Preliminary results of a phase II study
of bevacizumab (Avastin) and erlotinib
(Tarceva) in patients with meta-
static renal carcinoma show a substantial
number of durable partial responses
and support further study of this
regimen, said John D. Hainsworth,
MD, of the Sarah Cannon Cancer Center/
Tennessee Oncology in Nashville
(abstract 4502). "This tumor is refractory
to standard chemotherapy, and
only a small percentage of patients
benefit from cytotoxic therapy," he
told Oncology News International.
Dr. Hainsworth explained that
most patients with clear cell renal carcinoma
have loss of the VHL protein,
resulting in overexpression of a number
of genes including vascular endothelial
growth factor (VEGF), tumor
growth factor (TGF)-beta, epithelial
growth factor (EGF), and platelet derived
growth factor (PDGF). In second-
line use, bevacizumab, an anti-
VEGF antibody, prolongs time to
progression in advanced renal carcinoma.
"Based on renal carcinoma biology,
we hypothesized that combined
VEGF and EGFR inhibition would
enhance biological and clinical effects,"
Dr. Hainsworth said.
Original Protocol Amended
In this phase II trial, bevacizumab
was combined with the EGFR antagonist
erlotinib. The study enrolled patients with metastatic clear cell renal
carcinoma, and 0 or 1 previous systemic
regimen. Patients were treated
with bevacizumab at 10 mg/kg IV
q 2 weeks and erlotinib at 150 mg/d po.
Patients were evaluated for response
after 8 weeks. The investigators had
originally intended to continue treatment
for 12 months, but the original
study protocol was amended to permit
continuation in patients until
Dr. Hainsworth reported data for
58 treated patients with median follow-
up of 11 months. In contrast to
several other trials, 68% had no prior
treatment. Eighteen percent had pre-
interferon, 8% had previous interleukin-
2 (IL-2) plus interferon, and
6% had previous IL-2. Fifty three patients
had previous nephrectomies.
Sites of metastases included lungs (41),
liver (17), bone (15), adrenals (10),
and other sites (14).
"Nine of 12 patients with partial
responses and 10 of 12 with minor
responses [20% to 30% decrease in
tumor size] remain progression-free,"
said Dr. Hainsworth (see Table 1). "A
total of 42% of patients had measurable
decreases in their tumor size.
Twenty six of the 38 stable or minor
response patients remain alive and on
treatment for more than 6 months."
"Responses have been seen in all
areas of metastases and in most cases
included reductions of more than 50%.
For example, one patient had innumerable
bilateral lung metastases that
cleared substantially with treatment, "
Dr. Hainsworth said.
PFS of 50%
Six-month progression-free survival
(PFS) was 67%, and 12-month PFS
was 50%. Six-month overall survival
was 92%, and 12-month overall survival
Treatment was tolerable in most
patients but with a number of minor
side effects, Dr. Hainsworth noted.
Twenty-five patients (63%) had no
grade 3 or 4 toxicity. Only two patients
stopped treatment because of
toxicity, both as a result of rash.
Grade 3 or 4 toxicity included rash in
eight patients (13%), diarrhea in six
(10%), and nausea and vomiting in six
(10%). Grade 1 or 2 bleeding occurred
in 24 patients (39%) and grade 3 or 4
bleeding was reported in 3 patients
"The number of bleeding occurrences
may seem out of proportion.
We were somewhat concerned about
bleeding, which has been a problem
with bevacizumab, but most instances
were minor hemorrhoidal bleeding or
minor nosebleeds. We feel that this is
probably not a true level of treatmentrelated
toxicity," Dr. Hainsworth said.
"Most of the side effects were the rash
and diarrhea typical of EGF receptor
The investigators concluded that
bevacizumab/erlotinib produced a
major response rate of 21% in this
group of 58 evaluable patients with
advanced renal carcinoma. An additional
45% of patients had stable disease
or minor response for more than
6 months, and Dr. Hainsworth said
that an increasing number of patients
have now maintained this result for
more than 12 months with continued
treatment. One-year PFS was 50%,
and overall survival was 81%.
"This regimen appears to be one of
the most active and best tolerated regimens
in the treatment of advanced
renal carcinoma. The activity of this
combination of two targeted agents
appears greater than the activity of
either agent used alone in clear cell
renal carcinoma. Comparison of this
regimen to standard regimens is certainly
indicated. The results of this
trial also support further development
of combinations of targeted agents to
exploit tumor-specific biologic
mechanisms in renal cancer and other
malignancies," Dr. Hainsworth