On March 1,
2006, the U.S. Food and Drug Administration
granted approval to cetuximab (Erbitux, ImClone Systems, Inc.) for use in combination
with radiation therapy (RT) for the treatment
of locally or regionally advanced squamous
cell carcinoma of the head and neck (SCCHN) or
as a single agent for the treatment of
patients with recurrent or metastatic SCCHN
for whom prior platinum-based therapy has
failed. This approval is based on a
statistically significant improvement in
overall survival and duration of locoregional
disease control for RT plus cetuximab when
compared to RT alone. Evidence of cetuximab
safety and efficacy is also supported by
demonstration of durable objective tumor
responses with cetuximab when administered as
a single-agent in second- or third-line
treatment of advanced SCCHN.
The safety and efficacy of cetuximab in
combination with RT were demonstrated in a
phase 3 randomized trial of 424 patients with
Stage III/IV SCC of the oropharynx,
hypopharynx or larynx who had no prior
therapy. Patients were randomized to receive
either cetuximab plus RT (211 patients) or RT
alone (213 patients). Cetuximab was
administered as a 400 mg/m2 initial dose,
followed by 250 mg/m2 weekly for the duration
of RT(6-7 weeks), starting one week before RT.
RT was administered for 6-7 weeks as once
daily, twice daily or concomitant boost.
The median survival time was 49 months on the
cetuximab plus RT versus 29.3 months observed
in patients receiving RT alone [p=0.03,
stratified log-rank test; hazard ratio 0.74,
(95% CI 90.56, 0.97). The median duration of
locoregional control was 24.4 months in
patients receiving cetuximab plus RT versus
14.9 months for those receiving RT alone
[p=0.005, stratified log-rank test; hazard
ratio 0.68, 95 % CI (0.52, 0.89). The observed
effect was primarily confined to patients
enrolled in sites in the US.
Additional data were derived from a single-arm
trial of cetuximab monotherapy in 103 patients
with recurrent or metastatic SCCHN after
failure of platinum-based therapy. Eighty
percent had metastatic disease. Patients
received cetuximab as a 400 mg/m2 loading
dose, followed by 250 mg/m2 weekly. The
objective response rate of cetuximab
monotherapy was 12.6% (95% CI 7%–21%). Median
response duration was 5.8 months (95% CI 2.9;
5.8).
The most common adverse events reported for
both treatment arms were mucositis and
radiation dermatitis. The incidence of serious
mucositis, radiation dermatitis and allergic/anaphylatoid
reaction were > 2% higher in the RT +
cetuximab arm when compared with RT alone. The
following serious adverse reactions, some with
fatal outcome were observed in the cetuximab
plus RT arm: infusion reactions,
cardiopulmonary arrest and/or sudden death and
acneform rash.
The overall incidence of late radiation
toxicity (any grade) was higher in the
cetuximab plus RT arm compared with RT alone.
However, the incidence of Grade 3 or 4 late
radiation toxicities were generally similar
between the two treatment groups.
Death and serious cardiotoxicity were observed
in a single arm trial combining cisplatin with
cetuximab and RT conducted in patients with
locally advanced squamous cell cancer of the
head neck. The cetuximab, RT and cisplatin
combination should be reserved for controlled
clinical trials where toxicity can be clearly
evaluated.
Adverse events associated with cetuximab
monotherapy in patients with SCCHN were
generally consistent with the adverse
reactions previously described for cetuximab.
The following serious adverse reactions, some
with fatal outcomes, have been reported in the
cetuximab safety data base: infusion
reactions, interstitial lung disease, acneform
rash and hypomagnesemia.
Full prescribing information including
clinical trial information, safety, dosing,
drug-drug interaction and contraindications is
available at
Drugs@FDA.
Healthcare professionals should report all
serious adverse events suspected to be
associated with the use of any medicine and
device to FDA’s MedWatch Reporting System by
phone at 1-800-FDA-1088; by facsimile
1-800-FDA-0178 by mail using the Form 3500 at
http://www.fda.gov/medwatch.index.html.
For further information related to oncology
drug approvals, regulatory information, and
other oncology resources, please refer to the
FDA “Oncology Tools” website at
www.fda.gov/cder/cancer.