(Avastin) appears to add to the
efficacy of cetuximab(Drug information on cetuximab) (Erbitux) and
cetuximab/irinotecan (Camptosar) in irinotecan(Drug information on irinotecan)-refractory bevacizumab(Drug information on bevacizumab)naive
colorectal cancer patients," when
compared with historic controls, according
to Leonard B. Saltz, MD, of
Memorial Sloan-Kettering Cancer
Center in New York. He reported on a
phase II trial of the concurrent administration
of two monoclonal antibodies-
cetuximab and bevacizumab-
with or without irinotecan (abstract
"This is the first trial in which these
two antibodies were given to patients
at the same time," Dr. Saltz noted.
Cetuximab targets the epidermal
growth factor receptor (EGFR), whereas
bevacizumab targets the vascular
endothelial growth factor (VEGF).
Naive to Both Monoclonals
All patients in the phase II trial had
irinotecan-refractory disease and were
naive to both monoclonal antibodies
studied. Patients were randomized to
receive one of the two following regimens:
Cetuximab (400 mg/m2 loading
dose, then weekly at 250 mg/m2) plus
bevacizumab (5 mg/kg every other
week), and irinotecan (same dose and
schedule as last received prior to the
The same cetuximab and bevacizumab
dosing schedules but without
Cetuximab was started on day 1,
but for the first week only, bevacizumab
was started on day 2 "in order to
permit assessment of these agents separately,"
Dr. Saltz said.
The trial was initially planned to
accrue 75 patients in each arm, but
statistics were recalculated for a lower
number because of the widespread
commercial availability of bevacizumab
and "the scarcity of bevacizumab-
naive patients," Dr. Saltz said.
Data were reported for 81 patients
randomized to the two arms: 41 in the
arm with irinotecan and 40 in the arm
without irinotecan. "There was a slight
imbalance in terms of older patients
in the irinotecan arm," Dr. Saltz said.
"Otherwise, there were no significant
differences between the arms." The
median age in the irinotecan group
was 64 years (range, 43-86 years), and
in the arm without irinotecan it was
56 years (range, 24-80 years).
"Toxicities were as would be ex-
pected from the individual agents,
without clear evidence of synergistic
effect," Dr. Saltz said. The primary
toxicity related to the monoclonal antibodies
was skin rash (see Table 1).
"We don't see a significant interaction
between the arms as would be expected,"
Dr. Saltz said. "We see a degree of
toxicity that is not outside the parameters
we might expect from cetuximab
alone," he said.
"In terms of irinotecan-related toxicities,
as would be expected, we see
substantial increases in neutropenia,
diarrhea, both grades 2 and 3/4, as well
as fatigue, with over 40% of patients
having grade 2 or 3 fatigue when given
irinotecan, as compared with only 5%
having grade 2 fatigue with the antibodies
alone" (see Table 2).
"One of the concerns was whether
the adverse-event profiles would amplify
each other," Dr. Saltz noted. "We
did see some evidence of those events,
which could potentially be considered
relatable to either bevacizumab or
cetuximab. These are somewhat vague
in nature and certainly could also be
attributed to the advanced disease of
these patients." The adverse effects included
upper and lower gastrointestinal
bleeding, rectal fistula, and one
myocardial infarction (which was ultimately
Usefulness of Regimen
Partial responses occurred in 15
patients (37%; 95% confidence interval
[CI]: 22%-53%) in the irinotecan
arm and 8 patients (20%; 95% CI: 9%-
36%) in the cetuximab/bevacizumabonly
arm. Median time to progression
was 7.9 months for patients receiving
irinotecan and 5.6 months in those
not receiving irinotecan.
"The usefulness of bevacizumab
with cetuximab in patients with prior
bevacizumab exposure remains unknown.
Studies to address this question
are in development," Dr. Saltz
said. "But I would emphasize that at
this point, the applicability of these
data to practice today is highly questionable,
since patients who are bevacizumab-
naive getting to this point in
their therapy are quite rare," Dr. Saltz
"Perhaps most importantly, the
study served as the safety pilot for the
current CALGB/SWOG study, which
will be opening momentarily," Dr.
Saltz said. The Cancer and Leukemia
Group B/Southwestern Oncology
Group study gives investigators the
choice of using either FOLFOX (fluorouracil,
leucovorin, oxaliplatin(Drug information on oxaliplatin)
or FOLFIRI (fluorouracil, leucovorin,
irinotecan) and then
randomizing patients also to receive
cetuximab, bevacizumab, or the combination
of the two monoclonal antibodies.
The need for additional studies was
supported by Neal J. Meropol, MD, of
Fox Chase Cancer Center in Philadelphia,
who served as a discussant for
this ASCO session. "While the patient
numbers are small and this should not
lead to a change in practice, this pilot
study provides sufficient clinical validation
to warrant phase III testing of
this concept," he said.
"The study by Saltz and colleagues
lends credence to the notion that approaching
a cancer as a system of interrelated
and interdependent pathways
can yield clinical fruit. It is also
clear that colorectal cancers are a heterogeneous
group of diseases characterized
by various pathway addictions
and redundancies," Dr. Meropol continued.
"Ultimately, it is hoped that
describing the networks of individual
tumors will lead to individualized selection
of inhibitory strategies."
As potential examples of such
strategies, Dr. Meropol mentioned
"combinations of receptor inhibitors
or EGFR inhibitors in combination
with inhibitors of downstream pathways."