Download Epidermal Growth Factor Receptor Inhibitors

Special Report
Epidermal Growth Factor Receptor Inhibitors: Coming of Age
Amit Mahipal, MD, Nishi Kothari, MD, and Shilpa Gupta, MD
Background: Agents targeting the epidermal growth factor (EGFR)-mediated signaling pathway are used in the
treatment of various solid tumors, including lung, breast, pancreatic, colorectal, and head and neck cancers.
Methods: Clinical evidence supporting the benefits of targeted agents directed against EGFR/HER1 in various
solid tumors is discussed, as well as the survival end points used in the pivotal clinical trials, current
applications, and future research directions. Agents reviewed include the monoclonal antibodies cetuximab
and panitumumab, both of which block ligand binding to the extracellular domain, and the small-molecule
tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib that exert their effects at the intracellular portion
of the receptor to prevent tyrosine kinase phosphorylation and the activation of signal transduction pathways.
Results: EGFR inhibitors have a mechanism of action distinct from traditional cytotoxic therapies, and
combining these agents with chemotherapy produces synergistic anticancer activity without overlapping toxicity
profiles. The level of EGFR expression does not correlate with agent response, and many tumors are resistant
to treatment. Even if tumors are initially sensitive to these agents, they inevitably acquire resistance through
complex, poorly understood molecular mechanisms.
Conclusions: EGFR-directed therapies have changed the treatment paradigms in metastatic lung, colorectal,
and head and neck cancers and improved outcomes. A better understanding of mechanisms of resistance to
these agents is crucial for effective drug development. Predictive biomarkers are being developed to deliver
personalized therapies.
Introduction
The epidermal growth factor receptor (EGFR) family
is a group of receptor tyrosine kinases that mediates
cell proliferation, survival, migration, and differentiation.1 The EGFR family consists of 4 members: ERBB1/
EGFR, ERBB2 (formerly HER2/neu), ERBB3 (formerly
HER3), and ERBB4. The structure of these receptor tyrosine kinases spans from outside of the cell through
the plasma membrane and into the cytoplasm where
enzymatic activity can be mediated through linear
as well as horizontal interactions. These proteins are
inactive as single subunits and must be activated by
ligands to form homodimers or heterodimers to translate extracellular signals into intracellular activity.
In multiple tumor types, including head and
neck, lung, breast, and colorectal cancers, this family
of receptor tyrosine kinases has been found to be
deregulated, thus leading to an overexpression and
amplification of EGFR and ensuing inappropriate cellular stimulation.2 Receptor overexpression has been
correlated with a more aggressive clinical course in
multiple tumor types.3 Given the nature of this pathway in tumor development and proliferation, efforts
have been directed at anti-EGFR therapies. The most
developed anti-EGFR therapies include monoclonal antibodies, which target the extracellular domain of the
tyrosine kinase receptor, and tyrosine kinase inhibitors
(TKIs), which are small molecules that intracellularly
bind to interfere with downstream signaling. This article primarily reviews the role of approved anti-EGFR
therapy in several tumor types (Table). Anti-ERBB2
and experimental anti-ERBB3 agents are not addressed
because they are beyond the scope of this review.
Lung Cancer
From the Clinical Research Unit (AM, NK) and Department of
Genitourinary Oncology (SG) at the H. Lee Moffitt Cancer Center
& Research Institute, Tampa, Florida.
Submitted September 9, 2013; accepted September 16, 2013.
Address correspondence to Amit Mahipal, MD, Moffitt Cancer Center, 12902 Magnolia Drive, Clinical Research Unit, MCC#3177,
Tampa, FL 33647. E-mail: [email protected]
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
The authors have disclosed that this article discusses unlabeled/
unapproved use of the drug cetuximab for the treatment of non–
small-cell lung cancer.
74 Cancer Control
Cetuximab, an anti-EGFR immunoglobulin (Ig) G1 chimeric monoclonal antibody, was assessed in combination with chemotherapy in patients with EGFR-expressing non–small-cell lung cancer (NSCLC).4 Compared
with patients assigned to chemotherapy alone, those in
the cetuximab group had longer median survival rates
(11.3 months vs 10.1 months; P = .044) but a higher
incidence of adverse events, including febrile neutropenia, acne-like rash, diarrhea, and infusion-related
reactions. Higher EGFR expression was associated
with improved survival rates in the cetuximab group.5
January 2014, Vol. 21, No. 1
Table. — EGFR Inhibitors Approved for Use
Drug
Route of Administration
Molecular Properties
Approved Indications
Cetuximab
Intravenous
Chimeric human-mouse IgG1 monoclonal antibody
Metastatic colorectal cancer
Metastatic head and neck cancer
Panitumumab
Intravenous
Fully human IgG2 monoclonal antibody
Metastatic colorectal cancer
Gefitiniba
Oral
Reversible EGFR TKI
Metastatic NSCLC
Erlotinib
Oral
Reversible EGFR TKI
Metastatic NSCLC (EGFR mutation)
Afatinib
Oral
Irreversible EGFR TKI (+ anti-ERBB2 activity)
Metastatic NSCLC (EGFR mutation)
a
Approved for use only in Europe and Asia.
EGFR = epidermal growth factor receptor; IgG = immunoglobulin G; NSCLC = non–small-cell lung cancer; TKI = tyrosine kinase inhibitor.
Due to this relatively small benefit with significantly
increased toxicities, cetuximab has not been approved
in the United States or Europe for NSCLC.
Gefitinib was the first drug developed as an inhibitor of the EGFR tyrosine kinase domain. Gefitinib
reversibly competes with adenosine triphosphate for
binding to the intracellular domain of EGFR tyrosine kinase and prevents EGFR phosphorylation and
downstream signaling. It was initially evaluated in a
phase II trial that cited evidence of the drug’s activity
in Japanese patients with advanced NSCLC who had
been previously treated.6 Subsequent trials in Europe
and the United States showed less activity against
disease than what was seen in Japan, but the patient
cohort of young women of East Asian descent who
were never-smokers appeared to respond at greater
rates.7,8 Further work revealed that this cohort had an
increased rate of EGFR mutations primarily located
on exons 19 (deletion) and 21 (mutation).9,10 Based
on early trials, gefitinib was initially approved by the
US Food and Drug Administration (FDA) in 2003.
In a subsequent placebo-controlled phase III
trial, the Iressa Survival Evaluation in Lung Cancer
study, no survival advantage with gefitinib was reported in patients with unselected refractory NSCLC.11
Survival benefit was seen in patients of Asian origin
and nonsmokers. The FDA rescinded approval of the
drug in 2005 secondary to a lack of benefit compared
with placebo in an unselected population. The largest study of gefitinib was the IRESSA Pan-Asia Study
trial, which compared the drug to conventional chemotherapy in unselected patients with advanced
NSCLC and found improved progression-free survival (PFS) but no difference in overall survival (OS).12
A subgroup analysis of patients with EGFR mutations demonstrated improvement in PFS (hazard ratio
[HR] = 0.48; 95% confidence interval [CI], 0.36–0.64).
No statistically significant difference in survival was
seen, but patients in the gefitinib arm were favored.
Furthermore, in patients without the EGFR mutation,
a detrimental effect was seen with gefitinib (HR for
January 2014, Vol. 21, No. 1
PFS = 2.85). Based on these findings, a phase III trial
was conducted in Japan among patients with EGFR
mutations that compared gefitinib with combination
cisplatin/docetaxel.13 Median PFS combination rates
were significantly longer in the gefitinib arm compared
with the chemotherapy arm (9.2 vs 6.3 months). Gefitinib is currently available in Europe and Asia.
Erlotinib is another reversible TKI and is similar
to gefitinib. The difference in the mechanism of the
2 drugs is poorly understood but could be from a more
rapid hepatic clearance of gefitinib.14 The role of erlotinib in refractory NSCLC was evaluated in a randomized placebo-controlled, phase III BR.21 trial conducted
in Canada.15 OS rates were significantly higher in the
erlotinib group, with a median survival of 6.7 months
compared with 4.7 months in the placebo group
(HR = 0.70). Responses were more common in women,
in patients with adenocarcinoma, and in patients who
did not smoke. By contrast to prior reports, response
rates were higher in patients with EFGR-expressing
tumors.9,10 No significant difference in response rate
was observed by EGFR mutation status (16% vs 7%;
P = .37).16 Based on these trial results, the FDA approved the use of erlotinib in refractory NSCLC in 2004.
Subsequently, erlotinib was compared with conventional chemotherapy in treatment-naive patients
with advanced NSCLC who harbored the EGFR mutation (exon 19 deletion or L858R mutation in exon 21)
in 2 large trials, EURTAC17 and OPTIMAL.18 Significant
improvements in PFS were reported in both trials.
However, survival differences were not observed, presumably because of the crossover design. Patients in
the erlotinib group of the OPTIMAL trial experienced
better quality of life compared with those in the chemotherapy group.19 The utility of erlotinib as a maintenance therapy was assessed in a phase III, placebocontrolled study. Patients who had not progressed after
receiving chemotherapy were randomized to either
erlotinib or placebo. The OS rates were significantly
prolonged in this unselected population. Benefit was
seen irrespective of EGFR mutation status; however,
Cancer Control 75
patients with an EGFR mutation had improved PFS
(HR = 0.10; 95% CI, 0.04–0.25).20 In the ATLAS trial,
the addition of erlotinib to maintenance bevacizumab
therapy resulted in improved outcomes.21
Preclinical models suggest that erlotinib may improve the cytotoxic effects of chemotherapy.22 Several
phase III trials were conducted to improve the outcomes of patients with advanced NSCLC undergoing chemotherapy by adding gefitinib or erlotinib to
therapy.23-26 However, no differences in clinical outcomes were observed with combination EGFR TKI
and chemotherapy. One possible explanation for the
failure to demonstrate a survival advantage in this
combination could be secondary to the inclusion of
unselected patients regardless of their EFGR mutation
status. Prior studies have demonstrated that the benefits of gefitinib and erlotinib are primarily restricted to
patients with EGFR-mutated tumors.7,8,10,15,16 Another
explanation is that a negative interaction may exist
between EGFR TKIs and chemotherapy when they
are concurrently administered. EGFR TKIs results in
G1 cell-cycle arrest that may potentially interfere with
the cell-cycle specific (S and G2/M phase) cytotoxic
effect of chemotherapy.27 Thus, currently, erlotinib
and gefitinib cannot be recommended as concomitant
treatment to chemotherapy.
Afatinib is a novel, irreversible TKI with dual
specificity for ERBB1 and ERBB2. It was found to
have activity in preclinical models with the exon 20
gatekeeper T790 mutation, which is present in more
than one-half of patients with acquired resistance to
TKIs.28 Afatinib improved PFS rates in patients with
NSCLC who had previously progressed on erlotinib
or gefitinib.29 Results of a phase III trial comparing
afatinib with chemotherapy in patients with an EGFR
mutation were reported at the 2012 annual meeting
of the American Society of Clinical Oncology.30 An
improvement in PFS of 4.2 months was observed,
but OS data were still immature. The FDA recently
granted approval for the use of afatinib in patients
with EGFR-mutated NSCLC along with companion
diagnostic testing for EGFR mutations.
Based on current consensus guidelines, EGFR
mutations should be tested in newly diagnosed patients with advanced NSCLC.31,32 This testing can be
performed via polymerase chain reaction for the selected mutations (exons 18, 19, and 21) in a laboratory
that abides by the Clinical Laboratory Improvement
Amendments. Although this allows for information
only on prespecified alleles, it is more rapid and costeffective than direct sequencing or next generation
sequencing. Resistance to TKIs despite EGFR mutation has recently been described.33 Mechanisms of
secondary resistance, which are thought to occur
downstream of the target of the drug, have been hypothesized.34 Primary and secondary resistances have
76 Cancer Control
been associated with the T790M mutation, indicating
a clinical course similar to wild-type EGFR.35
Current recommendations endorse routine testing
for EGFR mutations in patients with advanced NSCLC,
especially those likely to harbor the mutation (young
patients, women, never-smokers, and those of Asian
descent).36 Patients with the EGFR mutation who have
metastatic disease should be started on TKIs in the
first-line setting. However, it is not yet known when
and if patients should be transitioned to cytotoxic
chemotherapy or how to treat resistant disease. Future
studies may help to answer these questions.
Colorectal Cancer
EGFR expression has been associated with malignant
transformation as well as worse clinical outcome in
colorectal cancer (CRC).37 Based on their activity in
lung cancer, the TKIs erlotinib and gefitinib have
been studied in phase II trials in CRC. Minimal effect
was seen when these TKIs were studied as single
agents.38,39 Combining TKIs with standard chemotherapy also did not show a significant benefit and was
associated with increased toxicities.40,41
Monoclonal antibodies have demonstrated more
encouraging results. Single-agent cetuximab has been
associated with an improvement in a median OS of
1.5 months in refractory patients with CRC.42 Subsequent analysis demonstrated that survival benefit was
limited to patients with wild-type Kirsten rat sarcoma
(K-ras) tumors. Combination cetuximab/irinotecan
therapy in patients with irinotecan-refractory CRC
resulted in improved response and PFS, with no significant difference in OS.43 This lack of difference in
OS was thought to be secondary to crossover design.
Patients with higher severity of rash derived more
benefit. These results led to the FDA approval of cetuximab for metastatic CRC.
The next step in the development of anti-EGFR
antibodies for CRC was the assessment of their activity in combination with standard chemotherapy in
earlier lines of therapies. In the CRYSTAL trial, cetuximab, in addition to 5-fluorouracil (5-FU)/leucovorin/
irinotecan chemotherapy, was compared with 5-FU/
leucovorin/irinotecan alone in patients with metastatic
CRC who were naive to chemotherapy.44 PFS marginally improved, but no difference was seen in OS. A
subsequent analysis demonstrated that the benefit
of cetuximab was limited to patients with wild-type
K-ras tumors with a 3.5-month improvement in OS.
In patients with mutant K-ras tumors, cetuximab had
a detrimental effect. Similar results were seen in the
OPUS trial,45 which assessed the role of cetuximab in
combination with 5-FU/leucovorin/oxaliplatin chemotherapy. However, the survival improvement did not
reach statistical significance in patients with wild-type
K-ras tumors, presumably due to small sample size.
January 2014, Vol. 21, No. 1
By contrast, the NORDIC-VII trial, which assessed
combination cetuximab/bolus 5-FU/leucovorin/irinotecan did not demonstrate any difference in PFS regardless of K-ras mutation status.46 In the unselected population, the median PFS in the experimental
group was 8.3 months vs 7.9 months in the control
group (wild-type K-ras median PFS = 7.9 months vs
8.7 months). In patients with K-ras–mutant tumors,
a trend was seen toward an increase in PFS in the
cetuximab group, with a median PFS of 9.2 months vs
7.8 months, but this did not reach statistical significance
(P = .07). Bolus 5-FU instead of standard infusional 5-FU
was used in this trial, which is the standard of care in
the United States. A large phase III COIN trial of 1,630
patients conducted in the United Kingdom evaluated
the addition of panitumumab to fluoropyrimidine
and oxaliplatin as first-line therapy.47 The choice of
fluoropyrimidine, 5-FU, or capecitabine was based on
patient and physician preferences, with the majority of
patients receiving capecitabine. K-ras mutation status
was prospectively evaluated in contrast to most of the
previous trials. No differences in survival or PFS were
reported in the unselected, wild-type K-ras and K-ras
mutant groups. Among patients with wild-type K-ras
tumor types receiving 5-FU–based treatment, the PFS
was prolonged in the cetuximab group (HR = 0.72;
95% CI, 0.53–0.98). Frequent dose reductions and interruptions were reported, particularly in the patients
receiving cetuximab. Further, the median OS of 17.9
months in the cetuximab arm and 17 months in the
control group was lower than that seen in first-line
CRC therapy trials.40-42
Panitumumab is a fully human monoclonal IgG2
antibody that has similar efficacy and adverse events
compared to cetuximab. A randomized, placebocontrolled, phase III trial in patients with refractory
CRC revealed that panitumumab use was associated
with improved PFS.48 The results from this study led
to FDA approval of the drug in 2006. Panitumumab
was evaluated as a first-line therapy in combination
with leucovorin/5-FU/oxaliplatin chemotherapy in the
randomized phase III PRIME trial.49 Similar to prior
studies, benefit was restricted to patients harboring
wild-type K-ras tumor with improvement in PFS and a
nonstatistical significant improvement in OS. In a phase
III trial, panitumumab in addition to leucovorin/5-FU/
irinotecan as a second-line therapy improved PFS in
patients with wild-type K-ras tumors.50
Based on the activity of anti-EGFR agents and
the vascular endothelial growth factor antibody
bevacizumab, in combination with chemotherapy for
metastatic CRC, randomized trials were conducted
to evaluate if anti-EFGR agents in addition to chemotherapy and bevacizumab would further improve
outcomes. A pilot phase II BOND-2 trial assessed the
dual antibody therapy, cetuximab and bevacizumab,
January 2014, Vol. 21, No. 1
alone or in conjunction with irinotecan.51 Response
rates, time to progression, and OS were more favorable in the experimental group. Results of this
study led to larger randomized trials. CAIRO-2 was a
phase III trial of 755 patients that evaluated the addition of cetuximab to capecitabine, oxaliplatin, and
bevacizumab as first-line treatment in patients with
metastatic CRC.52 No differences in PFS or OS rates
were observed in the unselected or wild-type K-ras
tumor group. Patients with K-ras–mutated tumors had
worse outcomes if they received cetuximab. Similar
results were seen with PACCE study, which evaluated
the combination of panitumumab, bevacizumab, and
chemotherapy.53 The addition of anti-EGFR antibody
not only failed to improve outcomes, but also led to
inferior PFS and OS, regardless of K-ras mutation
status. Thus, no role exists for dual antibody therapy
in the treatment of CRC.54
The results of prior studies suggest that (1) antiEGFR antibodies have activity only in wild-type Kras CRC, (2) cetuximab and panitumumab may be
interchangeably used, (3) cetuximab and panitumumab activity is present in any line of therapy in
combination with chemotherapy, (4) no role exists
for anti-EGFR antibodies in the adjuvant setting, and
(5) the backbone of chemotherapy may have a differential effect on the activity of these agents.55,56 The
National Comprehensive Cancer Network guidelines
suggest that cetuximab should not be combined with
oxaliplatin, but the guidelines do permit the use of
combination panitumumab/oxaliplatin.57 One possible explanation for the negative results seen in the
NORDIC and COIN trials could be that bolus 5-FU
and capecitabine, respectively, were utilized instead of
infusional 5-FU. Further, no advantage exists for the
addition of bevacizumab to combination anti-EGFR
antibody/chemotherapy.52-54
Head and Neck Cancers
In a randomized phase III trial, cetuximab was added
to radiotherapy for locally advanced disease and was
associated with improvements in response, PFS, and
OS.58 Combination cetuximab/cisplatin has been tested in patients with metastatic head and neck cancers.
A randomized controlled trial of cetuximab/cisplatin
compared with cisplatin alone demonstrated an improved response rate, with no significant difference in
OS, presumably due to small sample size.59 A larger
randomized phase III trial demonstrated that the
addition of cetuximab to 5-FU and platinum chemotherapy resulted in an improvement in median OS by
2.7 months.60 Cetuximab was approved by FDA in
2006 for use in locally advanced, recurrent, and metastatic head and neck cancers.
Among the TKIs, gefitinib has not been shown to
be effective and has been associated with an increased
Cancer Control 77
risk for hemorrhage.61 Although phase II data showed
some activity of erlotinib in metastatic head and neck
cancers, this was not supported in further studies.62
Pancreatic Cancer
EGFR is overexpressed in pancreatic cancer, and
EGFR overexpression has been associated with a
poor prognosis.63,64 Based on preclinical activity
and encouraging phase II trial results, a randomized phase III trial evaluated the role of cetuximab
in addition to gemcitabine.65 No differences in any
of the clinical outcomes were noted. By contrast,
another phase III trial comparing gemcitabine/erlotinib with gemcitabine alone demonstrated a small
but significant improvement in survival (HR = 0.82;
95% CI, 0.69–0.99).66 Despite the fact that the median OS was increased by only 2 weeks, this trial
was notable because it has been the only study to
show an improvement in outcomes with combination
gemcitabine/erlotinib in metastatic pancreatic cancer.
FDA approval was granted for the use of erlotinib
in metastatic pancreatic cancer. With the recent FDA
approval of combination nab-paclitaxel/gemcitabine,
the practical utility of erlotinib in pancreatic cancer
is significantly decreased.
Conclusions
Presently, the utility of epidermal growth factor receptor (EGFR)-blocking agents is limited to a small
number of tumor types. Predictive biomarkers, including EGFR mutation in non–small-cell lung cancer
and Kirsten rat sarcoma (K-ras) mutations in colorectal cancer, have been developed to help identify the
subgroup of patients who may derive benefit from
these agents. EGFR expression has not been found
to predict response with EGFR antagonists. Moreover, a predictive biomarker in one cancer type is
not helpful in another cancer type, suggesting that
different mechanisms may be involved. Rash severity
has been correlated with the efficacy of anti-EGFR
agents, but it alone cannot be used as criteria for
baseline selection. Preemptive skin treatment with
skin moisturizers, sunscreen, topical steroids, and
doxycycline may reduce the severity of the rash without compromising efficacy.67
Tumor cells eventually develop resistance to
anti-EGFR agents by using alternative growth factor receptor pathways or by constitutively activating
downstream intracellular signals.68 Novel therapeutic
strategies are needed to overcome resistance to EGFR
antagonists. One such strategy is the development of
afatinib, which is active against T790 mutant tumor
cells (acquired mutation), although at a lower potency.
Novel biomarkers also are needed to predict the development of resistance to these agents in individual
patients, thus offering personalized therapy.
78 Cancer Control
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