VOLUME 23 䡠 NUMBER 24 䡠 AUGUST 20 2005

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Phase II Multicenter Study of the Antiepidermal

From the Vall d’Hebron University
Hospital; Hospital Clinic, Barcelona;
Hospital Universitario 12 de Octubre,
Madrid, Spain; Institut Gustave-Roussy,
Villejuif; Centre Jean Perrin, Clermont-
Ferrand, France; Merck KGaA, Darm-
stadt; and Medizinische Hochschule,
Hannover, Germany.
Submitted July 21, 2004; accepted
February 23, 2005.
Supported by Merck KGaA,
Darmstadt, Germany.
Presented in part at the 38th Annual
Meeting of the American Society of
Clinical Oncology, Orlando, FL,
May 18-21, 2002.
Authors’ disclosures of potential con-
flicts of interest are found at the end of
this article.
Address reprint requests to José
Baselga, Vall d’Hebron University
Hospital, Oncology Service, P Vall
d’Hebron 119-129, Barcelona 08035,
Spain; e-mail: jbaselga@vhebron.net.
© 2005 by American Society of Clinical
Oncology
0732-183X/05/2324-5568/$20.00
Growth Factor Receptor Monoclonal Antibody
Cetuximab in Combination With Platinum-Based
Chemotherapy in Patients With Platinum-Refractory
Metastatic and/or Recurrent Squamous Cell Carcinoma
of the Head and Neck
José Baselga, José M. Trigo, Jean Bourhis, Jacques Tortochaux, Hernán Cortés-Funes, Ricardo Hitt,
Pere Gascón, Nadia Amellal, Andreas Harstrick, and André Eckardt
A B S T R A C T
Purpose
To evaluate the efficacy and safety of the antiepidermal growth factor receptor
monoclonal antibody cetuximab in combination with platinum-based chemotherapy in
patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the
head and neck (SCCHN).
Patients and Methods
Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by
subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the
same dose and schedule at which progressive disease was documented before entry
onto the study.
Results
The response rate, based on an independently read assessment, in the intent-to-treat
population was 10%, with a disease control rate (complete response, partial response [PR],
and stable disease) of 53%. The median time to progression and overall survival were 85 and
183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294
days, respectively). Treatment was well tolerated. The most common cetuximab-related
adverse events were skin reactions, particularly an acne-like rash.
Conclusion
The combination of cetuximab and platinum chemotherapy is an active and well-tolerated
approach to the treatment of this poor-prognosis patient population with platinum-
refractory recurrent or metastatic SCCHN for whom there are no recommended standard
therapeutic options.

DOI: 10.1200/JCO.2005.07.119 J Clin Oncol 23:5568-5577. © 2005 by American Society of Clinical Oncology

nificantly for 30 years.2,3 More than 50% of

INTRODUCTION
Squamous cell carcinoma of the head and
neck (SCCHN) is the sixth most common
cancer in the world, with approximately
600,000 new cases per year.1 Recurrent
and/or metastatic SCCHN patients have a
poor prognosis, which has not changed sig-
newly diagnosed patients with SCCHN are
not cured and will relapse locally or at a
distant site; 10% of newly diagnosed pa-
tients with SCCHN present with distant me-
tastases. Several therapeutic options are
available for recurrent and/or metastatic
SCCHN patients, including reirradiation

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 Cetuximab/Platinum in Platinum-Resistant SCCHN
and salvage surgery and chemotherapy, with best support-
ive care for patients unable or unwilling to undergo treat-
ment. Palliative chemotherapy has demonstrated survival
advantages over best supportive care,4 and the most com-
monly used agents are cisplatin and carboplatin, generally
in combination regimens with infusional fluorouracil (FU)
or a taxane. Only approximately one third of patients will
respond to first-line platinum-based therapy, and the me-
dian overall survival time can be expected to be approxi-
mately 6 to 9 months.4 Patients with advanced SCCHN
have limited alternative therapeutic options once they
progress on platinum-based chemotherapy, and response
rates are generally poor (approximately 3%).5 Thus, there is
clearly an unmet therapeutic need for new active agents for
the treatment of patients with recurrent and/or metastatic
SCCHN, particularly patients who have progressed on first-
line therapy.
Epidermal growth factor receptor (EGFR) has emerged
as a promising target for cancer therapy. EGFR is a tyrosine
kinase receptor of the ErbB family that is highly expressed
and/or abnormally activated in many epithelial tumors,
including SCCHN, colorectal cancer, and non–small-cell
lung cancer.6-8 Studies in SCCHN and nasopharyngeal can-
cer (NPC) showed that the vast majority of patients dem-
onstrated increased levels of EGFR expression.7,9,10 EGFR
expression in tumors is usually associated with more ag-
gressive disease, increased resistance to chemotherapy
and radiotherapy, increased metastasis, poor prognosis,
and decreased survival.11,12 In SCCHN, multivariate
analyses have shown EGFR levels to be an independent
predictor of poor outcome.9,13
Cetuximab is an immunoglobulin G1 monoclonal anti-
body that binds to the extracellular domain of the EGFR
with high affinity and competitively inhibits endogenous
ligand binding.14 It also induces antibody-mediated recep-
tor dimerization resulting in receptor downregulation and
degradation.6,15-17 A series of phase I and II studies of
cetuximab administered alone or in combination either
with chemotherapy or radiation have now been complet-
ed.6 After an initial clinical observation that the addition of
cetuximab to irinotecan and to cisplatin induced re-
sponses in patients with irinotecan-refractory advanc-
ed colorectal carcinoma and with cisplatin refractory
SCCHN, respectively,18 a series of phase II studies were
initiated in colorectal cancer and SCCHN. Cetuximab
has documented clinical efficacy in the treatment of colo-
rectal cancer19,20 and has been approved for use in com-
bination with irinotecan in Europe and the United States
and as monotherapy in the United States for use in the
treatment of EGFR-expressing metastatic colorectal can-
cer that has progressed on irinotecan-containing therapy.
The rationale for targeted therapy with cetuximab in
SCCHN is compelling; as mentioned, SCCHNs express
high levels of EGFR, and cetuximab has shown both in
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Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved.
vitro21 and in vivo activity against SCCHN-derived cells
and tumors.22 Importantly, cetuximab has been shown to
enhance the antitumor activity of cisplatin23 and radiation
therapy22,24 and is known to have no effect on the pharma-
cokinetic profile of cisplatin.25 In the clinical setting, a phase
IB study in patients with SCCHN demonstrated that the
combination of cetuximab and cisplatin was active, even in
a subset of patients who had been previously treated with
cisplatin and had documented cisplatin resistance.26
The aim of the present study was to determine, in a
phase II setting, the response rate to the combination of
cetuximab and platinum chemotherapy in patients with
recurrent and/or metastatic SCCHN who had progressed
on prior treatment with between two and four cycles of the
same platinum regimen. This is a poor-prognosis patient
population for whom there is currently no standard treat-
ment approach.
PATIENTS AND METHODS
Patient Eligibility
Patients were eligible for entry onto the study if they fulfilled the
following criteria: age ⱖ 18 years (19 years in Austria); Karnofsky
performance status (KPS) ⱖ 60%; histologically confirmed diag-
nosis of stage III and IV SCCHN stage (according to American
Joint Committee on Cancer staging system); not candidates for
local therapy; measurable disease; documented progressive disease
(PD) after a minimum of two and a maximum of four cycles of
cisplatin-based (ⱖ 60 mg/m2/cycle) or carboplatin-based (ⱖ 250
mg/m2/cycle) chemotherapy, with baseline disease being docu-
mented in the 30 days before the start of the platinum-based
regimen the patient was taking on study entry; tumor tissue avail-
able for immunohistochemical staining to demonstrate EGFR
expression; and adequate hematologic, renal, and hepatic func-
tion. Exclusion criteria included: history of drug abuse; pregnancy
or lactation; NPC; prior or concomitant surgery or irradiation in
the past 30 days (platinum-containing definitive radiochemo-
therapy was allowed if terminated at least 6 months before the
platinum-based regimen on which progression was documented);
known hypersensitivity to any of the treatment agents; and con-
comitant malignant disease, except adequately treated basal cell
cancer of the skin or cervical carcinoma-in-situ.
This was a multicenter study. The study protocol and any
amendments were approved by independent ethics committees in
each country, and the study was conducted in accordance with the
Declaration of Helsinki (October 1996). All patients provided
written informed consent before entry onto the study.
Treatment
Cetuximab was administered as an intravenous infusion be-
fore cisplatin or carboplatin as an initial 2-hour infusion of 400
mg/m2 (day 1), including a test dose of 20 mg, followed by weekly
1-hour infusions of 250 mg/m2. Patients received pretreatment
with an antihistamine. Patients remained under observation
throughout the infusion and for 1 hour afterwards.
Carboplatin or cisplatin were administered after the 1-hour
observation period after the end of the cetuximab infusion at the
same dose, schedule, and route of administration as in the cycle
5569
 Baselga et al
during which PD was documented before study entry. Treatment
was administered in 3- or 4-week cycles, according to the schedule
the patient progressed on before study entry.
Patients were intended to receive a minimum of two cycles of
therapy. At this point, patients achieving stable disease (SD) or
better continued treatment until PD or the occurrence of unac-
ceptable side effects (see Dose Reductions and Delays). Patients
with PD at any time point in the study discontinued treatment.
Concomitant treatment with topical and/or oral antibiotics
in the case of skin reactions was allowed. In addition, supportive
care to manage the side effects of chemotherapy was permitted (eg,
corticosteroids and antiemetics).
Dose Reductions and Delays
Cetuximab was interrupted for up to 2 weeks in case of grade
3 skin reactions. If a grade 3 skin reaction occurred for the second
or third time in the same patient, cetuximab doses were reduced to
200 and 150 mg/m2, respectively. Recurrence of a grade 3 skin
reaction despite two dose reductions warranted discontinuation
of cetuximab.
In the case of unacceptable platinum-associated toxicity
(ⱖ grade 2 ototoxicity, nephrotoxicity, or peripheral neurotox-
icity; or ⱖ grade 3 nausea/vomiting despite treatment with a
5-hydroxytryptamine-3 antagonist and dexamethasone), patients
benefiting from therapy (SD or better) could continue to receive a
reduced dose or single-agent cetuximab, whereas patients not
responding to therapy discontinued all study treatment.
End Points
The primary end point of this study was the response rate,
which was defined as the number of patients whose best response
(recorded between the start of treatment and the occurrence of
PD) was confirmed complete response (CR) or partial response
(PR) relative to the number of patients in the study population.
Responses were assessed by a blinded independent review com-
mittee (IRC) comprising three radiologists and one oncologist
who were responsible for assessing prestudy scans to determine
the date of PD on the previous platinum-containing regimen
and to determine the best response, date of response, and
confirmation of response, date of progression, and date of last
tumor assessment.
Baseline evaluation of lesions was determined according to
modified WHO criteria on the basis of computed tomography
(CT) or magnetic resonance imaging (MRI) scans. A maximum of
10 index lesions (lesions, which were measurable in two dimen-
sions, reflecting the extent of the disease and able to be followed up
on serial imaging) were selected at baseline for evaluation. Nonin-
dex lesions, which did not meet the measurable requirement for
index lesions, were also assessed. Tumors were assessed by the
same modality (CT or MRI) used for baseline evaluation. Tumor
responses, based on assessments for index lesions and nonindex
lesions, were defined as follows: CR, disappearance of all index
lesions; PR, a ⱖ 50% reduction in the size of index lesions
compared with baseline with no evidence of PD; no change
(SD), no significant change in nonindex lesions to qualify for
either CR or PD; and PD, ⱖ 25% increase in the size of index
lesions compared with the smallest size recorded for the study
period or the appearance of one or more new lesions and/or
progression of existing nonindex lesions. Response rate was
based on confirmed CR or PR (ie, responses persisting for at
least 4 weeks). Disease control was defined as CR plus PR plus
SD as best response. Patients were considered nonassessable if
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they had no baseline or follow-up scans or no index lesions
present at baseline (protocol deviation) and no evidence of PD
at the first follow-up.
Secondary end points were time to response, duration of
response, time to progression (TTP; defined as the number of days
from the first dose of cetuximab to the earliest day of progression,
as determined by the IRC), overall survival (OS; calculated as the
number of days from the first dose of cetuximab until death,
regardless of the cause), symptomatic changes, changes in KPS,
and quality of life.
Pretreatment Assessments and Response and
Toxicity Evaluations
All patients underwent pretreatment screening 2 weeks be-
fore the start of the study, including full medical history, physical
examination, determination of KPS, chest x-ray, echocardiogram,
laboratory values, baseline human antichimeric antibody levels,
disease staging history, EGFR status, chemotherapy history, CT or
MRI scans of target lesions (ⱕ 4 weeks before the start of the
study), and quality of life (using the European Organisation for
Research and Treatment of Cancer Quality of Life Questionnaire–
Head and Neck 35). The median duration of disease was defined as
the difference between the date of the first cetuximab infusion and
the date of diagnosis (defined as the earliest date of histologic
confirmation, surgery, or other cancer therapy).
EGFR expression was evaluated qualitatively using a stan-
dardized immunohistochemistry assay (DakoCytomation, Glostrup,
Denmark) designed to assess cell membrane staining. Control
slides provided with the kit comprised formalin-fixed, paraffin-
embedded human cell lines with staining intensity scores of 2⫹
and 0. Assays were performed centrally by an independent
pathologist on biopsy tissue fixed in 4% formalin. The percent-
age of stained cells and the staining intensity (0, no expression;
1⫹, faint; 2⫹, weak; 3⫹, strong) were evaluated by the same
independent pathologist.
Tumor response was assessed on day 15 or 22 of every other
3- or 4-week cycle, respectively, starting in cycle 2. Quality of life
and KPS were evaluated every cycle on day 15 or 22.
Adverse events were recorded according to National Cancer
Institute Common Toxicity Criteria (version 2). For this study, a
special adverse events category was defined comprising pooled
Coding Symbols for Thesaurus of Adverse Reaction Terms pre-
ferred terms for areas of clinical relevance. Adverse events were
recorded at each weekly visit before treatment administration.
Investigations for human antichimeric antibodies were made on
blood samples stored on day 15 or 22 of 3- and 4-week cycles,
respectively. Follow-up assessments were made 4 weeks after the
last dose of study medication.
Statistical Analyses
Efficacy analyses were conducted on both the intent-to-treat
(ITT) population (defined as all patients enrolled onto the study
who received at least one dose of cetuximab, including the test
dose) and the IRC-PD population (defined as patients in the ITT
population who had documented PD before study entry after two
to four cycles of platinum-based chemotherapy, as determined by
the IRC). Safety analyses were conducted on the ITT population.
Statistical analyses were carried out using SAS software, version 8.2
(SAS Institute, Cary, NC). Continuous variables were summarized
using descriptive statistics. Qualitative variables were summarized
using counts and percentages. Two-sided CIs were calculated for
response rates and disease control rates.
JOURNAL OF CLINICAL ONCOLOGY
 Cetuximab/Platinum in Platinum-Resistant SCCHN

RESULTS Table 1. Patient Characteristics at Entry Onto the Study

ITT IRC-PD
Between February 2000 and May 2001, 98 patients with Population Population
SCCHN were enrolled onto the study from 32 centers in Characteristic No. % No. %
seven European countries (Austria, Belgium, France, Ger-
Sex
many, Spain, Switzerland, and Poland). Two patients did Male 85 89 54 84
not meet the entrance criteria (one patient had suspected Female 11 11 10 16
drug abuse and one patient died during screening), leaving Age, years
96 patients in the ITT population. There were 64 patients in Median 56 56
Range 40-81 40-78
the IRC-PD population. The difference in the ITT and
KPS, %
IRC-PD populations reflects the fact that some patients Median 80 80
entering the study whose disease was designated as PD at Range 60-100 60-100
entry by the investigator were considered by the IRC not to Disease duration, months
have PD. Additionally, in some cases, the poor quality or Median 16.7 16.3
Range 2-191 2-101
absence of scans precluded a definite confirmation of PD by
EGFR expressionⴱ — 98 — 96
the IRC. At the cutoff date for the analysis (May 31, 2003), Primary tumor at screening
five patients were still undergoing treatment. Pharynx 46 48 25 39
The ITT population comprised 85 males and 11 fe- Larynx 23 24 15 23
males (median age, 56 years; Table 1). The median KPS was Other 24 25 21 33
Information missing 3 3 3 5
80%, the median duration of disease was 16.7 months, and
TNM staging
the median TTP on the most recent platinum regimen was M0 57 59 38 59
15 days. The most common site of the primary tumor was M1 39 41 26 41
the pharynx (48%), and 41% of patients had metastatic Duration of previous platinum-based
chemotherapy, days
disease. EGFR expression at baseline was determined in 86
Median 63 58.5
of 96 patients in the ITT population (56 of 64 patients in the Range 22-132 22-132
IRC-PD population). The collection of data for the remain- Other prior SCCHN therapy
ing patients was not available for a variety of reasons; these Chemotherapy 42 44 30 47
patients were considered to have minor protocol deviations Radiotherapy 76 79 50 78
Surgery 75 78 50 78
and, as such, were not excluded from the ITT analysis.
EGFR-expressing cells were found in 98% and 96% of ITT Abbreviations: ITT, intent-to-treat; IRC-PD, progressive disease as
determined by independent review committee; KPS, Karnofsky per-
and IRC-PD patients tested, respectively. Overall, 63% of formance status; EGFR, epidermal growth factor receptor; SCCHN,
the 86 ITT patients with EGFR data had strong EGFR stain- squamous cell carcinoma of the head and neck.
ⴱ
Determined in 86 and 56 patients in the ITT and IRC-PD populations,
ing (3⫹), 19% had weak staining (2⫹), 16% had faint respectively (information missing for the other 10 ITT and eight
staining (1⫹), and two patients (2%) had no staining. Sixty- IRC-PD patients).

six patients (77%) showed EGFR staining in between 75%

and 100% of the cells analyzed.
All patients had received cisplatin or carboplatin alone
(n ⫽ 5, 5%) or in combination with other agents; the most
common combinations were cisplatin/FU (n ⫽ 38, 40%)
and carboplatin/FU (n ⫽ 10, 10%). Seven (7%) of patients
had received cisplatin/docetaxel, three patients (3%) had
received carboplatin/docetaxel, and five patients (5%)
had received carboplatin/paclitaxel. Fifty-five patients re-
ceived platinum therapy according to a 3-week cycle, and 41
received platinum therapy according to a 4-week platinum
cycle. Just over half the patients (53%) had received two
cycles of therapy; the remaining patients had received either
three or four cycles. The median time between the end of the
prior platinum-based chemotherapy cycle and the first dose
of cetuximab was 15 days (range, 0 to 50 days).
Exposure to Cetuximab and Cisplatin Therapy
The median number of cetuximab infusions adminis-
tered by the cutoff date was 11 (range, one to 93 infusions),
and for the majority of patients (78%), the relative dose-
intensity of cetuximab was ⱖ 90%. Sixteen patients (17%)
received cetuximab single-agent therapy after discontinua-
tion of platinum therapy. The median number of platinum
cycles received was three.
Response and Disease Control Rates
The response rates were similar for the ITT and
IRC-PD populations and are listed in Table 2. Response
was not assessable in 18 patients (19%) and 10 patients
(16%) in the ITT and IRC-PD groups, respectively, be-
cause the scans were either of a poor quality or were
missing. The overall response and disease control rates were
10% and 53%, respectively, in the ITT population and 11%
and 52%, respectively, in the IRC-PD population (Table 2).
No CRs were recorded for either population. The median
time to response and duration of response were 40.5 days
(range, 29 to 79 days) and 153.5 days, respectively, in the

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 Baselga et al

although these data were not subject to formal statisti-

Table 2. Best Response and Disease Control Rates
cal analysis, and therefore, there were no significant
ITT IRC-PD
Population Population
differences observed.
(n ⫽ 96) (n ⫽ 64)
Response No. % No. % TTP and OS
The median TTP and median OS were 85 and 183 days,
Complete response 0 0 0 0
Partial response 10 10 7 11 respectively, in the ITT population and 72 and 150 days,
Stable disease 41 43 26 41 respectively, in the IRC-PD population (Figs 1 and 2). In
Progressive disease 27 28 21 33 general, characteristics favoring a prolonged TTP and OS
Not assessable 14 15 8 13
were a higher baseline KPS and no metastases (Table 3). In
Missing 4 4 2 3
Overall response rate (95% CI)
both populations, there was a trend for TTP and OS to be
% 10 11 longest in those patients achieving a PR (median, 203.5 and
95% CI 5 to 18 5 to 21 294 days, respectively, for the ITT population and 185 and
Disease control rate (95% CI) 272 days, respectively, for the IRC-PD population). In ad-
% 53 52
dition, the median TTP and median OS were longer in
95% CI 43 to 63 39 to 64
patients receiving the 3-week platinum cycle compared
Abbreviations: ITT, intent-to-treat; IRC-PD, progressive disease as de-
termined by independent review committee.
with patients receiving the 4-week cycle. The median TTP
for the 3- and 4-week cycles were 88 days (95% CI, 72 to 154
days) and 65 days (95% CI, 55 to 115 days), respectively.
The median OS times for the 3- and 4-week cycles were 191
ITT population and 36 days (range, 29 to 56 days) and 100 days (95% CI, 158 to 247 days) and 179 days (95% CI, 132 to
days, respectively, in the IRC-PD population. 212 days), respectively. However, because none of these
Response is also presented separately for patients data were subject to statistical analysis, significant differ-
receiving 3- and 4-week platinum cycles. The response ences were not reported.
rate and disease control rate were higher for patients
receiving the 3-week platinum cycle (13% and 64%, re- Quality of Life and KPS Trends
spectively) compared with patients receiving the 4-week Because of the small number of questionnaires com-
cycle (7% and 39%, respectively). Subgroup analysis re- pleted, it was not possible to assess the impact of treatment
vealed that there was a trend for older age, a higher on quality of life. However, KPS modifications seemed to
baseline KPS, and the absence of metastases to favor a correlate with response rate, TTP, and OS. These data are
higher response and/or disease control rate (Table 3), not presented here.

Table 3. Response Rate, Disease Control Rate, TTP, and OS According to Demographic, Disease, and Therapy-Related Characteristics
in the ITT Population
No. of Response Rate Disease Control Rate Median TTP Median OS
Subgroup Patients (%) (%) (days) (days)

All patients 96 10 53 85 183

Age
⬍ 65 years 78 9 50 83 185
ⱖ 65 years 18 17 67 88 181
Karnofsky performance status
⬍ 80% 30 7 53 72 131.5
ⱖ 80% 63 13 54 106 216
Metastasis stage
M0 57 12 63 108 193
M1 39 8 39 57 160
Best response to most recent platinum-based chemotherapy
Partial response 4 0 100 125 229.5
Stable disease 12 17 33 106 184
Progressive disease 80 10 54 76 179
Type of chemotherapy in present study
Cisplatin 58 12 53 85 184
Carboplatin 34 9 56 76 185

NOTE. The influence of skin reactions is shown in Table 4.

Abbreviations: TTP, time to progression; OS, overall survival; ITT, intent-to-treat.

5572 JOURNAL OF CLINICAL ONCOLOGY

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 Cetuximab/Platinum in Platinum-Resistant SCCHN
Fig 1. Kaplan-Meier plot of time to progression in the intent-to-treat (ITT) and
independent review committee progressive disease (IRC-PD) populations.
Efficacy End Points and Early Skin Reactions
The data suggest that there was a trend for patients
developing grade 1 or 2 skin reactions in response to treat-
ment (n ⫽ 58 of 96, 60%) to achieve slightly prolonged TTP
and OS (Table 4) compared with patients without skin
reactions (n ⫽ 37 of 96, 39%), although there was little
difference in the response and disease control rates between
these two groups. These data were not subject to statistical
analysis, and thus, significant differences were not ob-
served. There was only one incidence of a higher grade
early skin reaction (grade ⱖ 3), and thus, efficacy com-
parisons with this group were not considered valid. No
differences in the baseline characteristics between pa-
tients developing skin reactions and those not develop-
ing skin reactions were observed.
Adverse Events
All 96 patients who were treated experienced at least
one adverse event. Apart from anemia and asthenia, the
frequency of grade 3 and 4 events was less than 15%. The
Fig 2. Kaplan-Meier plot of overall survival in the intent-to-treat (ITT) and
independent review committee progressive disease (IRC-PD) populations.
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frequencies of adverse events (according to the special ad-
verse event category) are listed in Table 5. The most fre-
quent adverse events were skin reactions and acne-like rash.
All but three patients with skin reactions and acne-like rash
were classified as having grade 1 or 2 reactions. Most cases of
acne-like rash occurred within the first 21 days of treatment.
The median time to resolution of skin reactions and acne-
like rash after treatment discontinuation was 29 days
(range, 7 to 401 days) and 29 days (range, 7 to 84 days),
respectively. The patient for whom resolution occurred 401
days after treatment discontinuation had a nonmalignant
lesion on the nose, which was considered probably related
to cetuximab. Three patients had hypersensitivity reactions,
two of whom had received prophylactic corticosteroids and
one of whom had not. There were no grade 3 or 4 hypersen-
sitivity reactions. Serious adverse events were reported in
55% of patients and were considered to be related to cetux-
imab in 15 patients (16%).
Sixteen patients (17%) discontinued platinum-based
chemotherapy mainly because of side effects; all of these
patients continued receiving cetuximab monotherapy.
Cetuximab-related adverse events led to the discontinua-
tion of cetuximab in eight patients (8%), seven of whom
were receiving cetuximab and platinum combination ther-
apy (one patient each had life-threatening anemia, cardio-
vascular problems [atrial fibrillation], allergic reaction,
anaphylactoid reaction, stomatitis, mucositis, and inflam-
mation of a toe/nail disorder) and one of whom was receiv-
ing cetuximab monotherapy (asthenia). Cetuximab-related
adverse events led to the discontinuation of cetuximab and
platinum chemotherapy in three patients (3%). There were
no cetuximab-related deaths in the study.
DISCUSSION
This study demonstrates that the combination of cetuximab
and platinum chemotherapy has good activity in this pop-
ulation of platinum-refractory SCCHN patients. The pri-
mary end point of response rate, as assessed by IRC, was
10%, and responses lasted for a median of more than 5
months. Among responders, the median TTP was nearly 7
months, and OS was nearly 10 months, which are both
highly encouraging findings for a second-line therapy in
these poor prognosis patients. The results are particularly
promising in view of the fact that nearly half of the patients
had received prior treatment with more than two cycles of
platinum-based therapy.
It should be noted that there was quite a marked differ-
ence in the number of patients in the ITT population and
the IRC-PD population. This is mainly a reflection of
the stringent criteria used by the IRC in assessing PD. De-
spite this, it is notable that the response rates between the
two populations were almost identical (10% ITT and 11%
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 Baselga et al

Table 4. Response Rate, TTP, and OS According to the Occurrence of Early Skin Reactions Within the First 3 Weeks of Treatment in the ITT Population
Response Rate (%) Disease Control Rate (%) Median TTP (days)ⴱ Median OS (days)ⴱ
Skin Reaction No. of Patients (n ⫽ 96) (n ⫽ 96) (n ⫽ 87) (n ⫽ 94)

Skin reaction
None 58 8 51 55 111
Grades 1 and 2 37 12 55 82 188
Acne-like rash
None 43 9 51 64 127
Grades 1 and 2 52 12 56 86 179

Abbreviations: TTP, time to progression; OS, overall survival; ITT, intent-to-treat.

ⴱ
Time from 3 weeks after the first dose of cetuximab to progression or death. The numbers of patients with grade 3 or greater rash were too small to allow
comparisons (see text for details).

IRC-PD). These results suggest that it is probable that many analog-based chemotherapy.28 Recently, we have observed
of the patients classified by the IRC as nonassessable did that single-agent cetuximab can produce major objective
actually have PD. The trend towards a higher response rate responses in patients with platinum-refractory recurrent or
and median TTP observed with the 3-week compared with metastatic SCCHN with acceptable toxicity.29 Phase II
the 4-week cycle of platinum is of unclear significance be- studies with gefitinib and erlotinib have also demonstrated
cause the sample size is too small to draw a conclusion. the activity of EGFR blockade in refractory recurrent or
The results from our study are similar to those reported metastatic SCCHN.30,31
from another phase II study reported by Kies et al.27 In their Cetuximab was well tolerated in this study, with the
study, patients with recurrent SCCHN who had progressed most common associated adverse events being skin reac-
on two cycles of platinum-based chemotherapy received tions, particularly an acne-like rash. Skin reactions are not
cetuximab combined with platinum at the same dose and unique to cetuximab and are now an accepted and charac-
schedule previously administered.27 There was an overall teristic side effect of treatment with EGFR-directed mono-
response rate of 12%, with a median TTP among respond- clonal antibodies and tyrosine kinase inhibitors.31-34 In our
ers of more than 5 months.27 The combination of cetux- study, most skin reactions were of grade 1 or 2 severity. The
imab and carboplatin has also shown activity in NPC
acne-like rash decreases in severity over time during treat-
patients who experienced treatment failure on platinum
ment and resolves completely after treatment cessation.35
In the present study, the median time to resolution of the
rash was 29 days.
Table 5. Frequencies of Special Adverse Event Categories by As expected, patient outcome after treatment was in-
NCI-CTC Toxicity Grade in the ITT Population (n ⫽ 96)
fluenced by a number of factors, including good perfor-
Grade 3
Any Grade and 4 Grade 4 mance status and the absence of metastases. We also noted
No. of No. of No. of a relationship between the outcome to treatment and the
Category Patients % Patients % Patients % development of the skin reactions. Patients developing skin
Any category 95 99 41 43 14 15 reactions seemed to have a prolonged TTP and OS com-
Skin reactions 77 80 3 3 1 1 pared with patients not developing such reactions. A rela-
Acne-like rash 69 72 3 3 1 1
Asthenia 62 65 18 19 2 2
tionship between rash and response with cetuximab has
Nausea/vomiting 55 57 6 6 0 0 previously been reported for metastatic colorectal cancer,
Respiratory disorder 31 32 12 13 7 7 pancreatic cancer, and recurrent or metastatic SCCHN in
Fever 38 40 3 3 0 0 the phase II study reported by Kies et al27 and a randomized
Bleeding 23 24 8 8 4 4
study in the first-line setting.36,37 In addition, Saltz et al37
Mucositis 17 18 2 2 0 0
Diarrhea 15 16 0 0 0 0 reported that the more intense the rash, the longer the
Hypersensitivity reactions 3 3 0 0 0 0 survival seems to be. However, the small number of
Heart failure 2 2 0 0 0 0 patients developing grade 3 to 4 rash in our study pre-
Thromboembolism 2 2 2 2 1 1
cluded any conclusion regarding the impact of rash se-
NOTE: NCI-CTC toxicity grade: 1 ⫽ mild; 2 ⫽ moderate; 3 ⫽ severe; verity on outcome. A link between rash and response has
4 ⫽ life threatening. If a patient experienced more than one adverse
event within a special adverse event category, the patient was counted also been observed with the EGFR tyrosine kinase in-
once according to the highest toxicity grade in that category. hibitors erlotinib30,34 and gefitinib.31 The relationship
Abbreviations: NCI-CTC, National Cancer Institute Common Toxicity
Criteria; ITT, intent-to-treat. between rash and patient outcome after cetuximab con-
tinues to be investigated.

5574 JOURNAL OF CLINICAL ONCOLOGY

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 Cetuximab/Platinum in Platinum-Resistant SCCHN
An important aspect of targeting EGFR in SCCHN is
whether there is a correlation between EGFR levels and
response to cetuximab. In our study, although EGFR posi-
tivity was not an inclusion criterion, we were able to study
EGFR expression in the majority of patients (86 of 96 pa-
tients) using the same determination criteria as in the cetux-
imab pivotal cancer colon study.19 However, there is no
standardized method to determine EGFR expression in tu-
mors. More importantly, the level of EGFR expression re-
quired in the tumor to obtain clinical benefit with
cetuximab is not known at the present time.6 In our
study, the majority of patients showed 2⫹ or 3⫹ EGFR
staining intensity (70 patients), and a total of 60 patients
showed EGFR expression in between 75% and 100% of
the cells tested. However, our study was not large enough
to study the relationship between EGFR expression and
response to cetuximab.
One of the most interesting aspects of cetuximab is that
it seems to circumvent tumor resistance to chemotherapy,
such that the tumor again responds to therapy on which it
had previously progressed. This was noted in nonclinical
studies with cetuximab plus irinotecan in irinotecan-
refractory colorectal xenografts38 and was confirmed in the
clinical setting.19 In our study, the clinical activity could
have also been caused by reversal of platinum resistance. In
a subsequent study with single-agent cetuximab in patients
with platinum-refractory SCCHN, clinical activity has also
been observed.29 Therefore, the question of whether cetux-
imab, in addition to its own antitumor activity, has the
capacity to reverse platinum resistance in SCCHN would
require a two-arm randomized study of cetuximab alone
versus cetuximab plus platinum in this study population.
The data available to date show that cetuximab is likely
to play an important role in the treatment of SCCHN. The
results from our studies and from that of Kies et al27 dem-
onstrate the activity of cetuximab alone and in combination
with platinum in the setting of cisplatin- or carboplatin-
refractory recurrent or metastatic SCCHN.29 A phase III
study by Burtness et al36 demonstrated that the combina-
tion of cisplatin and cetuximab was active in the first-line
treatment of recurrent or metastatic SCCHN.36 The effi-
cacy analysis showed a statistically significant higher re-
sponse rate for cisplatin plus cetuximab compared with
cisplatin plus placebo (26% v 10%, respectively; P ⫽ .048).
In the cisplatin plus cetuximab and the cisplatin plus pla-
cebo arms, there was no significant difference in median
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progression-free survival (4.2 and 3.4 months, respectively)
and overall survival (9.3 and 8.0 months, respectively). It is
possible that the lack of a difference in survival between the
treatment arms may be, at least in part, a result of under-
powering of the trial. In addition, the activity of cetuximab
in combination with radiation for locoregionally advanced
SCCHN was suggested by an early phase I study39 and
recently confirmed by a phase III study.40
The effective integration of cetuximab in the clinical
setting will depend greatly on the selection of patients who
will most likely respond to treatment. Some markers, for
example skin reactions and downstream signaling trans-
duction markers like mitogen-activated protein kinase,
may be useful once cetuximab therapy is initiated. How-
ever, the identification of pretreatment predictive markers
is a priority. A major advance has recently been made in this
area with the identification of mutations in the adenosine
triphosphate– binding cleft of the EGFR that predicts for
increased receptor signaling and sensitivity to gefitinib in
patients with non–small-cell lung cancer.41,42 It will be im-
portant to observe whether a similar relationship exists for
cetuximab. In summary, this study shows that the combi-
nation of cisplatin or carboplatin and cetuximab in recur-
rent and/or metastatic SCCHN patients refractory to
platinum-based chemotherapy has good clinical efficacy
and an acceptable safety profile in this population of poor-
prognosis patients for whom there are no recommended
standard therapeutic options.
■ ■ ■
Appendix
The following investigators were involved in this study:
Austria: J. Meindl (Linz), K. Boheim (St Pölten), G. Kornek
(Vienna); Belgium: S. van Belle (Gent), A. van Oosterom
(Leuven), J. Vermorken (Edegem); Germany: A. Eckardt
(Hannover), W. Eberhardt (Essen), T. Beinert (Berlin), R.
Knecht (Frankfurt), B. Will (Kassel), B. Wollenberg (Mu-
nich), P. Volling (Oldenburg); Poland: J. Jassem (Gdansk),
P. Koralweski (Krakow); France: J. Bourhis (Villejuif), M.
Debled (Rouen), F. Rolland (Nantes), X. Pivot (Nice), P.
Pommier (Lyon), J. Tortochaux (Clermont-Ferrand), L.
Cals (Toulon), D. Cupisol (Montpellier); Spain: J.M. Trigo
(Barcelona), R. Hitt and H. Cortés-Funes (Madrid), V.
Guillem Porta (Vallencia), E. Diaz-Rubio (Madrid), A.
Lopez Pousa and P. Gascon (Barcelona); and Switzerland:
F. Heitzmann (Aarau), M. Pless (Basel).
5575

Authors’ Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family
members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being
evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts
of Interest section in Information for Contributors.
Authors Employment Leadership
José Baselga
Pere Gascón
Nadia Amellal Merck KGaA
Andreas Harstrick Merck KGaA
André Eckardt
Dollar Amount Codes
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