TITLE: EGFR Therapy in Head and Neck Cancer
SOURCE: Grand Rounds Presentation,
The University of Texas Medi=
cal
Branch, Department of Otolaryngology
DATE: March 31, 2011
RESIDENT PHYSICIAN: Francisco G. Pernas, MD
FACULTY PHYSICIAN: Vicente A. Resto, MD,=
PhD
DISCUSSANT: Vicente A. Resto, MD, PhD
SERIES EDITOR: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Qui=
nn,
MSICS
=
&q=
uot;This
material was prepared by resident physicians in partial fulfillment of
educational requirements established for the Postgraduate Training Program =
of
the UTMB Department of Otolaryngology/Head and Neck Surgery and was not
intended for clinical use in its present form. It was prepared for the purp=
ose
of stimulating group discussion in a conference setting. No warranties,
either express or implied, are made with respect to its accuracy, completen=
ess,
or timeliness. The material does not necessarily reflect the current or past
opinions of members of the UTMB faculty and should not be used for purposes=
of
diagnosis or treatment without consulting appropriate literature sources and
informed professional opinion."
=
=
;
Introducti=
on
=
;
Squamous-cell cancers of the head and neck with adv=
anced primary
lesions, with or without regional lymph-node metastases, are challenging to
treat effectively while maintaining the function of vital healthy structure=
s. Extensive
surgical resection of the primary tumor and regional cervical lymphatics used to be the standard of care in the USA. More
recently, additional organ-preserving strategies using either radiation alo=
ne
or chemoradiotherapy have become a treatment op=
tion
for these patients, and have been the focus of much investigation.
Increased understanding of molecular alterations in=
head
and neck squamous cell carcinoma (HNSCC) and other cancers has ushered in
efforts to develop molecularly targeted therapies. Among these alterations,
overexpression of the epidermal growth factor receptor (EGFR) has been
identified in many cancers, including 80% to 100% of HNSCC, where it has al=
so
been implicated in a more aggressive phenotype, increased resistance to
treatment, and poorer clinical outcome.
Head and neck squamous cell carcinoma is the 5th mo=
st
common cancer worldwide. In US alone 40,000 are newly diagnosed annually. It
represents close to 11,000 Deaths annually, just in the US. Worldwide that figure grows to 200,000=
deaths
annually. The majority of the cases present in advanced stages, likely rela=
ted
to the poorer outcomes. It is estimated that 60% of patients develop local =
disease
recurrence within 2 years. Improvements in surgery and chemoradiation
offer better organ preservation but they have resulted in only modest
improvement in the 5-year survival of HNSCC in the past three decades. 5-ye=
ar
survival rates of patients with locally advanced or metastatic disease are =
48%
and 26%, respectively. We need a better understanding of HNSCC at the cellu=
lar
and molecular levels to guide development and use of new therapeutic
interventions.
Site
|
New Diagnoses
|
Figure 1.
Site of H&N cancers and =
related
deaths annually.
|
|
Deaths
|
|
oral cavity & pharynx
|
30,990
|
7,430
|
|
larynx
|
9,510
|
3,740
|
|
nasal cavity, nasopharynx, paranasal sinuses, cervical esophagus, skin
|
Molecular =
Therapeutics
=
;
The
systematic clinical investigation of organ-preserving radiotherapy and chemoradiotherapy regimens suggested that these regim=
ens
could produce overall survival results as good as surgical resection for
patients with locoregionally advanced squamous-=
cell
cancer of the head and neck (LASCCHN), thus radiation had become a cornerst=
one
of treatment for patients with LASCCHN by the 1990s. The addition of
chemotherapy to radiotherapy has also been extensively investigated. A rece=
nt
meta-analysis of 87 randomised trials that comp=
ared locoregional treatment with or without chemotherapy f=
ound
that the addition of chemotherapy to locoregional
treatment was associated with an absolute survival advantage of 4・=
5%
at 5 years.
There are many therapeutic agents being investigate=
d to
target the EGFR receptor in the head and neck. Of those, only cetuximab (erbitux) has b=
een
approved for unresectable head and neck SCCA. T=
here
are several drugs that are currently in phase III investigation. There are
several tyrosine kinase inhibitors being investigated, such as erlotinib and gefinitib (=
already
approved for lung cancers). Avastin, a VEGF
monoclonal antibody is also being investigated. In addition COX-2 inhibitor=
s, farnesyl inhibitors, and proteasome inhibitors are al=
so
being investigated in H&N.
These observations have led to interest in the
development of molecularly targeted small-molecule inhibitors of EGFR for t=
he
treatment of HNSCC. Gefitinib (Iressa),
an EGFR tyrosine kinase inhibitor, has been tested in clinical trials in so=
lid
tumors, including HNSCC, as a single agent, or in the combination with other
chemotherapies or radiation, but has shown limited clinical efficacy with
response rates of 10% to 15%. Molecular biomarkers that could identify pati=
ents
responsive to gefitinib or other EGFR inhibitors
would be useful in the selection of patients for therapy. The EGFR is a
membrane-bound glycoprotein with an extracellular cysteine-rich ligand-bind=
ing
domain linked by a short single transmembrane
sequence to an intracellular tyrosine kinase and carboxyl-terminal scaffold=
ing
domains.
EGF Recept=
or
The EGF receptor is a 170–180 kD
transmembrane glycoprotein tyrosine kinase rece=
ptor
that is ubiquitous in cells in the upper aerodigestive=
tract. EGFR binds epidermal growth factor (EGF), transforming growth factor
(TGF)-alpha, and other regulating proteins. Activation of EGFR results in a
complex cascade of signaling pathways that influence normal cellular
proliferation and differentiation and lead to strong m=
itogenic
activity. Ligand binding results in:
·
receptor dimerisation
·
activation of the intrinsic kinase domain
·
phosphorylation of tyrosine residues within =
the
cytoplasmic tail.
![3D"Diagram](3D"EGFR--2011_files/image002.jpg")
Proteins dock on phosphorylated residues, leading t=
o the
activation of signaling pathways that promote cell growth, proliferation,
differentiation, and migration. ErbB family lig=
ands
are EGF and transforming growth factor-a (TGF-a). The =
erbB
family consists of four closely related members:
·
erbB1
·
erbB2
·
erbB3
·
erbB4
ErbB1 is also known as EGFR and HER1, it is targete=
d by gefitinib, cetuximab and =
erlotinib. ErbB2 is also known as Her2/neu
and it is targeted by herceptin. Upon binding o=
f the
extracellular ligand EGFR forms homo-dimers and heterodimers with other erbB members, such as erbB2. Herein lays the rational=
e for
targeting Her2/neu receptor in head and neck ca=
ncer.
Other interesting features of the erbB family a=
re that
ErbB2 is unique, as none of the known ErbB fami=
ly
ligands activates ErbB2 homodimers. Instead, Er=
bB2
seems to function primarily as a hetero-dimerization partner for other ErbB family members. ErbB3 differs from the other ErbB receptors - possesses inefficient tyrosine kinase
domain.
Overexpression of EGFR is observed in 42% to 80% of
studied HNSCCs. 90% of trials showed a poorer outcome for patients with EGFR
overexpression in a study that analyzed 756 patients. EGFR seems to be stro=
ngly
correlated with worse prognosis in HNSCC in patients treated with either
chemotherapy or RT.
This finding suggests that overexpression of EGFR m=
ay be
associated with chemotherapy resistance in these patients.
The presence of naturally occurring mutations of th=
e EGFR
gene in tumors may account for the limited clinical response to EGFR-target=
ed
therapies. Various mutations of the EGFR gene have been described. However,=
the
presence of mutant EGFR (EGFRvIII) and/or EGFRwt has not been systematically evaluated in HNSCC=
tumors
before treatment with EGFRtargeted therapy. Rec=
ently,
somatic mutations in the tyrosine kinase domain of the EGFR gene have been
described in non– small cell lung carcinomas that are associated with
increased sensitivity to EGFR-specific TKIs. However, in HNSCC, the inciden=
ce
of these mutations is low and varies according to ethnic origin (1% of
Caucasians versus 7% of Asians with
HNSCC).
A commonly described EGFR mutation is a truncation
mutation, EGFR variant III (EGFRvIII). In gliomas, where it has been most extensively studied, =
EGFRvIII expression correlates with increased tumorigenicity in mouse models and poor prognosis in =
the
clinical setting. Moreover, the expression of EGFRvIII=
is unique to cancer. EGFRvIII has not been obse=
rved
in normal tissue, but it has been detected in other malignancies, such as
non–small cell lung carcinoma, breast cancer, and ovarian carcinoma. =
This
deletion produces a truncated 150-kDa protein that is weakly constitutively
phosphorylated in a ligand-independent manner. Ligand-independent activatio=
n of
EGFRvIII may explain the relative inability of
blocking mAbs to downregul=
ate
this receptor.
Figure 3.
EGFRvIII preferentially
activates cascade by PI3k
|
|
![](3D"EGFR--2011_files/image004.jpg")
|
|
Tyrosine Kinase
Inibitors (TKIs)=
|
Monoclonal
Antibodies (mAb)
|
|
Agents
|
gefitinib (I=
ressa)
erlotinib (T=
arceva)
lapatinib
|
cetuximab (Erbitux)
panitumumab
|
|
Mechanism
|
bind selectively to
intracellular tyrosine kinase
domain of EGFR
|
bind specifically to
extracellular ligand-binding
domain of EGFR
|
|
Administration
|
oral
daily
|
intravenous
every 1-3 weeks
|
|
Adverse Effects
|
rash
diarrhea
nausea
|
rash
hypersensitivity reactions
|
&nb=
sp; =
&nb=
sp;
|
|
Table 1.
Comparison of TKis an=
d mABs
|
|
Updates in mA=
b
Literature
First, Bonner and colleagues conducted a phase III =
study
comparing cetuximab plus radiotherapy with
radiotherapy alone in locoregionally advanced S=
CCHN.
A significant improvement in locoregional contr=
ol
(median: 24.4 versus 14.9 months) and OS (median: 49 versus 29.3 months) was
found in favor of the cetuximab and radiotherap=
y regimen.
Second, cetuximab was investigated as a first-l=
ine
treatment in patients with incurable recurrent and/or metastatic disease in
combination with chemotherapy. Vermorken and
colleagues showed that the addition of cetuximab to
5-fluorouracil (5-FU) and platinum-based therapy prolongs OS and
progression-free survival (PFS) in this setting. Most researchers are foreg=
oing
comparing cetuximab to traditional chemotherapy=
but
rather are working to integrate it into the doublet chemotherapy regimen th=
at
has become standard of care in Head and Neck Cancer treatment. One such stu=
dy
per Grandis and colleagues added cetuximab
to docetaxel and cisplatin=
along with radiation for advanced stage. They identified that HPV expression
resulted in better progression free survival and overall survival. In addit=
ion
they also found EGFR expression was observed in 37 of 39 available biopsies=
and
did not impact response to therapy or clinical outcome. They found the 3-ye=
ar
progression-free survival was 87% and the 3-year overall survival was 91%. =
In
that study a complete response was seen in 70% of patients.
Tishler et. al. publish=
ed the
results of a phase I trial with 19 previously untreated patients with Stage=
III
or IV SCCA. Their treatment algorithm was as follows:
• =
Panitumumab was administered weekly
• =
Paclitaxel
was given weekly i.v. over 60 min after panitumumab
• =
Carboplatin
was given i.v. over 30–45 min following
paclitaxel
• =
Patients
were treated using a dose-painting IMRT approach with a single plan to deli=
ver
35 fractions once daily over 7 weeks
As this was a phase I trial, no definitive conclusi=
ons
can be drawn regarding the utility of Panitumumab in
the treatment of advanced head and neck cancer, but it was fairly well
tolerated (comparable to cetuximab) and they
demonstrated at median follow-up of 21 months, 18 of 19 patients (95%) rema=
ined
disease free.
Other areas of the EGFR spectrum that remain to be
extensively studied is EGFRvIII. As described a=
bove
it is a mutant form of EGFR which is constitutively activated in a ligand
dependent fashion. It does not have a binding site for a ligand. It does
however retain its intra-cellular tyrosine kinase residue which can be
targeted. In a study by Grandis et al. EGFRvIII was identified in 42% of patients with HNSCC=
. They
demonstrated less in-vitro cellular death in cell treated with cetuximab and generally larger tumor volumes and decr=
eased
in response to cetuximab in a mouse model. They=
also
concluded that EGFRvIII transfected cells are a=
lso
less sensitive to cisplatin and cetuximab.
Interestingly these cells remain equally susceptible to EGFR Tki targeting.
Cetuximab has been show=
n to
produce a characteristic acneiform rash. The acneiform rash induced by cetuxi=
mab
was initially thought to be reason to stop therapy. Now it seems we are
findings that the more severe the rash the better response to cetuximab. The rash may be due to EGFR-R521K genotype=
or
other EGFR variation. Specifically EGFR-R521K demonstrates increased cetuximab binding. Patients with EGFR-R521K developed=
more
severe rash. Patients with the G/G genotype of EGFR-R521K who significantly
developed skin rash showed a trend to prolonged progression-free survival o=
n cetuximab/docetaxel treat=
ment.
Updates in=
Tki Literature
EGFR pathway inhibition can be achieved with low
molecular weight tyrosine kinase inhibitors (TKIs) or with MoAbs.
TKIs bind intracellularly to EGFR tyrosine kina=
se and
inhibit phosphorylation and downstream signaling pathways. The two main
compounds are erlotinib and gefitinib.
Besides cetuximab, panitum=
umab
and zalutumumab are two fully humanized anti-EG=
FR MoAbs. Nimotuzumab is a h=
umanized
MoAb with intermediate affinity for EGFR. EGFR
inhibitors have been investigated either with curative intent in combination
with radiation therapy or in incurable SCCHN as palliation.
Very important to understand when thinking about
targeting receptors at the cellular level is the tumor microenvironment. It=
is
how tumor cells interact with each other, how well they oxygenate and how t=
hey
will ultimately receive chemotherapy medications. The response of a tumor to
radiation depends on cell-extracellular matrix interactions and tumor
oxygenation. Manipulating this microenvironment has proven challenging. One
potential method would be to target VEGF. Anti-angioge=
nic
therapy has been used to normalize tumor microenvironment (VEGF) Pharmacolo=
gic
inhibition of EGFR can decrease VEGF expression and therefore angiogenesis.=
The
theory is that Erlotinib, a Tki,
would indirectly lead to vascular normalization and decrease tumor hypoxia
thereby leading to greater effects of chemo and radiotherapy. In a study by=
Maity et. al. they demonstrated that erlotinib
decreased hypoxia and increased blood supply to tumors in a mouse model. In=
addition,
they also identified chemo and radio sensitization properties of EGFR
inhibition by erlotinib.
One of the potentially attractive properties of Tkis is their ability to inhibit nuclear translocatio=
n of
EGFR. Nuclear translocation of EGFR has been shown to correlate with resist=
ance
to both chemotherapy and radiation. Cetuximab h=
as
been shown to paradoxically activate EGFR. Wheeler and colleagues demonstra=
ted
in a very nice investigation that cetuximab and
radiation both induce EGFR translocation to the nucleus. Dasatinib
was able to successfully block radiation and chemotherapy induced EGFR
translocation to nucleus as well as inhibit phosphorylation of EGFR at resi=
due
845.
Future
Work started by Bonner et. al. by adding cetuximab to XRT needs to be supplemented in view of =
doublet
chemotherapy advanced in HNSCC treatment. Further studies combining EGFR
targeted therapies with cisplatin/5FU are neede=
d to
prove it as an effective adjunct to standard therapy. Demonstrating the che=
mo
and radio sensitizing properties of EGFR blockade in patients would also be
beneficial in order to take advantage of sensitizing properties of EGFR
biologics and design new medications for this purpose.
EGFR is highly over expressed in H&N cancer, we=
know
that mutant forms exist, which are constitutively activated, resulting in
decreased activity of extracellular EGFR blocking by c=
etuximab,
but retained activity by Tkis. Early Phase II t=
rial
data suggests addition of cetuximab or erlotinib improves disease free progression and survi=
val. HPV
status may help target therapy as such there is an ongoing RTOG 0920 trial =
that
will look in this. Acneiform rash is a marker of
positive response to both monoclonal antibodies and TK=
i.
Further work is needed to determine which tumors are responders to EGFR
targets. And finally, further work is needed to develop new protocols that
limit toxicities of combining chemo and EGFR biologics.
=
;
Discussant’s Remarks: EGFR Therapy by Vicente A. Resto, MD, PhD =
March 31, 2011
The question was how often are we seeing an EGFR
positivity in our patient population and we have instituted a prospective
protocol to assess EGFR positivity among other markers in our cancer patien=
ts
now for about a year and although the numbers don’t come to mind
immediately they seem not to be very high although there seems to be a
concentration of positivity in patients with oral cavity cancers.
References:
1. &n=
bsp;
Open-label, uncontrolled, multicenter phase =
II
study to evaluate the efficacy and toxicity of cetuxim=
ab
as a single agent in patients with recurrent and/or metastatic squamous cell
carcinoma of the head and neck who failed to respond to platinum-based ther=
apy.
Vermorken JB. J Clin Oncol. 2007 Jun 1;25(16):2=
171-7.
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