received at least one dose of panitumumab. Seven patients had
partial responses for a confirmed ORR of 13.5% (95% CI: 5.6, 25.8). Median PFS was 8.0
weeks (95% CI: 7.4, 11.4) and median OS was 9.3 months (95% CI: 7.1, 12.8).
Panitumumab pharmacokinetics were consistent with prior studies in Japanese and non-
Japanese patients. The most common treatment-related adverse events (all, worst grade 3)
were acne (81%, 2%), dry skin (62%, 0%), rash (46%, 2%), paronychia (33%, 2%), pruritus
(33%, 0%) and hypomagnesemia (33%, 0%). No adverse event of infusion reaction was
reported by the investigators.
Conclusions: Panitumumab monotherapy was active in Japanese patients with chemotherapy-
refractory mCRC, with pharmacokinetic and safety profiles similar to those seen in prior
Key words: panitumumab – pharmacokinetics – colorectal neoplasms – metastases – drug toxicity
Cancer is one of the leading causes of death in Japan, and
the incidence of colorectal cancer (CRC) has been increasing
(1). In Japan, 131 438 new cases (87 825 colon cancers and
43 613 rectal cancers) and 55 070 deaths are anticipated in
2010 (2). Of newly diagnosed patients with CRC, 15–25%
of the patients have metastatic disease (3) and 50% or more
of the patients who are initially diagnosed with localized
disease ultimately develop metastatic CRC (mCRC) (4).
Expression of the epidermal growth factor receptor
(EGFR) is frequently associated with malignant transform-
ation in carcinomas, including CRC (5,6). Currently, there
are two anti-EGFR monoclonal antibodies, panitumumab
and cetuximab, that are approved in the USA and Europe for
the treatment of mCRC. Tumor expression of EGFR is a
labeling requirement for both drugs (7,8).
Panitumumab is a fully human, monoclonal antibody with
high affinity (KD¼ 5 ? 10211M) for EGFR (7). Efficacy,
pharmacokinetics and safety of panitumumab have been
tested in Japanese patients with solid tumors (9). In that
study, patients received panitumumab at doses of 2.5 mg/kg
For reprints and all correspondence: Kei Muro, Aichi Cancer Center
Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, Japan. E-mail:
# The Author (2009). Published by Oxford University Press. All rights reserved.
Jpn J Clin Oncol 2009;39(5)321–326
by guest on June 12, 2013
once weekly, 6.0 mg/kg every 2 weeks (Q2W) and 9.0 mg/
kg every 3 weeks as monotherapy. All responders in that
study (4 patients of 18 enrolled) had advanced CRC. The
study described here extends the evaluation of panitumumab
in Japanese patients with mCRC.
PATIENTS AND METHODS
STUDY DESIGN AND ELIGIBILITY CRITERIA
This was a multicenter, open-label, single-arm, Phase 2
clinical study in Japanese patients with mCRC who devel-
oped disease progression during or after prior fluoropyrimi-
dine, irinotecan and oxaliplatin chemotherapy. The study
was approved by Institutional Review Boards at all study
Panitumumab (derived from Chinese hamster ovary cells
on a 12 kl production scale) was supplied at a concentration
of 20 mg/ml in 10 ml vials (Amgen Inc., Thousand Oaks,
CA, USA). Panitumumab was administered by intravenous
infusion using a 0.22 mm in-line filter at a dose of 6.0 mg/kg
Q2W over approximately 60 min. This dose of panitumumab
was selected based on pharmacokinetic modeling, which
indicated that 6.0 mg/kg Q2W would maintain a trough
serum concentration at or above that necessary to achieve
EGFR saturation levels while providing a convenient Q2W
dosing. This dose has also been tested and deemed to be tol-
erable in a small study of Japanese patients (9).
Patients received panitumumab until they developed pro-
gressive disease or were unable to tolerate treatment. Patients
who discontinued treatment for any reason underwent a
safety follow-up visit. All patients were followed for 24
months after the first panitumumab infusion at approximately
3-month intervals to assess survival.
Eligible patients were men and women .20 years old
who provided written informed consent. All patients had a
pathologic diagnosis of colorectal adenocarcinoma with
documented radiographic evidence of progressive disease
during or after the most recent regimen with fluoropyrimi-
dine, irinotecan and oxaliplatin. To ensure adequate exposure
to prior chemotherapy, average dose-intensity of irinotecan
(?50 mg/m2/week) and oxaliplatin (?30 mg/m2/week) was
required. Patients were also required to have: unidimension-
ally measurable disease (?20 mm in at least one dimension);
an Eastern Cooperative Oncology Group (ECOG) perform-
ance status of 0–2; and EGFR expression on ?1% of evalu-
ated tumor cells. EGFR expression was determined by
immunohistochemistry using the EGFR pharmDXTMkit
(DakoCytomation, Carpenteria, CA, USA) and all tests were
performed at a central laboratory (Esoterix Clinical Trials
Services BVBA, Mechelen, Belgium).
Efficacy endpoints included the objective response rate
(ORR; primary endpoint), time to response, duration of
response, duration of stable disease, time to treatment
failure, progression-free survival (PFS) time and overall sur-
vival (OS; secondary endpoints). Time to treatment failure
was calculated as the time from the date of enrollment to the
date a decision was made to end the treatment period for any
reason. Panitumumab pharmacokinetic endpoints included
the area under the concentration–time curve (AUC);
maximum (Cmax) and minimum (Cmin) observed concen-
trations; and half-life during the dosing interval (t1/2). Safety
endpoints included incidence of all adverse events; changes
in laboratory values and vital signs; and the incidence of
anti-panitumumab antibody formation and infusion reactions.
Patients were evaluated for tumor response according to the
modified Response Evaluation Criteria in Solid Tumors
(RECIST) at weeks 8, 12, 16, 24, 32, 40 and 48 and every
8 weeks thereafter until disease progression. Tumor
responses were confirmed no less than 4 weeks after the cri-
teria for response were first met. In addition to investigators’
assessments, radiographic scans of all patients were reviewed
by a central reviewer.
Predose serum samples for pharmacokinetic analyses were
collected from a subset of patients and at 0.5, 24, 96, 168
and 240 h after completion of the first infusion and within
0.5 h before and 0.5 h after completion of infusions at
Weeks 3, 5 and 7 and every 8 weeks thereafter. An
additional sample was collected during the safety follow-up
visit. A validated immunoassay with electrochemilumines-
cence detection was used to measure panitumumab concen-
trations in the serum samples (10). Pharmacokinetic assays
were performed by Amgen Inc.
Serum samples to test for anti-panitumumab antibodies
were collected before panitumumab infusion at Weeks 1, 7
and 23, and during the safety follow-up visit. This study uti-
lized the same validated assays to detect the potential pre-
sence of anti-panitumumab antibodies as has been used in
previous panitumumab clinical trials (11). An ELISA assay
and a BiacoreTMassay were used for screening, and a cell-
based bioassay was used to detect neutralizing antibodies.
Anti-panitumumab antibody assays were performed by
A retrospective analysis of tumor KRAS status was per-
formed. DNA extracted from archived paraffin-embedded
tumor tissue was analyzed for mutant KRAS sequences using
a K-RAS Mutation Test Kit (DxS Ltd, Manchester, UK) that
used allele-specific real-time polymerase chain reaction (12).
Adverse events were graded using the National Cancer
Institute Common Toxicity Criteria (NCI-CTC) version 2.0
with the exception of skin or nail toxicities, which were
graded using the modified Common Terminology Criteria
for Adverse Events (CTCAE) version 3.0.
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Efficacy and safety analyses were conducted on the Full
Analysis Set, which comprised all patients who had received
at least one infusion of panitumumab. The Pharmacokinetics
Analysis Set included all patients who received panitumu-
mab and had evaluable serum data.
Mean values and standard deviations (SDs) are provided
for continuous endpoints and frequency and percentage dis-
tributions are provided for discrete data. The ORR and its
two-sided 95% confidence interval (CI) (13) were calculated.
Survival time (progression-free and overall), time-to-event
and duration endpoints are summarized with Kaplan–Meier
curves and two-sided 95% CIs.
Of 98 patients who were screened, 53 patients were enrolled
in six study sites in Japan. The most common reasons for
screen failure were: tumor was EGFR-negative, EGFR
expression was not diagnostic, and insufficient dose-intensity
of irinotecan or oxaliplatin. One patient did not receive pani-
tumumab because of disease progression clinically judged
by the investigator, and 52 patients received at least one
dose of panitumumab and were included in the Full Analysis
Set. Forty-nine (94%) patients ended treatment because of
disease progression, one (2%) patient withdrew consent and
no patient withdrew from the study because of adverse
events. Two patients remained with the study at the time of
data cut-off (12 April 2007). Baseline demographic and
clinical characteristics are summarized in Table 1.
The median number of infusions per patient was 6 (range:
2–20 infusions). The median average weight-adjusted
dosage of panitumumab was 6.04 mg/kg and the median
weight-adjusted cumulative dosage was 35.5 mg/kg (range:
Objective responses were observed in seven patients for a
rate of 13.5% (95% CI: 5.6, 25.8) by central radiographic
image review. All seven responders had a partial response
and no patient had a complete response. Seventeen (33%)
and 26 (50%) patients had stable disease and progressive
disease, respectively. Two (4%) patients could not be evalu-
ated for objective response because of withdrawn consent for
one patient and lack of confirmation of response in the other
patient. Similar to results from central assessment, the ORR
was 15.4% (8 of 52 patients; 95% CI: 6.9, 28.1) based on
the investigators’ assessments. Twenty-three (44%) and 19
(37%) patients had stable disease and progressive disease,
The median time of follow-up for all 52 patients was 26.1
weeks (range: 5.4–42.0 weeks). The mean time to response
in the seven responders was 7.6 weeks (95% CI: 6.1, 9.1)
and the median duration of response was 16.2 weeks (95%
CI: 16.1, 24.1). The median duration of stable disease was
15.0 weeks (95% CI: 11.4, 16.3). The median time to treat-
ment failure was 11.4 weeks (95% CI: 8.4, 15.0). At the
time of data cut-off, the median PFS was 8.0 weeks (95%
CI: 7.4, 11.4) (Figure 1). The median OS was 9.3 months
(95% CI: 7.1, 12.8).
Objective responses were also analyzed by EGFR
expression (percentage of EGFR-positive cells and staining
intensity) and grade of skin-related toxicity (Table 2). No
correlation was observed between panitumumab efficacy and
percentage of tumor cell membrane staining. All responders
had grade 2 or 3 skin-related adverse events.
Tumor samples for retrospective KRAS testing were avail-
able for testing from only 16 patients in this study; however,
data for 8 Japanese patients with mCRC enrolled in a prior
Phase 1 panitumumab study (9) were also available. In a
pooled analysis of these 24 patients, 14 (58%) had wild-type
KRAS and 10 (42%) had mutated KRAS. Four (17%) patients
Table 1. Patient demographics and disease characteristics at baseline
CharacteristicAll patients (N ¼ 52)
34 (65) Male sex, n (%)
Age, median years (minimum, maximum) 59.0 (23, 77)
Primary diagnosis, n (%)
Colon cancer30 (58)
Rectal cancer 22 (42)
ECOG performance status, n (%)
0 29 (56)
1 23 (44)
Prior chemotherapy, n (%)
2 lines 27 (52)
Cells with EGFR membrane staining, n (%)
1% to ,10%30 (58)
10–35% 16 (31)
.35% 6 (12)
Highest membrane staining intensity, n (%)
ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth
Jpn J Clin Oncol 2009;39(5)323
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had a partial response to panitumumab therapy; all of these
patients had tumors expressing wild-type KRAS. Median
(95% CI) PFS was 13.2 (8.0, 23.1) weeks in patients with
wild-type KRAS and 7.3 (7.1, 7.6) weeks in patients with
mutated KRAS in their tumors.
Serum samples for pharmacokinetic analyses were collected
from 20 patients who received panitumumab 6 mg/kg Q2W.
After the first panitumumab dose, the mean (SD) Cmaxwas 113
(36.1) mg/ml and the mean (SD) Cminwas 15.4 (8.5) mg/ml;
during the first dosing interval, the mean AUC (SD) was
approximately 640 (174) mg day/ml and the mean (SD) t1/2was
5.6 (2.0) days. After multiple panitumumab administrations,
the mean (SD) steady-state concentrations based on data from
the third dose and beyond were 31.7 (21.3) mg/ml before
infusion and 146 (34.6) mg/ml immediately after infusion;
these values were 2.0- and 1.3-fold higher, respectively, than
the corresponding value after the first administration.
Figure 1. Progression-free survival (PFS) based on central assessment. The Kaplan–Meier curve of PFS for all patients (N ¼ 52) is shown. Dashed lines
represent 95% CI and censored patients are designated by vertical lines.
Table 2. Objective response and progression-free survival by EGFR tumor cell membrane staining and skin toxicity per central independent radiographic
Objective response Progression-free survival
Median time weeks (95% CI)c
Patients responding,an (%) Rate % (95% CI)b
1% to ,10%30 4 (13) 13.3 (3.8, 30.7) 8.0 (7.4, 11.4)
10% to 35%16 3 (19) 18.8 (4.1, 45.7)7.4 (7.1, 23.0)
.35%60 0 (0, 45.9)11.2 (7.6, 15.0)
Maximum gradedof skin toxicity
294 (14) 13.8 (3.9, 31.7) 7.6 (7.3, 11.1)
141 (7) 7.1 (0.2, 33.9)12.0 (7.1, 15.3)
9 2 (22)22.2 (2.8, 60.0)11.4 (7.6, 23.4)
Grade 180 0 (0, 36.9) 7.6 (4.1, 7.6)
Grade 2 416 (15) 14.6 (5.6, 29.2)11.0 (7.4, 12.0)
Grade 33 1 (33) 33.3 (0.8, 90.6) 15.0 (7.1, 23.0)
CI, confidence interval; n, number of patients; EGFR, Epidermal growth factor receptor.
aPatients with a complete response or partial response.
bCIs for objective response rate were calculated based on the F distribution method (13).
cCIs for progression-free survival were calculated based on a sign test (25).
dGrades based on the National Cancer Institute Common Toxicity Criteria version 2.0 with the exception of skin or nail toxicities, which were graded using
the modified Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
324Panitumumab in metastatic colorectal cancer
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All patients had at least one adverse event and most patients
(98%) had at least one adverse event that was considered by
the investigator to be possibly related to treatment with pani-
tumumab. No patient discontinued the study because of
an adverse event. Most adverse events were grade 1 or 2.
Thirteen (25%) patients had an adverse event with a worst
grade of 3, and three (6%) patients had events with a worst
grade of 4. The most common grade 3 adverse events
were anorexia (n ¼ 4) and hypophosphatemia (n ¼ 3). Five
grade 4 adverse events occurred in three patients, including
anemia, fatigue, abnormal hepatic function, hepatic failure
and hyperuricemia. One patient had a grade 5 event that was
attributed to disease progression within 30 days of the last
dose of panitumumab.
Most treatment-related events were grade 1 or 2, and skin-
related events were most common (Table 3). One patient had
a grade 3 serious adverse event of deep vein thrombosis. No
grade 4 or higher treatment-related adverse event was
reported. Fifty-one (98%) patients had treatment-related skin
toxicities. The most common skin toxicities were acne
(81%), dry skin (62%), rash (46%), paronychia (33%), pruri-
tus (33%), nail disorder (15%) and erythema (13%). Three
(4%) patients had grade 3 treatment-related skin toxicities
(acne, rash and paronychia). In a Kaplan–Meier analysis of
skin toxicities, the median time to first toxicity was 6 days
(95% CI: 5, 7) and the median time to most severe toxicity
was 9 days (95% CI: 7, 13).
Grade 3 or 4 laboratory toxicities were seen in 12 (23%)
patients; 11 (21%) patients had grade 3 and 1 (2%) patient
had a grade 4 laboratory toxicity. Nineteen patients had
grade 1 and two patients had grade 2 hypomagnesemia.
Non-transient anti-panitumumab antibodies were seen in two
(4%) patients; these patients did not have any severe or
serious adverse events. Serum antibodies from these two
patients did not exhibit neutralizing activity.
There were no investigator-reported adverse events of infu-
sion reactions in this study. In a conservative post hoc analy-
sis of adverse event terms (categories of acute infusion
reaction/cytokine release syndrome and allergic reaction/
hypersensitivity occurring on the day of infusion and resol-
ving the same day or the day after the infusion), potential
infusion reactions were reported in 6 (12%) patients, yielding
a per-infusion incidence of 7/367 (2%). All potential infusion
reactions were grade 1 and included pyrexia (n ¼ 3), vomit-
ing (n ¼ 1), hypertension (n ¼ 1) and fatigue (n ¼ 1).
The ORR (13.5%) in this study of panitumumab in Japanese
patients with mCRC was similar to rates reported in prior
studies in non-Japanese patients (11,14,15). Consistent with
results from prior studies that examined the relationship
between level of EGFR expression and efficacy of
anti-EGFR monoclonal antibodies (15–19), no apparent cor-
relation was observed between panitumumab efficacy and
percentage of tumor cell membrane EGFR staining. These
observations suggest that EGFR staining may not identify
patients who are more likely to respond to anti-EGFR anti-
body therapy, and patients should not be denied this treat-
ment based on EGFR testing. Patients with grade 2 or 3
skin-related adverse events had higher response rates and
longer PFS than patients with grade 1 events. These findings
are consistent with studies associating skin toxicity with
response to anti-EGFR antibodies (15–17,19).
The presence of mutated KRAS in tumors has been seen to
be a negative predictor of response to anti-EGFR mono-
clonal antibody therapies (12,20). In a pooled analysis (21)
of patients with available KRAS status in this study and a
prior Phase 1 study in Japanese patients with mCRC (9), all
patients who had a response to panitumumab had tumors
that expressed wild-type KRAS. Although a comparison of
efficacy between Japanese patients with tumors expressing
wild-type KRAS and those with mutated KRAS is not con-
clusive because of the small sample size, our findings are
Table 3. Treatment-related adverse eventsaoccurring in ?10% of patients
Adverse event,bn (%) All patients (N ¼ 52)
All gradesGrade 3
Patients with any treatment-related adverse event51 (98) 6 (12)c
Skin toxicities51 (98)3 (6)
Acne42 (81)1 (2)
Dry skin 32 (62)0
Rash24 (46)1 (2)
Paronychia17 (33) 1 (2)
Nail disorder 8 (15)0
Erythema 7 (13)0
Fatigue 13 (25)0
Anorexia 11 (21)1 (2)
Diarrhea 8 (15)0
Vomiting 7 (13)0
Decreased weight5 (10)0
aThe investigator considered there to be a reasonable possibility that the
event may have been caused by panitumumab.
bAdverse events were coded using the MedDRA dictionary version 9.0.
Grades based on the National Cancer Institute Common Toxicity Criteria
version 2.0 with the exception of skin or nail toxicities, which were graded
using the modified Common Terminology Criteria for Adverse Events
(CTCAE) version 3.0.
cThe remaining treatment-related grade 3 events not included in the table
were anemia (n ¼ 1) and hypophosphatemia (n ¼ 1).
Jpn J Clin Oncol 2009;39(5)325
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consistent with other panitumumab (12) and cetuximab Download full-text
The pharmacokinetic profile of patients who were tested in
this study was similar to those from prior studies in Japanese
patients (23) and non-Japanese patients (24). At the 6 mg/kg
Q2W dose and schedule, steady-state concentrations are
attained by the third infusion.
Similar to observations in prior clinical trials of the
anti-EGFR monoclonal antibodies (15–17,19), the most
common adverse events reported in this study were skin-
related. The skin reactions were primarily mild to moderate
in severity. Only 6% of skin-related adverse events were
severe (grade ?3) compared with ?16% in prior studies (7).
In conclusion, this Phase 2 study examined the effects of
panitumumab in Japanese patients with mCRC who devel-
oped disease progression or relapsed while on or after prior
fluouropyrimidine, irinotecan and oxaliplatin chemotherapy.
Results from this study indicate that panitumumab at a dose
of 6 mg/kg Q2W was well tolerated and exhibited clinically
meaningful antitumor activity in this patient population. The
pharmacokinetic and safety profiles were similar to those
observed in previous non-Japanese panitumumab clinical
The authors thank the patients, their families and friends for
participation in the study and the clinical study staff at all
participating institutions. We also wish to thank the follow-
ing individuals at Amgen Inc.: Peggy Lum, BS, for pharma-
cokinetic studies; Toru Sasaki for study management; and
Julia R. Gage, PhD, for writing assistance on behalf of
This study was funded by Amgen Inc.
Conflict of interest statement
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