(Erbitux) added to first-line treatment
with FOLFIRI or FOLFOX-4 has an
acceptable safety profile, is active, and
has yielded a low rate of progressive
disease in patients with metastatic colorectal
cancer, two phase II studies
show. While results are still early, the
response rates reported to date by investigators
suggest cetuximab has
promise when incorporated into standard
first-line therapy for this patient
First-line cetuximab with FOLFIRI
is a logical progression from earlier
studies assessing use of the monoclonal
antibody in patients who had already
failed first-line therapy. Previous researchers
confirmed the efficacy of
cetuximab plus irinotecan in metastatic
colorectal cancer, showing a
greater response rate and lower rate of
progressive disease vs cetuximab alone
(ASCO 2003, abstract 1012).
Philippe Rougier, MD, of Hpital
Ambroise Pare, Boulogne, France, re-
ported safety and some efficacy data
from a phase II study in 42 patients
with epidermal growth factor receptor
(EGFR)-expressing metastatic colorectal
cancer (abstract 3513). They
received cetuximab at an initial dose
of 400 mg/m2 followed by 250 mg/m2
IV weekly. The FOLFIRI regimen was
administered every 2 weeks, with either
a low or high dose of fluorouracil
(5-FU). Those in the low-dose group
received irinotecan (CPT-11, Camptosar)
180 mg/m2, folinic acid 400
mg/m2, and 5-FU 300 mg/m2 bolus
plus infusion of 2,000 mg/m2 over 46
hours. In the high-dose group, 5-FU
was given as a 400 mg/m2 bolus plus
infusion of 2,400 mg/m2 over 46 hours.
Acceptable Safety Profile
No dose-limiting toxicities were
seen with the low-dose regimen.
Among an initial 13 patients treated at
the higher dose level, dose-limiting
toxicities were seen in 2 patients (15%).
Based on this acceptable safety profile,
investigators enrolled an additional
29 patients at the higher dose level.
At that dose level, partial responses
were seen in 17 patients (43%), while
18 (45%) had stable disease, for a total
tumor growth control in 35 patients
(88%). The 43% response rate excludes
some unconfirmed responses, which
the researchers reclassified as stable
disease. Regardless of that, the low
rate of progressive disease is notable,
according to Dr. Rougier. In addition,
five partial responders with initially
unresectable liver metastases went on
to surgery after treatment. Of those,
four had a documented complete resection.
There were few dose-limiting toxicities,
even at the higher dose level.
The most common grade 3/4 toxici-
ties were leukopenia (17%), diarrhea
(14%), and skin toxicity (7%). Only
two of these toxicities (4%) were classified
as grade 4, including one leukopenia
and one asthenia.
"The important thing is that only
12% of patients progressed, which is
in the lower range of what has been
reported with more recent [studies],"
Dr. Rougier said. "[The combination]
is really worth a phase III trial that just
started, which is a European multicenter
comparison of FOLFIRI alone
vs FOLFIRI and cetuximab."
Combination With FOLFOX-4
Researchers from Vall d'Hebron
University Hospital in Barcelona,
Spain, reported on a phase II trial using
cetuximab plus FOLFOX-4 in patients
with EGFR-expressing metastatic
colorectal cancer (abstract 3512).
Almost all had at least stable disease,
and a few had complete responses.
"The data from our study are consistent
with earlier study results, and
indicate the potential for earlier use of
cetuximab in combination with standard
first-line therapies," said lead investigator
Josep Tabernero, MD, PhD,
of Vall d'Hebron University Hospital.
Dr. Tabernero reported on 43 patients
who received cetuximab/FOLFOX-
4. Responses were seen in 34,
including 2 complete responses (5%)
and 32 partial responses (76%). Another
7 (17%) had stable disease. Serious
adverse events included neutropenia,
diarrhea, and skin rash.
Researchers said those findings
were encouraging enough to merit
further investigation. "With 5-year
survival reported at only 3% in patients
with metastatic colorectal cancer,
there is a real need to improve
treatment options for these patients,"
Dr. Tabernero said.
A monoclonal antibody with
activity against epidermal growth
factor receptor (EGFR), cetuximab
was approved by the US Food and
Drug Administration in February
2004 for patients with metastatic colorectal
cancer in combination with
irinotecan, or alone if patients cannot
tolerate irinotecan. FOLFIRI is a combination
of 5-FU/folinic acid/ irinotecan,
and FOLFOX-4 is a combination
of 5-FU/folinic acid/oxaliplatin (Eloxatin).