targeted therapies for advanced renal
cell carcinoma (RCC) "merit further
investigation if not Food and Drug
Administration approval," asserted
Michael Atkins, MD, of Beth Israel
Deaconess Medical Center, Boston, in
discussing trials of some of the RCC
targeted drugs reported at ASCO.
A novel tyrosine kinase inhibitor
(TKI), AG-013736, has produced high
response rates in patients with metastatic
RCC, according to results of a
phase II trial (abstract 4509).
High ORRs With AG-013736
"The objective response rate of this
drug for patients with advanced renal
cancer is better than that of any other
drug approved for this indication,"
said lead investigator Brian Rini, MD,
assistant professor of medicine at the
University of California, San Francisco.
One of the molecular features of RCC
is overexpression of genes that promote
tumor cell growth, including
vascular endothelial growth factor
(VEGF), epidermal growth factor(EGF), and platelet-derived growth
factor (PDGF). AG-013736 is a tyrosine
kinase inhibitor that targets the
VEGF receptors and the PDGF beta
Favorable Outcomes vs
Dr. Rini reported that 46% of the
52 patients on the trial had a partial
response and 40% had stable disease.
Only about 15% of patients usually
respond to interleukin-2 and interferon-
alpha, the current standard treatments
for metastatic RCC.
At a median follow-up of 1 year, 1
patient with a partial response hadrelapsed, and 16 patients (32%) had
progressive disease. Dr. Rini later noted
that 3 of the 21 patients who
achieved a partial response subsequently
progressed. Seven, or 13%,
withdrew from the trial because of
adverse events. Median time to progression
had not yet been reached, Dr.
Toxicities were manageable and included
rash, diarrhea, and hypertension.
The most common grade 3/4
toxicity was hypertension, which was
controlled with medication.
Other targeted therapies are also
showing promise in RCC.
The novel multikinase inhibitor
BAY 43-9006 (Sorafenib) is being
tested in a phase III trial, and preliminary
results reported at ASCO show a
significant effect on disease progres-sion (abstract LBA4510). After 12
weeks, progression-free survival for the
BAY 43-9006 arm of this trial was 79%,
compared with 50% for the placebo
arm. Partial response rates were low,
occurring in only 2% of patients based
on RECIST (Response Evaluation
Criteria in Solid Tumors), but there
was tumor shrinkage in a large number
of patients, according to Bernard J.
Escudier, MD, of Institut Gustave
Roussy, who led the study.
Erlotinib Plus Bevacizumab
Erlotinib (Tarceva) combined with
the anti-VEGF monoclonal antibody
bevacizumab (Avastin) also had very
promising results in a phase II study
(abstract 4540) (see report on page 12
of this supplement).
Noting that "we've come a long
way in renal cancer," Dr. Atkins cautioned
that many questions remain,
including whether optimal schedules
of the drugs are intermittent or continuous,
whether there is cross-resistance
among them, and how they combine
with interferon and other drugs
Another unknown is whether
AG-013736 and other novel therapies
will do better as single agents or in
combination with other drugs.
"Despite our zeal for combination
therapies, it remains to be seen whether
combinations of targeted therapies
can produce better results than optimal
multi-targeted single agents," he