Download Current Status of Studies on Targeted Therapy for Renal Cell

Chin J Clin Oncol (2008) 5: 294~298
DOI 10.1007/s11805-008-0294-x
294
Current Status of Studies on Targeted Therapy for Renal Cell
Carcinoma
Shaoqi Wang1
Shaoxiang Wang2
Juan Wang1
Department of Oncology, Hebei People’s
Hospital, Shijiazhuang 050051, Hebei Province, China.
2
Shenzhen People’s Hospital, Shenzhen
518020, Guangdong Province, China.
1
Correspondence to: Shaoqi Wang
E-mail: [email protected]
ABSTRACT Renal cell carcinoma (RCC) is regarded as one of
the most refractory malignancies. A further study of the molecular
mechanism of RCC formation has led to a series of successful
examples for treatment of patients with advanced RCC. Over the
past 20 years, a nonspecific immunotherapy, with cytokines, has
been employed as the gold standard for therapy of metastatic
RCC. However, with scientific development and clinical testing of
new drugs, targeted molecular cancer therapy has become a focus
of interest. At the same time, with a beĴer understanding of RCC,
the treatment method has converged on anti-vascular endothelial
growth factor (VEGF) and related molecular-targeted pathways.
A large amount of research and numerous clinical trials have
demonstrated the clinical efficacy of the targeted molecular
therapies in patients with metastatic RCC. For example sorafenib
and sunitinib were approved, in 2005 and 2006 respectively, by the
U.S. FDA for treating advanced RCC. In this report, issues such as
the importance of VEGF in RCC and the studies of bevacizumab,
sunitinib and sorafenib in treating metastatic RCC etc., are
reviewed.
KEY WORDS: targeted molecular therapy, renal cell carcinoma,
vascular endothelial growth factor.
Copyright © 2008 by Tianjin Medical University Cancer Institute &
Hospital and Springer
Introduction
Received January 12, 2008; accepted June 2,
2008.
CJCO http://www.cjco.cn
E-mail: [email protected]
Tel (Fax): 86-22-2352 2919
Based on statistics from 2007, about 51,190 people are diagnosed
with a renal carcinoma or a renal pelvic carcinoma in the U.S. each
year. Most of the patients had renal cell carcinoma (RCC). Each year
worldwide a total of 12,890 people die from the disease[1]. Over the
past 20 years, the incidence of renal carcinoma has increased progressively at a rate of approximate 2% per year. The 5-year survival
only reaches up to 5%~10% because of the insensitivity of RCC to
radiotherapy and chemotherapy. For RCC therapy, an application of
nonspecific immune supportive treatment has had a reasonable curative effect[2]. At present, recombinant interleukin 2 (rIL-2) and recombinant Hu-interferon-α (IFN-α) are the main agents for immunotherapy[3], however, the application of these drugs has been severely
restricted owing to factors such as toxicity and low efficacy etc.
A series of retrospective studies has demonstrated that vascular
endothelial growth factor (VEGF) is a potential target for treating
metastatic RCC. Depression of VEGF expression by various methods
has proven to produce a better anticancer effect and clinical benefit,
which has significantly improved the overall treatment of RCC.
Chin J Clin Oncol (2008) 5: 294~298
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Expression of VEGF in RCC
VEGF is a glycoprotein dipolymer, and is a member
of the platelet-derived growth factor (PDGF) family
that includes VEGF-A, VEGF-B, VEGF-C, VEGF-D,
VEGF-E and placenta growth factor (PlGF). VEGF is
of great importance to normal or tumor-related angiogenesis, and at the same time it can induce endothelial
cell division, cellular transplantation, thus enhancing
the survival rate of endothelial cells, reducing apoptosis,
and reversing endothelial cell aging[4]. VEGF exerts its
own biological action via receptors on the cell surface.
These transmembrane protein tyrosine kinase (PTK) receptors include VEGFR-1 and VEGFR-2, which are selectively expressed in vascular endothelial cells (VEC),
the VEGFR-3 in lymphatic vessels and blood vessel endothelium, and the neural receptors on the blood vessel
endothelium and neurons[5].
VEGF is expressed in most RCC cases, and the VEGF
protein can be differentiated from RCC tissues[6]. The
other proteins that relate to the biological characteristics
and treatment of RCC include PDGF, fibroblast growth
factor, erythropoietin, and α-type transforming growth
factor.
Development of RCC treatment by targeting
VEGF
Over-expression of VEGF in RCC has stimulated interest in targeting VEGF and its correlated pathway for
RCC therapy, especially, in cases of metastatic or advanced RCC. Table 1 summarizes the clinical progress
in treating RCC, with VEGF as the therapeutic target.
Bevacizumab
Bevacizumab (or Avastin) is a recombinant humanized
anti-VEGF monoclonal antibody. It can be conjugated
with the VEGF receptor (VEGFR) and can inhibit the
bioactivity of all VEGF subtypes.
Studies on bevacizumab monotherapy
Phase-II clinical trial using bevacizumab for treating
metastatic RCC[7]: a total of 116 patients with metastatic
water-clear cell renal carcinoma were randomized into
bevacizumab and control groups (n = 40). Then the
bevacizumab group was subdivided into a low-dose (3
mg/kg, n = 37) and high-dose group (10 mg/kg, n = 39),
with i.v. administration, once every 2 weeks. Among
the patients, 108 (93%) also received IL-2 therapy. The
clinical trial showed that the median time of tumor progression (mTTP) was doubled in the high-dose group
compared to the control group (4.8 and 2.5 months,
respectively, P = 0.001), whereas the mTTP was 3.0
months in the low-dose group. A portion of the cases in
the high-dose group (10%, 4/39) achieved partial remission (PR). No life-threatening reactions occurred, and
there were no deaths related to bevacizumab medication. Frequent toxic reactions included hypertension,
asymptomatic proteinuria, chest pain, or other various
complaints etc., in the high-dose group. All reactions
disappeared after the drug was withdrawn. Hemoptysis
of Grade-I to II was found in only 4 cases, i.e. 1 in each
of the high and low-dose groups, and 2 in the controls.
Also one pulmonary embolism occurred in the control
group. It was shown that bevacizumab can significantly
prolong the TTP of RCC patients.
Joint study of bevacizumab
In a multi-centrally cooperative and jointly completed
phase-II clinical trial[8], the EGFR inhibitor, erlotinib,
combined with bevacizumab, was used to treat metastatic RCC. All patients received bevacizumab (10
mg/kg, i.v., once every 2 weeks) and erlotinib (150 mg,
peroral, once a day). A total of 63 patients were involved
in the trial, all of whom underwent nephrectomy, but
68% of them did not receive a systematic treatment. The
objective response rate (ORR) was 25% (15/63), and
36 patients maintained stable disease (SD) following an
8-week treatment. Two patients withdrew because a skin
rash, but all other remained in the study. The rash of
Grade-1 to 2 and diarrhea were the most frequent toxic
reactions. Owing to a reasonable target in various tumors, the study showed that a combination of drugs for
targeted therapy will be the direction of future development. In another phase-II clinical trial of combined drug
therapy, the results were not satisfactory[9]. Comparison
of the curative effect between bevacizumab plus placebo
Table 1. Clinical trials and results of targeted treatment of RCC patients.
Subjects
Targeted drugs
Targets
Cases
Plan of clinical trials
Previous treatment records
Response
rate (%)
Time
(months)
Yang et al.[7]
Bevacizumab
VEGF ligand
116
Bevacizumab; placebo
Immunotherapy
10; 0
4.8; 2.5
Bukowski et al.[9]
Bevacizumab
VEGF ligand
150
Bevacizumab + placebo;
Bevaqcizumab + erlotinib
No
13.7; 14
8.5; 8.9
Motzer et al.[12]
Motzer et al.[13]
Sunitinib
VEGFR
63
106
Sunitinib
Immunotherapy
40
34
8.7
8.3
Motzer et al.[14]
Sunitinib
VEGFR
750
Sunitinib; IFN-α
No
31; 6
11.1; 5.0
Escudier et al.[19]
Sorafenib
VEGFR and
Raf kinase pathway
903
Sorafenib; placebo
Immunotherapy
2; 0
5.5; 2.8
296
treatment and the drug combination was conducted. The
results indicated that the ORR (13.7% and 14%) and
the median progression-free survival (mPFS) (8.5 and
9.9 months) were the same in both groups. Although
combined medication increases the anti-EGFR targets, it
does not improve the clinical efficacy.
Bevacizumab combined with biotherapy: Rini et al.[10]
have conducted a phase-III clinical trial on a combination of bevacizumab with IFN-α treatment for advanced
RCC. This combination has not been utilized before,
with the results still being under analysis. This research
will shed light on the efficacy of using bevacizumab
along with immunotherapy for treating advanced RCC
patients.
Micromolecular inhibitors of the VEGF receptor
The micromolecular substances that selectively inhibit
VEGF activity include receptor tyrosine kinase (RTK)
inhibitors. These micromolecular substances can not
only depress the VEGFR, but also inhibit the plateletderived growth factor receptor (PDGFR). They are
multi-targeting drugs.
Sunitinib
Sunitinib, is an oral multi-target micromolecular RTK
inhibitor, which can depress the activity of VEGFR and
PDGFR. In vitro experiments have demonstrated that
sunitinib can inhibit endothelial cell proliferation induced by VEGF, and the proliferation of rat fibroblasts
induced by PDGF[11].
There have been 2 large-scale phase-II clinical trials
for sunitinib. In Trial I [12] , 63 metastatic RCC patients
who had failed to respond to immunotherapy were studied. Most of these cases (87%) had been confirmed by
histology as clear-cell carcinoma. Nephrectomy was not
a requirement for inclusion in the trial, nevertheless 93%
of the patients have undergone surgery. Recommended
sunitinib dosage was given to all the patients (50 mg,
peroral, once a day, over a 4 continuous weeks of administration, followed by 2 weeks of drug withdrawal;
1 cycle every 6 weeks). PR occurred in 25 cases (40%)
and SD in 27% of the patients 3 months after medication. The mTTP was 8.7 months, and median survival
time was 16.4 months. In trial II, a total of 106 metastatic RCC patients, with a failure of a response to immunotherapy, were observed in another trial[13]. All were
confirmed as clear-cell renal carcinoma by pathology
and had received a surgical excision. PR was achieved
in 36 cases (34%), and mTTP was 8.3 months.
In both the trials, frequent toxic reactions were as follows: fatigue (28%), diarrhea (20%), stomatitis (26%),
dermatitis (12%) and hypertension (11%). These reactions can disappear after withdrawal, and can actively be
prevented and treated during the treatment. These data
show that sunitinib may have a reliable efficacy in the
Chin J Clin Oncol (2008) 5: 294~298
treatment of advanced RCC. Therefore in 2006, the U.S.
FDA approved the use of sunitinib for treating advanced
RCC patients.
In 2007, Motzer et al.[14] published the results of
phase-III clinical trials for sunitinib medication. A total
of 750 cases were shown to be clear-cell carcinoma.
Systematic treatment had not been conducted previously
in all the patients, who were randomized into a sunitinib
group (recommended medication) and a IFN-α group (9
× 106 U hypo, 3 per week, 1 cycle every 6 weeks). The
ORRs were respectively 31% and 6% (P = 0.000001),
and the mPFSs were 11 and 5 months (P = 0.00001).
The toxic reactions in the phase-III clinical trial was
similar to the results in the phase-II trial, the incidence
rate of Grade-III and IV fatigue was significantly increased in the sunitinib group compared to the IFN-α
group, and the incidence of diarrhea was also high. The
curative effect of sunitinib in treating metastatic RCC
was obviously superior to that of IFN-α therapy, indicating that sunitinib might be a favorable choice for treatment of advanced RCC patients.
In another multi-center phase-II clinical trial[15], the
therapeutic efficacy of sunitinib in treating the patients,
who failed to benefit from a treatment with bevacizumab
as the cardinal remedy, was assessed. The recommended
dosage of sunitinib was used in 61 patients who had undergone and failed bevacizumab treatment. In this trial
the ORR was 16%, SD occurred in 61% of the patients
and there was tumor reduction in 56%. Grade-III toxic
reactions mainly included fatigue, hypertension, dermatitis, hand-foot-mouth syndrome and diarrhea, with the
incidence of 31%, 15%, 5% and 5%, respectively. The
trials indicated that sunitinib can inhibit the signaling
pathway in cases when there is bevacizumab resistance.
Sorafenib
Sorafenib is a stretch serine threonine protein kinase
(Raf) and tyrosine kinase inhibitor. It was shown, by
a xenogeneic graft modeling of a human tumor, that
sorafenib can depress the expression of the Ras gene[16],
which can activate the RAF-MEK-ERK pathway and
promote cell proliferation. It has been demonstrated that
sorafenib can directly inhibit the VEGFR-2, VEGFR-3
and PDGFR-β[17]. In December 2005, sorafenib was approved by the U.S. FDA to be used in treating advanced
RCC patients.
In phase-II clinical trials[18], 202 advanced RCC patients were enrolled. All received sorafenib treatment
(400 mg, peroral, b.i.d). A double-blind randomized test
was conducted in patients with SD following a 12-week
treatment, and then another 12-week sorafenib or placebo treatment was conducted. Sorafenib medication was
continued with 73 patients achieving tumor size reduction of over 25%. The drug treatment was ceased in 64
patients who showed tumor enlargement of ≥ 25%. The
other 65 SD patients were randomized into a sorafenib
(32) or placebo group (33). At the 24th week of drug
Chin J Clin Oncol (2008) 5: 294~298
treatment, the progression-free survival (PFS) occurred
in 50% of the patients receiving sorafenib treatment,
a significant increase compared to the control group
(18%, P = 0.0077). The mPFS was respectively 24 and 6
weeks in the 2 groups (P = 0.0087), with an mPFS of 29
weeks in all patients. The main toxic reactions included
skin rash or desquamation, hand-foot cutaneous reaction
and fatigue. The drug had to be withdrawn in 9% of the
patients because of toxic reactions.
The results of successive phase-III sorafenib clinical trials were serially reported at the ASCO Meetings
from 2005 to 2007. The findings were mainly in relation
to patients with refractory RCC after immunotherapy
[19-21]
. PR was achieved in 7 of the total patients (2%)
during the trial. SD was seen in a 78% of the patients
from the sorafenib-treated group, and only 55% from
the control group. In the group receiving sorafenib, tumor reduction to various degrees occurred in a 74% of
the patients. The mPFS was 24 weeks in the sorafenibtreated group, while in the control group it was 12
weeks (P = 0.0000001), with an improvement of the
survival rate in 39% of the patients. The mPFS was significantly increased in the sorafenib-treated group. Then
the initial plan of the test was changed, so the patients
of the control group were diverted to a drug-treatment
group to receive sorafenib administration. A total of
216 patients from the control group later were diverted
to the sorafenib group. Six months after conducting the
inversion program, the median overall survival (mOS)
was 19.3 months in the sorafenib-treated group, and
14.3 months in the control group (P = 0.015), with an
improvement of the survival rate in 30% of the treated
patients. Based on the end-results of the trial reported at
the 2007 ASCO Meeting, there were 561 deaths up to
September 2006. The mOS was respectively 17.8 and
15.2 months in the 2 groups, with no statistical difference between the 2 groups (P = 0.116). Improvement
of the survival rate was achieved in 13.5% of the cases.
The toxic reactions mainly included Grade-I and II hypertension, fatigue, and the symptoms related to the GI
tract, skin and nervous system. The test suggested that
the sorafenib treatment failed to significantly improve
the mOS, but the therapeutic efficacy of the sorafenib
treatment was obvious in the 1st and the 2nd phases of
the tests.
The curative effect of sorafenib combined with IFN-α
on new RCC cases, without any previous treatment, was
assessed in 2 tests in which all 31 patients were given
400 mg sorafenib peroral, b.i.d., and IFN-α, 100,000 U
hypo, t.i.d.[22] Twenty-four of the cases were worthy of
appraisement. The ORR was 42% (38% PR, 4% CR),
with a SD of at least 8 weeks in 46% of the patients,
among which a 20% reduction of tumor size occurred
in 8% of these patients. The toxic reactions mainly included Grade-I and II fatigue (78%), anorexia (74%),
skin rash (70%, 11% Grade III), diarrhea 67%), nausea
(56%), neutropenia (48%, 19% Grade III), alopecia
297
(44%) and stomatitis or oral mucositis (26%). Based
on the report of another trial [23], 62 metastatic RCC patients, without any previous treatment, were treated with
the above-mentioned medication. The ORR was 19%,
SD 31%, mPFS 7 months, and toxic reactions were
basically similar in the patients. The results of the trial
showed that the curative effect of sorafenib combined
with IFN-α in treating RCC patients is superior to either
sorafenib or IFN-α monotherapy, and that the toxic reactions are tolerable.
Discussion
A further understanding of the molecular pathogenesis
of RCC, and development and application of drugs designed for targeted molecular therapy, both have greatly
influenced previous concepts and modes of RCC therapeutics. Although the mTTP and mOS have not been remarkably improved from the tests, it is encouraging that
tumor reduction occurred in a 70% to 75% of the patients in the trials, and that the ORR reached 2% to 40%
of the cases. The therapeutic efficacies of bevacizumab,
sunitinib and sorafenib are equivalent, so it is difficult to
say which drug produced the best efficacy in these clinical trials. The availability of several drugs with equal
curative effects raises questions, as to the drug choice,
risk-benefit ratio of a drug combination versus monotherapy, drug tolerance and the sequence of drug administration. These questions need to be answered from
further clinical trials.
The growth of tumor cells is the result of a common
effect on multiple pathways. All patients can not benefit from targeted molecular therapy that solely inhibits
VEGF and the related pathways. So a variety of drugs
are needed to concurrently inhibit the pathways in relation to the pathogenesis of RCC. Multiple clinical trials
to address this concept are under way, which hopefully
will explain the theoretical prospect of multi-target therapy for RCC patients.
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