From Medscape Hematology-Oncology

Expert Interview
Evolution of EGFR Inhibition for Metastatic Colon Cancer: An Expert
Interview With Dr. Neal Meropol
Posted 07/31/2006


Editor's Note:

Approximately 150,000 Americans are diagnosed with colorectal cancer
(CRC) each year, with half a million cases reported worldwide. After
several decades of incremental improvements in chemotherapy, 2 new
targeted monoclonal antibodies were approved by the US Food and Drug
Administration in February 2004 for treatment of patients with
metastatic colorectal cancer. Cetuximab, which targets the epidermal
growth factor receptor (EGFR), and bevacizumab, which targets the
vascular endothelial growth factor (VEGF) receptor, have been shown
to improve the outcome of patients with metastatic colorectal cancer.
At this juncture, researchers are eager to evaluate the potential
value of these targeted agents earlier in disease, and clinical
trials in the adjuvant setting are ongoing. The challenge moving
forward in the metastatic setting is to determine optimal sequencing
and combinations, as well as ways to identify patients for whom
treatment may be curative. At the 2006 annual meeting of the American
Society of Clinical Oncology, there were a number of studies
demonstrating some intriguing and promising early results. On behalf
of Medscape, Sally Church, PhD, interviewed Neal J. Meropol, MD,
Director of the Gastrointestinal Cancer Program and Director of the
Gastrointestinal Tumor Risk Assessment Program at Fox Chase Cancer
Center in Philadelphia to discuss how treatment regimens for patients
with metastatic CRC have evolved and to review newly reported data.

Medscape: We have heard much about the role of VEGF inhibition in
CRC, but what is the significance of blocking EGFR? Is there a role
for it in treating front-line CRC, in addition to its current use in
later lines of therapy?

Dr. Meropol: It has been known for decades that the EGFR is
associated with neoplastic transformation. Many different types of
human tumors express EGFR on the surfaces of cancer cells. Once this
discovery was made, a variety of experiments were conducted in the
laboratory, showing that interruption of signaling from these
receptors on the cell surface could result in either the death of
cancer cells -- apoptosis -- or a reduction in their proliferation.
Based on these preclinical findings, reagents were developed to try
to target the EGFR pathway in humans.

When signaling takes place through growth factor receptors, a cascade
of events brings a signal from the surface of the cell to the nucleus
that results, ultimately, in the production of proteins leading to
proliferation, metastatic potential, and a decrease in apoptosis --
all of which are hallmarks of cancer. So, the hope was that by
interrupting the signaling of growth factor receptors -- in this
case, EGFR -- these processes would be reduced, and the virulence of
cancer cells in humans would be attenuated. The first proof of
principle of this hypothesis is represented by cetuximab, a chimeric
monoclonal antibody directed against the EGFR. This antibody
interferes with the usual interaction of this receptor with its
ligand or ligands in the extracellular matrix and also perturbs the
signaling of the receptor.

Additionally, other reagents, which are not antibodies but are small
molecules that interact with the tyrosine kinase domain of the EGFR,
have also shown activity in human cancer, particularly in non-small-
cell lung cancer and pancreatic cancer. These drugs include gefitinib
and erlotinib. VEGF as a target has received a lot of press recently
because of the success of clinical trials using bevacizumab in a
variety of different types of cancer, but there is also a significant
buzz with regard to EGF blockade.

Medscape: What is the significance of potentially blocking VEGF and
EGFR simultaneously? Is this a feasible strategy? Might it be more
effective than blocking these targets individually?

Dr. Meropol: Cetuximab and panitumumab -- an investigational
monoclonal antibody against EGFR that is far along in clinical
development -- were both initially developed as second- or third-line
agents to be used after failure of initial chemotherapy. Cetuximab
was evaluated as a single agent as well as in combination with
irinotecan chemotherapy, initially. Notably, the response rate with
cetuximab in combination with irinotecan was twice as high as with
cetuximab by itself, which validated findings of preclinical
experiments. One of the most interesting observations from this study
was that this doubling of response rate occurred in patients who had
previously failed therapy with irinotecan, so somehow there is a
cooperation between cetuximab and irinotecan that overcomes
irinotecan resistance or perhaps, in some patients, overcomes
cetuximab resistance. After it became evident that both cetuximab and
panitumumab had activity in second- or third-line treatment of
metastatic colorectal cancer, there was a natural effort to try to
move them into earlier lines of treatment. These clinical trials
addressing the earlier use of the EGFR monoclonal antibodies in colon
cancer are currently ongoing. Of note, although the monoclonal
antibodies against EGFR have shown activity against CRC, the small-
molecule inhibitors of EGFR have not.

At this year's ASCO meeting, Alan Venook from UCSF described
preliminary results from a clinical trial[1] with EGFR inhibitors as
first-line treatment. Patients with previously untreated metastatic
CRC were given chemotherapy alone or chemotherapy in combination with
cetuximab. The choice of the chemotherapy was left up to the
discretion of the treating physician and could be FOLFOX or FOLFIRI.
The study was originally designed to include more than 1000 patients,
but because of changes in the CRC treatment landscape, notably the
introduction of bevacizumab into front-line therapy, the study was
discontinued because of poor accrual. Nevertheless, preliminary
results with approximately 60 patients in each of the 4 treatment
groups showed that those who received cetuximab in combination with
either oxaliplatin or irinotecan had a higher response rate than
those patients who did not receive cetuximab. At this point, the
impact of those higher response rates on overall survival or
progression-free survival cannot be determined because of the small
sample size. Furthermore, it is not clear at this time whether there
is greater cooperation of cetuximab with a particular chemotherapy
regimen, that is to say whether it works better with FOLFIRI or with
FOLFOX.

The study that Dr. Venook reported has been replaced by a new
intergroup study in which patients are randomly assigned to 1 of 3
treatment approaches as initial management of metastatic CRC. The
first is chemotherapy with cetuximab; the second is chemotherapy with
bevacizumab, which has now become standard; and the third arm is
chemotherapy with both cetuximab and bevacizumab. This study is
currently accruing patients. As in the previous study, the choice of
chemotherapy backbone (ie, FOLFOX or FOLFIRI) is left up to the
discretion of the treating physician.

The other new drug in development is panitumumab, which is not yet
approved by the FDA for marketing in the United States but has been
associated with an improvement in progression-free survival compared
with best supportive care in a European study of patients with
refractory CRC. An ongoing study in North America is comparing
chemotherapy plus bevacizumab vs chemotherapy with bevacizumab plus
panitumumab. One of the distinguishing features of panitumumab
compared with cetuximab is the structure of the antibody. Whereas
cetuximab is a chimeric monoclonal antibody (meaning that it has
about 30% of a mouse murine component to it), panitumumab is a fully
human antibody. For this reason, panitumumab appears to be associated
with a significantly lower chance of allergic reactions. At this
point, the comparative efficacy of these 2 antibodies is uncertain.

The concept of using both EGFR and VEGF inhibitors in colorectal
cancer is currently being explored. The reason that there is so much
interest in this type of combination is that it has been known for
some time that one of the downstream effects of EGFR stimulation is
an increase in production of VEGF. This led to the hypothesis that
blocking both ends of this sequence of events might produce a more
potent antitumor effect. There has been an early signal that this
might, in fact, be the case in a small randomized phase 2 study[2]
reported at the ASCO meeting in 2005 by Leonard Saltz. Patients who
had failed therapy with irinotecan but had never received bevacizumab
were randomly assigned to receive either cetuximab plus bevacizumab
or cetuximab, bevacizumab, and irinotecan. The 35% response rate in
the group of patients that received both antibodies with irinotecan
appeared to be in excess of what one would expect. In contrast, the
group that received bevacizumab plus cetuximab without irinotecan had
a response rate of about 20%. These were intriguing and provocative
results, but there were only about 40 patients in each arm, so it was
quite preliminary. The current ongoing front-line studies will
clearly define the role of dual blockade of EGFR and VEGF in
metastatic CRC.

Medscape: Were there any other presentations of interest with regard
to EGFR inhibition in metastatic CRC?

Dr. Meropol: Jose Baselga reported on a phase 1 study[3] combining 2
classes of EGFR inhibitors, that is to say a monoclonal antibody,
cetuximab, along with a tyrosine kinase inhibitor, gefitinib. This
phase 1 dose-finding study concluded that it was safe to administer
full doses of both drugs. One of the most provocative findings from
this study was that of 9 CRC patients who were treated with both
drugs, 5 experienced a partial response. This is a very small number
of patients in a very early study, so it is premature to conclude
that a response rate in excess of 50% should be expected with this
combination. Nevertheless, the data certainly support further
exploration of dual inhibition of the EGFR signaling pathway in
patients with CRC.

Other EGFR-related reports included 2 small studies from Randolph
Hecht[4] and Jordan Berlin[5] that looked at the use of an every-
other-week schedule of panitumumab administration. Cetuximab is
currently administered weekly, but because of the pharmacokinetic
properties of panitumumab, it may be possible to administer that
agent on an every-other-week schedule. In these 2 small preliminary
studies, a response rate of approximately 10% confirmed the activity
of panitumumab administered as a single agent on an every-other-week
schedule in patients who had previously received oxaliplatin,
irinotecan, and 5-fluorouracil for metastatic CRC.

Medscape: How do you see future regimens for patients with CRC
evolving?

Dr. Meropol: Right now, there are 2 major directions for research.
One is in refinement of new therapeutic approaches that have come to
the clinic in the past few years. The large studies going on in CRC
are geared toward helping us optimize use of the available agents.
Questions about the optimal use of therapy include not only whether
more is better, but also how to determine which patients are most
likely to benefit from a particular treatment so that we can better
match our treatments to individual patients. Also, a major focus is
the identification of those patients with metastatic CRC who are
potentially curable. Unlike most other solid tumors, metastatic CRC
is curable if the metastases are surgically resectable. Some patients
whose disease is not resectable at time of diagnosis can be treated
with effective systemic treatment, which shrinks the tumor to the
point where the patient can then undergo surgery with curative
intent. The challenge for us is to identify those patients who might
ultimately be surgically curable and provide them the greatest
opportunity for long-term survival by initiating the most aggressive
treatment available as their initial therapy. In essence, we are
learning how to stratify patients with metastatic CRC into 2 groups:
those for whom metastatic disease will be a chronic process with on-
again, off-again treatment over a course of years, and those who
might be cured with more intensive initial therapy followed by
surgical resection.

The second major ongoing research direction is a vigorous effort to
identify novel agents with new mechanisms of action that might be
added to our armamentarium against CRC. Inhibitors of other growth
factor receptor pathways, such as the insulin-like growth factor
receptor pathway, are being tested in a number of different tumor
types.[6,7] In addition, there are molecular targets that have not
been previously explored and are not affected by current treatments,
such as the TRAIL receptor pathway,[8] which is a proapoptotic
pathway. These new directions hold promise for additional benefit,
and trials to investigate safety and efficacy are underway.

References
Venook A, Niedzwiecki D, Hollis D, et al. Phase III study of
irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) {±}
cetuximab for patients (pts) with untreated metastatic adenocarcinoma
of the colon or rectum (MCRC): CALGB 80203 preliminary results. Proc
Am Soc Clin Oncol. 2006;24:148s. Abstract 3509.
Saltz LB, Lenz HJ, Hochster H, et al. Randomized phase II trial of
cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab
(CB) in irinotecan-refractory colorectal cancer. Proc Am Soc Clin
Oncol. 2005;23:248s. Abstract 3508.
Baselga J, Schoffski P, Rojo F, et al. A phase I pharmacokinetic (PK)
and molecular pharmacodynamic (PD) study of the combination of two
anti-EGFR therapies, the monoclonal antibody (MAb) cetuximab (C) and
the tyrosine kinase inhibitor (TKI) gefitinib (G), in patients (pts)
with advanced colorectal (CRC), head and neck (HNC) and non-small
cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2006;24:122s.
Abstract 3006.
Hecht J, Mitchell E, Baranda J, et al. Panitumumab antitumor activity
in patients (pts) with metastatic colorectal cancer (mCRC) expressing
low (1-9%) or negative (<1%) levels of epidermal growth factor
receptor (EGFr). Proc Am Soc Clin Oncol. 2006;24:157s. Abstract 3547.
Berlin J, Neubauer M, Swanson P, et al. Panitumumab antitumor
activity in patients (pts) with metastatic colorectal cancer (mCRC)
expressing &#8805; 10% epidermal growth factor receptor (EGFr). Proc Am Soc
Clin Oncol. 2006;24:158s. Abstract 3548.
Attard G, Fong PC, Molife R, et al. Phase I trial involving the
pharmacodynamic (PD) study of circulating tumour cells, of CP-751,871
(C), a monoclonal antibody against the insulin-like growth factor 1
receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced
cancer. Proc Am Soc Clin Oncol. 2006;24:126s. Abstract 3023.
Morgillo F, Hong WK, Lee H. Insulin-like growth factor-1
receptor/epidermal growth factor receptor (EGFR) heterodimerization
and resistance to epidermal growth factor receptor tyrosine kinase
inhibitors in non-small-cell lung cancer. Proc Am Soc Clin Oncol.
2006;24:604s. Abstract 13032.
Herbst RS, Mendolson DS, Ebbinghaus S, et al. A phase I safety and
pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-
inducing protein in patients with advanced cancer. Proc Am Soc Clin
Oncol. 2006;24:124s. Abstract 3013.


Related Links
Resource Centers
Colorectal Cancer


Funding Information

Supported by an independent educational grant from Bristol-Myers
Squibb/Imclone.




Interviewee Affiliation: Neal J. Meropol, MD, Director,
Gastrointestinal Cancer Program, Fox Chase Cancer Center,
Philadelphia, Pennsylvania


Disclosure for Interviewer: Sally Church, PhD, has disclosed that she
has served as a consultant for sanofi-aventis and NeoRx.

Disclosure for Interviewee: Neal J. Meropol, MD, has disclosed that
he has received grants for clinical research from Bristol-Myers
Squibb and Pfizer. Dr. Meropol has also disclosed that he has served
as an advisor or consultant to Genentech, Bristol-Myers Squibb,
Amgen, and Pfizer.


Medscape Hematology-Oncology. 2006;9(2) ©2006 Medscape