Download Dose and Schedule Study of Panitumumab Monotherapy in Patients

Cancer Therapy: Clinical
Dose and Schedule Study of Panitumumab Monotherapy in
Patients with Advanced Solid Malignancies
Louis M. Weiner,1 Arie S. Belldegrun,2 Jeffrey Crawford,3 Anthony W. Tolcher,4 Pamela Lockbaum,5
Rosalin H. Arends,5 Lynn Navale,6 Rafael G. Amado,6 Gisela Schwab,5 and Robert A. Figlin2
Abstract
Purpose: This phase 1 study evaluated the safety, pharmacokinetics, and activity of panitumumab, a fully human, IgG2 monoclonal antibody that targets the epidermal growth factor
receptor in patients with previously treated epidermal growth factor receptor ^ expressing
advanced solid tumors.
Experimental Design: Sequential cohorts were enrolled to receive four i.v. infusions of panitumumab monotherapy at various doses and schedules. Safety was continuously monitored.
Serum samples for pharmacokinetic, immunogenicity, and chemistry assessments were drawn
at preset intervals. Tumor response was assessed at week 8.
Results: Ninety-six patients received panitumumab. Median (range) age was 61 years
(32-79 years), and 72 (75%) patients were male. Tumor types were 41% colorectal cancer, 22%
prostate, 16% renal, 15% non ^ small cell lung, 3% pancreatic, 3% esophageal/gastroesophageal,
and 1% anal. The overall incidence of grade 3 or 4 adverse events was 32% and 7%, respectively.
The incidence of skin-related toxicities was dose dependent. No maximum tolerated dose was
reached. No human anti-panitumumab antibodies were detected. No investigator-determined
panitumumab infusion-related reactions were reported. Serum panitumumab concentrations
were similar in the 2.5 mg/kg weekly, 6.0 mg/kg every 2 weeks, and 9.0 mg/kg every 3 weeks
dose cohorts. Five of 39 patients (13%) with colorectal cancer had a confirmed partial response,
and 9 of 39 patients (23%) with colorectal cancer had stable disease.
Conclusions: Panitumumab was well tolerated with comparable exposure and safety profiles
for the weekly, every 2 weeks, and every 3 weeks administration schedules. Rash and dry skin
occurred more frequently in the dose cohorts receiving z2.5 mg/kg weekly dose. Panitumumab
has single-agent antitumor activity, most notably in patients with advanced colorectal cancer.
The epidermal growth factor receptor (EGFR) is a member of
The EGFR pathway has been linked to cancer through
mutations or gene overexpression that may enhance EGFR
signaling (4, 5). Overexpression of EGFR has been reported in
many tumor types, including renal cell carcinomas (6, 7),
pancreatic (8), non– small cell lung cancer (9), and colorectal
cancer and has been shown to predict tumor progression (4, 10).
Targeted agents such as small-molecule kinase inhibitors and
monoclonal antibodies directed against EGFR have shown
promising clinical results (11). A number of anti-EGFR monoclonal antibodies (e.g., cetuximab, panitumumab, matuzumab)
are currently indicated or under investigation in clinical trials
for the treatment of various solid malignancies (12). Cetuximab
is a chimeric anti-EGFR monoclonal antibody indicated in the
United States in patients with colorectal cancer refractory or
intolerant to irinotecan and in patients with squamous cell
carcinoma of the head and neck (13). Preliminary data from
studies of these antibodies administered with chemotherapy
have suggested high response rates (12).
Panitumumab is a fully human IgG2 anti-EGFR monoclonal
antibody that binds with high affinity (K D = 5 10-11 mol/L)
to the EGFR (14). Clinical trials have shown antitumor activity
of panitumumab in patients with chemorefractory metastatic
colorectal cancer (15 – 17).
Pharmacokinetic and pharmacodynamic data from a phase 2
study in patients with renal cell carcinoma were used to
the erbB family of transmembrane tyrosine kinase receptors
that includes family members erbB1/EGFR, erbB2/Her2, erbB3,
and erbB4. Ligands including EGF, transforming growth factora, amphiregulin, betacellulin, heparin-binding EGF, epiregulin,
and neuregulin (1, 2) bind with high specificity to the EGFR,
resulting in autophosphorylation and internalization of the
EGFR and activation of diverse signaling pathways that induce
proliferation, angiogenesis, inhibition of apoptosis, and metastasis (3).
Authors’ Affiliations: 1Georgetown University Medical Center, Washington,
District of Columbia; 2University of California at Los Angeles School of Medicine,
Los Angeles, California; 3Duke University Medical Center, Durham, North Carolina;
4
CancerTherapy and Research Center, San Antonio,Texas; 5Abgenix, Inc., Fremont,
California; and 6Amgen, Inc.,Thousand Oaks, California
Received 6/18/07; revised 9/5/07; accepted 10/22/07.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Current address for R.A. Figlin: City of Hope, Los Angeles, CA.
Requests for reprints: Louis M. Weiner, Georgetown University Medical Center
Research Building, Suite E501, 3970 Reservoir Road Northwest, Washington DC
20057-1465. Phone: 202-687-2110; Fax : 202-687-6402; E-mail: Weinerl @
georgetown.edu.
F 2008 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-07-1509
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Dose and Schedule of Panitumumab for Advanced Cancers
100% at 2.5 mg/kg, suggesting a plateau in panitumumab pharmacologic activity. Higher weekly doses, including 3.5 and 5 mg/kg, further
characterized panitumumab safety. Less frequent dosing schedules were
tested, chosen based on pharmacokinetic modeling which predicted
that 6.0 mg/kg every 2 weeks and 9.0 mg/kg every 3 weeks would result
in trough concentrations similar to those observed for the 2.5 mg/kg
weekly cohort.
Patients with a tumor response or stable disease were allowed to
continue treatment on a separate maintenance trial at their respective
dose for an additional 6 months or until disease progression. Data from
this maintenance trial are included in this report.
Study objectives. The primary objective was to assess the safety and
tolerability of multidose administration of panitumumab in patients
with advanced, treatment-refractory solid malignancies. Secondary
objectives were to determine the pharmacokinetics, dose-response
relationship, and clinical effect of panitumumab.
Assessments. Adverse events were assessed by the investigator at
each patient visit using the National Cancer Institute Common Toxicity
Criteria, version 2.0. Immunogenicity was assessed by evaluating the
human anti-panitumumab antibody response by ELISA at baseline and
at two time points following the last panitumumab administration. An
interim safety review of adverse events, vital sign data, laboratory tests,
and all serious adverse events, followed by a dose escalation, occurred
when all weekly patients completed their last dosing visit and when
every 2 weeks and every 3 weeks patients completed their second dosing
visit.
Blood was obtained for serum panitumumab pharmacokinetic analyses within 15 min before administration of each dose and 30 min
after completion of each infusion. Additional pharmacokinetic samples
were taken for the weekly dosing cohorts 1, 4, 8, and 24 h and 4 days
following the week 0 dose; for the every 2 weeks dosing cohorts,
additional pharmacokinetic samples were taken 8 and 24 h and 4, 7,
10, and 12 days following the week 0 and week 4 doses; and for the
every 3 weeks dosing cohorts, additional pharmacokinetic samples were
taken 8 and 24 h and 4, 7, 14, and 17 days following the week 0 and
week 6 doses. Serum panitumumab concentration profiles were
described by a two-compartment model previously reported (18).
Objective tumor response for measurable disease was evaluated by
investigator assessment using modified WHO criteria (19, 20). Prostatespecific antigen levels were assessed to evaluate response in patients
with prostate cancer. Responses were confirmed at least 4 weeks after
response criteria were initially met.
Drug administration. Panitumumab was administered i.v. for 2 h at
doses V1 mg/kg and for 1 h at doses z1.5 mg/kg (infusion times were
reduced after initial safety assessments). No premedication was required
but could be administered at the discretion of the investigator. Patients
were monitored for any reactions up to 8 h after the completion of the
infusion.
Statistics. The primary efficacy and safety analyses included all
enrolled patients who received any amount of panitumumab. Tumor
response was summarized by tumor type, EGFR staining intensity, and
incidence and severity of skin rash.
For pharmacokinetic analyses, panitumumab serum concentrations
were not measurable at doses of 0.02 and 0.06 mg/kg after the first dose
and were only available 24 h after dosing at the 10-fold higher 0.2 and
0.6 mg/kg doses, insufficient for characterizing the pharmacokinetic
profile for weekly treatments at these low dose levels. Therefore,
pharmacokinetic profiles for doses <0.75 mg/kg were not included in
the mean profiles presented for the higher dose cohorts.
calculate the optimal panitumumab dose of 2.5 mg/kg weekly
(18). In this study, panitumumab exhibited nonlinear pharmacokinetics in a dose range of 1 to 2.5 mg/kg weekly. Clearance
decreased with increasing dose, consistent with progressive
saturation of the EGFR. The 2.5 mg/kg weekly dose resulted in a
100% incidence of skin rash, a known dose-dependent surrogate biomarker for EGFR blockade in skin, with no grade 4
adverse events or human anti-panitumumab antibodies.
Here, we report on a phase 1, open-label study evaluating
panitumumab monotherapy in patients with advanced refractory EGFR-expressing tumors at various doses and schedules to
assess safety, pharmacokinetics, and activity.
Patients and Methods
Patients. Eligible patients were z18 years old; had advanced,
treatment-refractory renal, prostate, pancreatic, non – small cell lung,
colorectal, or esophageal/gastroesophageal junction cancer (tumor
must be evaluable by standard criteria for the specific tumor type);
had EGFR staining tumor cells (must be the sum of 1+, 2+, and 3+ in
z10% of evaluated tumor cells); had adequate hematologic, renal, and
hepatic function; had an Eastern Cooperative Oncology Group score of
0 to 1; and had a Karnofsky performance score of z70%. Selected
exclusion criteria included uncontrolled brain metastases, concomitant
cancer therapy of any kind (concomitant steroid or hormone therapy
was allowed), chemotherapy within 6 weeks of first panitumumab
infusion, systemic anticancer therapy within 30 days of first panitumumab infusion, or prior anthracycline therapy.
The protocol was approved by institutional review boards at
participating centers, and patients provided informed consent before
any study-related procedures were done.
Study design and methods. This was a multicenter, sequential, doseescalating, phase 1 study of panitumumab monotherapy. Patients
received four doses of panitumumab in one of the following dose
schedules: weekly at 0.01, 0.03, 0.1, 0.3, 0.75, 1.0, 1.5, 2.0, 2.5, 3.5, or
5.0 mg/kg; every 2 weeks at 6.0 mg/kg; and every 3 weeks at 9.0 mg/kg.
Patients receiving weekly doses of 0.01 to 0.3 mg/kg also received a
2 loading dose at week 1; patients receiving weekly doses of 0.75
to 1.0 mg/kg were evaluated either with or without a 2 loading dose
(Fig. 1).
Patients were enrolled sequentially into ascending dose cohorts
after an interim safety review of the previous cohort. A dose-limiting
toxicity (DLT) was defined as any grade 3 or 4 adverse event
(considered related by the investigator) as defined in the National
Cancer Institute Common Toxicity Criteria, version 2.0, or any severe or
life-threatening abnormality not covered in National Cancer Institute
Common Toxicity Criteria, version 2.0, or any toxicity deemed probably related or any skin toxicity as previously described that required
discontinuation of panitumumab (18). Dosing of any higher dose
cohort did not continue until 2 additional patients (3 patients for the
6.0 mg/kg every 2 weeks and 9.0 mg/kg every 3 weeks dose cohorts)
were dosed, and these 2 (or 3) new patients did not exhibit a DLT.
If one (or more) of these patients exhibited a DLT, then the dose level
below this dose was considered the maximum tolerated dose. Two to
4 patients were planned for each of the weekly cohorts, and 5 patients
were planned for the every 2 weeks and every 3 weeks cohorts. Any
cohort could be expanded up to 10 patients if deemed necessary by
the investigator and sponsor.
The doses selected in this study were based on preclinical xenograft
findings and a toxicology study in monkeys. A dose of 0.01 mg/kg
weekly was selected as the starting dose in this study. Loading doses
(twice the assigned dose at the first infusion only) were administered
at doses ranging from 0.01 to 1.0 mg/kg weekly to achieve steady-state
more rapidly. As the dose was increased from 0.75 to 2.5 mg/kg weekly,
an increase in skin rash incidence was observed, reaching a rate of
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Results
Patients. Of 97 patients enrolled, 96 patients received at
least one dose of panitumumab. Fifty-six patients were enrolled
in the weekly group, 17 patients in the 6.0 mg/kg every 2 weeks
group, and 23 patients in the 9.0 mg/kg every 3 weeks group.
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Fig. 1. The mean observed serum panitumumab concentrations after 4 weekly i.v. infusions of panitumumab, represented as symbols with (o), (y), (5), (.), (5), (E), (w ),
for the 0.75, 1.0, 1.5, 2.0, 2.5, 3.5, 5.0 mg/kg/wk doses, respectively on linear scale (left) and on log scale (right).
Safety and adverse events. Panitumumab administration at
all dose levels was generally well tolerated. Dose escalation to
the 9.0 mg/kg every 3 weeks cohort was achieved without
reaching the maximum tolerated dose. No infusion reactions
were reported as adverse events by the investigators.
Two patients in the 1.0 mg/kg weekly cohort had a DLT
of severe maculo-papular rash. The dose was deescalated to
0.75 mg/kg weekly; no further DLTs were observed, and
dose escalation was resumed in the 1.0 mg/kg weekly cohort.
One patient in the 2.5 mg/kg weekly cohort had a DLT of
severe asthenia, angina pectoris, and dyspnea. No other DLTs
were observed, and dose escalation continued into all planned
cohorts.
Adverse events of all grades were evenly balanced across all
groups (Table 2), with an overall incidence of 32% grade 3 and
7% grade 4 events. Serious adverse events were reported in 18
(19%) patients and were not considered related to panitumumab in 17 patients. One patient in the 9.0 mg/kg every 3 weeks
cohort experienced a grade 4 treatment-related serious adverse
event of hypomagnesemia, which resolved without sequelae
after the patient received i.v. and oral magnesium replacement.
The most common adverse events across all dose groups were
rash (61%), fatigue (39%), nausea (27%), diarrhea (23%), dry
skin (19%), and constipation (18%; Table 3). The most
common treatment-related adverse events were skin-related
toxicities, including rash (60%) and dry skin (19%). Fatigue,
diarrhea, and nausea were less frequently attributed to
panitumumab treatment, with treatment-related incidences of
any grade of 16%, 14%, and 13%, respectively.
Skin-related toxicities were frequent in every cohort, ranging
from 58% in the weekly cohorts (excluding the 2.5 mg/kg
weekly cohort), to 94% in the 6.0 mg/kg every 2 weeks cohort,
to 100% in both the 2.5 mg/kg weekly cohort and the 9.0 mg/kg
every 3 weeks cohorts. However, most skin-related toxicities
Baseline demographics included 75% men; mean age was
60.4 years. The most common tumor types included colorectal
(41% of patients), prostate (22% of patients), renal (16% of
patients), and lung (15% of patients; Table 1) cancers.
Table 1. Demographics and baseline disease
characteristics
All patients (N = 96)
Age, y
Mean
Median
Range
Sex, n (%)
Men
Women
Race, n (%)
White
Black
Hispanic
Asian
Other
Baseline ECOG, n (%)
0
1
Primary diagnosis, n (%)
Colorectal cancer*
Prostate cancer
Renal cancer
Non – small cell lung cancer
Pancreatic cancer
Gastroesophageal cancer
Esophageal cancer
Anal cancer
60.4
61.0
32-79
72 (75)
24 (25)
84
8
2
1
1
(88)
(8)
(2)
(1)
(1)
40 (42)
56 (58)
39
21
15
14
3
2
1
1
(41)
(22)
(16)
(15)
(3)
(2)
(1)
(1)
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
*Refers to colon or rectum.
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Dose and Schedule of Panitumumab for Advanced Cancers
Table 2. Grade 3 and 4 adverse events—all doses and most common doses
All other doses* 2.5 mg/kg
6.0 mg/kg
9.0 mg/kg
Total
QW (n = 48)
QW (n = 8) Q2W (n = 17) Q3W (n = 23) (N = 96)
Patients with any adverse event, n (%)c
Grade 3
Grade 4
Any serious
Patients with any treatment-related adverse events, n (%)
Grade 3
Grade 4
Any serious
Deaths on study, n (%)
47
13
4
7
38
3
0
1
1
(98)
(27)
(8)
(15)
(79)
(6)
(0)
(2)
(2)b
8 (100)
2 (25)
1 (13)
1 (13)
8 (100)
1 (13)
0 (0)
0 (0)
0 (0)
16 (94)
6 (35)
0 (0)
4 (24)
16 (94)
1 (6)
0 (0)
0 (0)
0 (0)
23 (100)
10 (44)
2 (9)
6 (26)
23 (100)
4 (17)
1 (4)
1 (4)
0 (0)
94
31
7
18
85
9
1
2
1
(98)
(32)
(7)
(19)
(89)
(9)
(1)
(2)
(1)
Abbreviations: QW, weekly; Q2W, every 2 wk; Q3W, every 3 wk.
*Doses ranged from 0.01 to 5.0 mg/kg weekly, excluding the 2.5 mg/kg weekly dose.
cAdverse events were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0.
bThis patient was in the 3.5 mg/kg weekly cohort; death was due to disease progression.
Pharmacokinetics. Serum panitumumab concentrations increased with weekly doses of 0.75 to 5 mg/kg (Fig. 1). In
the terminal phase of the weekly dose concentration profile,
there was a rapid decline in levels for doses 0.75 to 1.5 mg/kg
weekly, whereas at higher doses this nonlinear decline was less
apparent. Using preliminary pharmacokinetic data from all
weekly dose groups, panitumumab pharmacokinetics were
fitted to a model that accurately predicted a steady-state level
of 50 Ag/mL for the 6.0 mg/kg every 2 weeks and 9.0 mg/kg
every 3 weeks dosages. This target concentration was based on
the observed steady-state level of 50 Ag/mL for the 2.5 mg/kg
weekly dose (18). After the third dose cycle, mean (SE) C trough
values were 47 Ag/mL (5) and 49 Ag/mL (10) for the 6.0 mg/kg
every 2 weeks and 9.0 mg/kg every 3 weeks cohorts, respectively
(Fig. 2).
A profound dose-response relationship was observed for the
skin-related toxicity incidence (Fig. 3). This relationship was
similar to the one that has been previously reported for panitumumab in patients with renal cell carcinoma (18). Using the
were grade 1 (25% across all cohorts) or grade 2 (46% across all
cohorts) with a low incidence of grade 3 (7% across all cohorts)
and no grade 4 (0% across all cohorts) toxicities. The severity of
skin-related toxicities increased with increasing dose of panitumumab: 2 of 56 (4%) patients in the weekly cohort, 1 of 17
(6%) patient in the every 2 weeks cohort, and 4 of 23 (17%)
patients in the every 3 weeks cohort had a grade 3 skin-related
toxicity. The 2 patients in the weekly cohort had received a
loading dose of panitumumab.
Median time to first skin toxicity of any grade was 7 days
[95% confidence interval (95% CI), 7-10 days] with a median
time to resolution of 71 days (95% CI, 59-109 days). Median
time to most severe skin toxicity of any grade was 14 days (95%
CI, 12-20 days) with a median time to resolution of 39 days
(95% CI, 29-46 days).
Human anti-panitumumab antibodies. Eighty patients
(83%) had a baseline and post-dose sample available for
antibody analysis. No patients tested positive for human antipanitumumab antibodies after receiving panitumumab.
Table 3. Adverse events occurring in at least 10% of subjects—all doses and most common doses
All doses (N = 96)
Adverse event, n (%)
Rash
Fatigue
Nausea
Diarrhea
Dry skin
Constipation
Pyrexia
Abdominal pain
Vomiting
Anorexia
Stomatitis
Arthralgia
Dyspnea
Headache
Anxiety
Back pain
Dizziness
59
37
26
22
18
17
16
14
14
12
12
11
11
11
10
10
10
(61)
(39)
(27)
(23)
(19)
(18)
(17)
(15)
(15)
(13)
(13)
(11)
(11)
(11)
(10)
(10)
(10)
2.5 mg/kg QW (n = 8)
8 (100)
2 (25)
0 (0)
1 (13)
2 (25)
1 (13)
2 (25)
1 (13)
0 (0)
1 (13)
3 (18)
1 (13)
2 (25)
1 (13)
0 (0)
0 (0)
1 (13)
6.0 mg/kg Q2W (n = 17)
14
5
6
5
4
0
4
4
3
3
3
0
2
1
4
1
2
(82)
(29)
(35)
(29)
(24)
(0)
(24)
(24)
(18)
(18)
(18)
(0)
(12)
(6)
(24)
(6)
(12)
9.0 mg/kg Q3W (n = 23)
18 (78)
3 (13)
1 (4)
4 (17)
11 (48)
0 (0)
0 (0)
2 (9)
3 (13)
1 (4)
3 (13)
0 (0)
5 (22)
5 (22)
2 (9)
1 (4)
0 (0)
NOTE: Adverse events were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0.
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31-118 days); however, the duration of exposure was longer on
the every 2 weeks and every 3 weeks schedules (8 and 12 weeks,
respectively) than on the weekly schedule (4 weeks). Median
duration of response for the five responders was 32 weeks (95%
CI, 28-32 weeks).
Discussion
Targeted cancer therapies have the potential to be highly
effective with less toxicity than chemotherapy and radiotherapy. Here, we describe the initial clinical experience with panitumumab, the first fully human monoclonal antibody directed
against the EGFR for the treatment of advanced solid malignancies.
In this dose-finding study, panitumumab was generally well
tolerated. Dose escalation to 9.0 mg/kg every 3 weeks was
achieved and no maximum tolerated dose was reached. Premedication before panitumumab administration was not
required, short infusion times were safe, and no investigatordetermined infusion-related reactions were reported. The
incidence of adverse events was comparable with the safety
profiles of other anti-EGFR agents, and the most prevalent
treatment- and dose-related adverse events were dry skin and
rash (21). Similar to studies of other anti-EGFR agents, rash was
associated with response (22 – 24). Further analysis of skin toxicity as a pharmacodynamic response marker is needed in future
studies.
No de novo anti-panitumumab antibodies were detected. This
finding contrasts with a phase 1 study of the chimeric antiEGFR monoclonal antibody cetuximab that reported that 4%
of patients generated human anti-chimeric antibodies (25).
In this study, panitumumab exhibited predictable pharmacokinetics, with low intrapatient and interpatient variability.
The minimal serum panitumumab concentrations (C trough)
were similar among the 2.5 mg/kg weekly, 6.0 mg/kg every
2 weeks, and 9.0 mg/kg every 3 weeks doses, with steady-state
Fig. 2. Observed concentration-time course for 6 mg/kg every 2 wk and 9 mg/kg
every 3 wk compared with the observed and fitted concentration-time course for
2.5 mg/kg weekly.The observed panitumumab concentrations are represented with
(.), (o), and (!) for the 2.5 mg/kg weekly, 6 mg/kg every 2 wk and 9.0 mg/kg
every 3 wk doses, respectively. Points, mean; bars, SE. The model fit for the
2.5 mg/kg weekly dose is represented by the dashed line and predicts the levels
beyond the 4 wk of treatment.
same analytic method as that for the renal cell carcinoma data
(18), we observed mean (95% CI) estimates for the two
variables that describe this relationship of 2.1 mg/kg (1.22.9 mg/kg) for the ED90, which is the panitumumab dose
that yields a 90% incidence of skin toxicity and of 4.1 (1.4-6.8)
for the exponent c, which is the constant that describes the
sigmoidicity or steepness of the curve.
Objective tumor response. Across all dosing schedules, five
patients had a best objective response of partial response (5%).
The five confirmed responders included 1 patient in the
2.5 mg/kg weekly cohort, 2 patients in the 6.0 mg/kg every
2 weeks cohort, and 2 patients in the 9.0 mg/kg every 3 weeks
cohort (Table 4). None received a loading dose of panitumumab. All five responders had colorectal cancer, prior surgery,
and prior chemotherapy (fluorouracil, irinotecan, and oxaliplatin); 1 of these 5 patients had also received prior radiotherapy. These 5 patients had grade 2 or 3 skin toxicity, most
commonly rash. Responders also had slightly greater EGFR
tumor membrane staining (percentage of cells with positive
staining: 94% for the responders and 72% for the nonresponders).
Nineteen (20%) patients had stable disease and included
9 patients in the weekly cohort (excluding the 2.5 mg/kg weekly
cohort), 5 patients in the 6.0 mg/kg every 2 weeks cohort, and
5 patients in the 9.0 mg/kg every 3 weeks cohort. Eight patients
had colorectal cancer, 5 had non – small cell lung cancer, 3 had
prostate cancer, 2 had renal cancer, and 1 had gastroesophageal
cancer.
Duration of treatment and duration of response. The study
was designed for patients to receive four total doses of
panitumumab. For patients who had at least stable disease
and tolerated panitumumab, they could continue treatment
on an extension study. Duration of treatment in the extension
study ranged from 1 to 15.9 months. Median duration of skin
toxicity was longer in the 6 mg/kg every 2 weeks and 9 mg/kg
every 3 weeks dose cohorts (range of medians for all doses,
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Fig. 3. Scatter graph of the incidence of skin rash at different weekly panitumumab
doses (.), with the dashed line representing the predicted percentage of skin rash
using a sigmoidal E max model. This model predicted that 90% of patients would
develop skin toxicity at 2.1mg/kg weekly (95% CI, 1.2-2.9 mg/kg weekly).
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Dose and Schedule of Panitumumab for Advanced Cancers
Table 4. Objective response with panitumumab
Best response
Disease
Partial response
All, n (%)
Colon, n
Stable disease
Progressive disease
Patients with response
All, n (%)
Colon, n
Rectal, n
Prostate, n
Renal, n
Non – small cell lung, n
Gastroesophageal, n
All, n (%)
Colon, n
Rectal, n
Prostate, n
Renal, n
Non – small cell lung, n
Pancreatic, n
Gastroesophageal, n
Anal, n
5/96 (6)
1
2
2
19/96 (20)
7
1
3
2
5
1
70/96 (73)
23
2
18
13
9
3
1
1
Panitumumab dose
2.5 mg/kg QW
6.0 mg/kg Q2W
9.0 mg/kg Q3W
QW dose; 6.0 mg/kg
9.0 mg/kg Q3W
QW dose; 9.0 mg/kg
QW dose; 6.0 mg/kg
QW dose; 6.0 mg/kg
QW dose
Q2W;9.0 mg/kg Q3W;
Q3W
Q2W
Q2W
All doses
6.0 mg/kg Q2W
All doses
QW doses
2.5 mg/kg QW, QW doses
QW doses
QW dose
6.0 mg/kg Q2W
NOTE: Tumor response was determined by investigator assessment using modified WHO criteria. Responses confirmed >4 wk after the initial
assessment of response. ‘‘QW dose’’ represents all other QW doses than 2.5 mg/kg weekly.
reached after f6 weeks for all schedules. Although the maximum tolerated dose was not reached, it is unlikely that increasing the dose beyond these doses would result in increased
panitumumab activity because EGFR seems to be saturated at
these dose levels, and no additional anti-EGFR activity would
be predicted at increased doses.
In our study, five patients experienced partial responses,
and 19 patients showed stable disease. All five responders
had colorectal cancer and received panitumumab 2.5 mg/kg
weekly or at higher doses given less frequently, resulting in
a 13% response rate in patients with colorectal cancer. In
addition, 23% of patients with colorectal cancer had stable
disease. One colorectal cancer patient improved to partial response during the extended maintenance period after achieving stable disease during the study trial period, indicating that
long-term administration of panitumumab is beneficial for
some patients. Additionally, no cumulative toxicities were observed with long-term administration of panitumumab in this
study; skin-related toxicities were not dose-limiting in the five
partial responders who received panitumumab for a mean of
235 days.
At the time of the design and execution of this study, EGFR
tumor membrane expression level was presumed to be
important. The restriction of patient eligibility to patients with
at least 10% of tumor cells expressing EGFR may have excluded
individuals who may have benefited from therapy. Other
studies have shown that EGFR levels detected by immunohistochemistry do not correlate with response to anti-EGFR
treatment (15, 17, 22, 24).
Although some colorectal cancer patients experienced dramatic responses to therapy, most patients did not respond.
Identification of patients likely to benefit from therapy remains
an urgent priority for treatment with EGFR inhibitors. EGFR
gene amplification, EGFR polymorphisms, KRAS mutations,
and gene signatures have recently been reported as possible
predictive markers of response to EGFR inhibitors, but the role
www.aacrjournals.org
of these biomarkers remains unclear (26 – 28). Ongoing studies
examining the role of EGFR ligands and downstream and
parallel signaling pathways may help identify predictive markers
of benefit with panitumumab therapy, alone or with chemotherapy.
From our pharmacokinetic findings, panitumumab may be
flexibly dosed from weekly to every 3 weeks schedule, which
allows for panitumumab administration with common every
2 weeks or every 3 weeks chemotherapy regimens. Panitumumab dosing on the same day of chemotherapy may result
in greater compliance and increased quality of life. While a
study combining panitumumab with bevacizumab and chemotherapy showed increased toxicity and no efficacy benefit
(29), other studies suggested that panitumumab can be safely
administered with irinotecan-containing regimens (FOLFIRI)
in patients with metastatic colorectal cancer, and with other
chemotherapy or targeted agents in patients with solid tumors
(30 – 32). Further evaluations of combination regimens with
panitumumab are ongoing.
In summary, panitumumab monotherapy is well tolerated
at various doses and dosing intervals. Panitumumab administration does not require premedication or a loading dose.
Panitumumab monotherapy has antitumor activity with
durable objective responses in patients with colorectal cancer,
and is under further clinical investigated in numerous tumor
types.
Acknowledgments
We thank the patients and their families who participated in this study; the clinical
study staff at all of the institutions; and the following individuals: Eric Rowinsky,
M.D., for study participation; Sophie Visonneau, Ph.D., for study management;
Michiel Hagendoorn, B.S.; for programming support; Tab Hoda, M.S., for data
management; Bing-Bing Yang, Ph.D., and Peggy Lum, B.S., for pharmacokinetics
analyses; and James Ziobro, B.A., and Mee Rhan Kim, Ph.D., for assistance with
the writing and preparation of the manuscript.
507
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Cancer Therapy: Clinical
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Clin Cancer Res 2008;14:502-508.
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