Highlights from ASCO and ECCO 2007: Update

Transcription

Cancer Therapy Vol 6, page 425
Cancer Therapy Vol 6, 425-438, 2008
Highlights from ASCO and ECCO 2007: Update on
targeted treatment of metastatic renal cell
carcinoma
Review Article
Robert J. Motzer
Memorial Sloan-Kettering Cancer Center, New York, NY
__________________________________________________________________________________
*Correspondence: Robert J Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA;
Tel.: 646 422 4312; Fax: 212 988 0806; E-mail: [email protected]
Key words: Metastatic renal cell carcinoma, Receptor tyrosine kinase inhibitors, Targeted therapy, Combination therapy, First-line
treatment, Second-line treatment, Cytokine-refractory, Sunitinib, Sorafenib, Temsirolimus, Bevacizumab, Novel agents, Interferon-alfa,
Tumor response, Overall survival, Prognostic factors, Quality of life, Cost-efficacy
Abbreviations: Advanced Renal Cell Carcinoma Sorafenib Expanded Access Program-North America, (ARCCS); Adverse event, (AE);
American Society of Clinical Oncology, (ASCO); confidence interval, (CI); continuous daily dosing, (CDD); dose-limiting toxicity,
(DLT); Eastern Cooperative Oncology Group, (ECOG); epidermal growth factor receptor, (EGFR); European Cancer Conference,
(ECCO); Functional Assessment of Cancer Therapy - Biological Response Modifiers, (FACT-BRM); glial cell line-derived neurotrophic
factor receptor, (RET); hazard ratio, (HR); imatinib mesylate, (IM); interferon-alfa, (IFN-!); intravenously, (IV); loss of function,
(LOF); mammalian target of rapamycin, (mTOR); Memorial Sloan-Kettering Cancer Center, (MSKCC); metastatic renal cell carcinoma,
(mRCC); million units, (MU); objective response rate, (ORR); orally, (PO); overall survival, (OS); partial response, (PR); performance
status, (PS); platelet-derived growth factor, (PDGF); platelet-derived growth factor receptor, (PDGFR); progression-free survival, (PFS);
progressive disease, (PD); quality-adjusted life-year, (QALY); quality of life, (QoL); receptor tyrosine kinase, (RTK); renal cell
carcinoma, (RCC); selective endothelin-A receptor antagonist, (SERA); stable disease, (SD); stem-cell factor receptor, (KIT); time to
tumor progression, (TTP); time without symptoms and toxicity, (TWiST); twice daily, (BID); vascular endothelial growth factor,
(VEGF); vascular endothelial growth factor receptor, (VEGFR); Von Hippel-Lindau, (VHL)
Received: 10 June 2008; Revised: 20 July 2008
Accepted: 21 July 2008; electronically published: July 2008
Summary
Metastatic renal cell carcinoma (mRCC) is highly resistant to conventional forms of treatment and is associated
with a poor prognosis in most patients; only approximately 10% of patients with metastatic disease remain alive 5
years after diagnosis. However, recent years have witnessed the successful development of a number of targeted
agents and combination therapies that have shown efficacy and tolerability in the treatment of mRCC in first-line
and second-line settings, including sunitinib, sorafenib, temsirolimus, and bevacizumab plus interferon-alfa. This
report reviews current reference standards for the first- and second-line treatment of mRCC, and discusses efficacy
and safety data for the targeted agents in this setting based on presentations given at the 2007 American Society of
Clinical Oncology and European Cancer Conference meetings. Clinical trial data presented at the meetings
concerning novel targeted agents, including everolimus, axitinib, and volociximab, are also reviewed, and new
combination therapies, sequential treatments, and dosing schedules with targeted agents are discussed. As targeted
therapies are beginning to improve prognoses in patients with mRCC, and quality of life (QoL) is becoming an
increasing focus, so the importance of prognostic and predictive factors for treatment response and survival is
gaining increasing recognition. Recent trial evidence concerning prognostic and predictive factors that may assist in
tailoring treatments and optimizing patient management are reviewed. Finally, key data presented at the meetings
concerning the cost-efficacy of targeted agents and their effects on QoL in mRCC patients are evaluated.
al, 2006). RCC is estimated to account for about 2% of all
cancers worldwide, with the highest rates observed in
North America, Australia, and Europe (Parkin et al, 2005).
Until recently, patients with metastatic RCC (mRCC) had
I. Introduction
In the USA, approximately 51,000 new cases of renal
cell carcinoma (RCC) and approximately 12,900 deaths
from this malignancy were expected in 2007 (Schöffski et
425
Motzer: Highlights from ASCO and ECCO 2007: Update on targeted treatment of metastatic renal cell carcinoma
extremely poor prognoses, as advanced disease is highly
resistant to conventional forms of chemotherapy,
radiotherapy, and hormonal therapy (Lilleby and Fosså,
2005; Rohrmann et al, 2005). As a result, the 5-year
survival rate for patients with metastatic disease is
approximately 10% (Godley and Taylor, 2001; Ravaud,
2007).
Within the last 3 years, advances in our
understanding of mRCC have resulted in the successful
development of a number of novel targeted anticancer
agents that have shown efficacy and tolerability in the
clinical setting. This has resulted in a move away from
conventional cytokine-based therapies, which are
associated with low response rates and high risks of
toxicity (Négrier et al, 1998; Yang et al, 2003a;
McDermott et al, 2005; Schöffski et al, 2006). Several
targeted agents are currently indicated for the treatment of
advanced RCC, including sunitinib malate (SUTENT®;
Pfizer Inc., New York, NY, USA), sorafenib (Nexavar®;
Bayer Healthcare AG, Leverkusen, Germany), and
temsirolimus (Torisel™; Wyeth Pharmaceuticals Inc.,
Philadelphia, PA, USA). Sunitinib is an oral multitargeted
inhibitor of several receptor tyrosine kinases (RTKs),
including vascular endothelial growth factor receptors
(VEGFR-1, -2, and -3), platelet-derived growth factor
receptors (PDGFR-! and -"), stem-cell factor receptor
(KIT), FMS-like tyrosine kinase 3, colony-stimulating
factor 1 receptor, and glial cell line-derived neurotrophic
factor receptor (RET) (Abrams et al, 2003; Mendel et al,
2003; Murray et al, 2003; O’Farrell et al, 2003; Kim et al,
2006). RTKs play a key role in tumor growth and
angiogenesis (Krause and Van Etten, 2005), and VEGF
and PDGF are viable targets in the RCC setting. Sunitinib
is approved multinationally for the treatment of advanced
RCC and imatinib-resistant/-intolerant gastrointestinal
stromal tumors (SUTENT® Prescribing Information,
2007). Sorafenib, also a multikinase inhibitor, targets a
range of RTKs (VEGFR-1, -2, and -3, PDGFR-", c-KIT,
and RET) and downstream Raf kinase isoforms (Raf1, BRaf, and mutant b-raf V600E) in tumor cells and the tumor
vasculature (Wilhelm et al, 2006; Nexavar® Prescribing
Information, 2007). Sorafenib is indicated for the
treatment of patients with advanced RCC who are
unsuitable for interferon-alfa (IFN-!) or interleukin-2
therapy or in whom such treatment has failed, and for the
treatment of patients with hepatocellular carcinoma
(Nexavar® Summary of Product Characteristics, 2007).
Temsirolimus is an inhibitor of mammalian target of
rapamycin (mTOR) that reduces levels of hypoxiainducible factor-1 and -2! and VEGF, and arrests tumor
cell growth; temsirolimus is indicated for the treatment of
advanced RCC (Torisel™ Prescribing Information, 2007).
This report discusses the use of targeted agents for
the treatment of mRCC, including sunitinib, temsirolimus,
sorafenib, and the anti-VEGF monoclonal antibody,
bevacizumab (Avastin®; F. Hoffmann-La Roche Ltd,
Basel, Switzerland). The data are based on presentations
given at the American Society of Clinical Oncology
(ASCO) 43rd annual meeting (1-5 June 2007; Chicago,
Illinois, USA), and include updates from the 14th European
Cancer Conference (ECCO; 23-27 September 2007;
Barcelona, Spain). The report reviews current reference
standards for the first- and second-line treatment of
mRCC, and summarizes clinical trial data concerning
novel targeted agents, new combination therapies and
dosing schedules with targeted agents, and prognostic and
predictive factors for treatment response and survival with
RTK inhibitors. Through this report, I aim to translate
findings from recent trials into the clinical practice setting.
II. First-line treatment of mRCC
Current international treatment guidelines (Ljungberg
et al, 2007; National Comprehensive Cancer Network,
2008) recommend angiogenesis inhibitors, including
sunitinib, bevacizumab plus IFN-!, temsirolimus (in poorrisk patients), and sorafenib (in selected patient
populations), as first-line treatments for mRCC. Efficacy
and safety data for a number of targeted agents, including
sunitinib, temsirolimus, sorafenib, and bevacizumab, in
the first-line setting in mRCC were presented at the ASCO
and ECCO 2007 meetings.
A. Sunitinib
Sunitinib is indicated for the first-line treatment of
clear-cell mRCC, when administered as an oral dose of 50
mg/day for 4 weeks, followed by a 2-week rest period in a
6-week cycle (Schedule 4/2); this agent continues to be the
standard of care in the first-line setting (Motzer et al,
2007a). Updated data from the phase III clinical trial
support the significant efficacy advantage of sunitinib over
IFN-! in patients with mRCC, regardless of their
prognostic risk, according to Memorial Sloan-Kettering
Cancer Center (MSKCC) risk status (Motzer et al,
2007b,c). Independent assessment showed an objective
response in 39% of sunitinib-treated patients (n=365)
compared with 8% of patients treated with IFN-! (n=346)
and a median progression-free survival (PFS) of 11.0
months (95% confidence interval [CI], 10.7-13.4) with
sunitinib versus 5.1 months (95% CI, 3.9-5.6) with IFN-!
(Motzer et al, 2007c). When assessed by MSKCC risk
group, median PFS was longer in each prognostic group
treated with sunitinib compared with IFN-! therapy
(Motzer et al, 2007b,c).
Sunitinib 37.5 mg in combination with IFN-! 3
million units (MU) may have clinical utility as a first-line
combination therapy for patients with mRCC, as shown in
a recent phase I dose-finding study (Kondagunta et al,
2007a,b). Three patients showed partial responses (PR) in
this study, resulting in an objective response rate (ORR) of
12% (95% CI: 2.5-31.2) in 25 evaluable patients; median
time to tumor progression (TTP) was 11.9 months (95%
CI: 5.5-12.3). Dose-limiting toxicities (DLTs) with this
combination treatment included myelosuppression and
fatigue. The investigators concluded that sunitinib 37.5 mg
in combination with IFN-! 3 MU is tolerable in this
patient population, while higher dose combinations
(sunitinib 50 mg/IFN-! 9 MU, sunitinib 50 mg/ IFN-! 6
MU, and sunitinib 37.5 mg/ IFN-! 6 MU) were poorly
tolerated (Kondagunta et al, 2007b).
426
insufficient number of patients with intermediate
prognostic risk was enrolled to enable any meaningful
assessment of this subgroup (Dutcher et al, 2007). These
data suggest that, in line with international treatment
guidelines, temsirolimus may be an effective treatment for
poor-risk RCC patients who exhibit three or more
predictors of short survival (Figure 1).
B. Temsirolimus
Phase III clinical trial data in patients with mRCC
receiving temsirolimus, the latest agent indicated for the
treatment of advanced RCC, were released immediately
prior to the ASCO 2007 meeting and updated at ECCO
2007 (De Souza et al, 2007; Hudes et al, 2007). In patients
with untreated, advanced RCC and poor prognoses
(defined as exhibiting #3 of 6 modified MSKCC risk
criteria predictive of short survival), weekly single-agent
intravenous temsirolimus 25 mg significantly improved
overall survival (OS; 10.9 versus 7.3 months; hazard ratio
[HR], 0.78; 95% CI, 0.63-0.97; p=0.0252) and PFS (3.8
versus 1.9 months; HR, 0.74; 95% CI, 0.60-0.90; p=0.003)
compared with IFN-! monotherapy. However, OS in the
temsirolimus/IFN-! combination arm of the trial did not
differ significantly from that in the IFN-! monotherapy
group (8.4 versus 7.3 months; HR, 0.93; 95% CI, 0.751.15; p=0.4902). Further supporting the benefits of
temsirolimus in poor-risk mRCC, fewer patients receiving
single-agent temsirolimus reported severe (grade 3-4)
adverse events (AEs) compared with IFN-! monotherapy
(69% versus 79%; p=0.024) (De Souza et al, 2007). Based
on the data published by Hudes and colleagues in 2007,
the US Food and Drug Administration approved
temsirolimus for the treatment of advanced RCC.
Further analyses of data from this trial showed that
temsirolimus was superior to IFN-!, regardless of tumor
histology, with improved OS and PFS in both clear-cell
and non-clear-cell RCC with temsirolimus versus IFN-!
(clear-cell RCC: OS, 10.6 versus 8.2 months; PFS, 5.5
versus 3.8 months; other RCC subtypes: OS, 11.6 versus
4.3 months; PFS, 7.0 versus 1.8 months) (Dutcher et al,
2007). The data also revealed improvements in OS and
PFS with temsirolimus versus IFN-! therapy regardless of
age (<65 versus #65 years), and showed no apparent agerelated differences in terms of reported AEs. In the trial,
temsirolimus was shown to be superior to IFN-! in
patients with poor prognostic features (OS, 10.2 versus 6.0
months; median PFS, 5.1 versus 2.3 months). However, an
C. Sorafenib
Data from a phase II trial of first-line sorafenib in
189 patients with advanced RCC found no significant
improvement in the primary endpoint of PFS compared
with the active comparator IFN-! (5.7 versus 5.6 months,
respectively, p=0.504), suggesting that sorafenib may be
of limited benefit as a first-line treatment for advanced
RCC (Szczylik et al, 2007). The ORR, determined by
independent assessment, was 5% with sorafenib 400 mg
twice daily (BID) versus 9% with IFN-!. Of interest,
however, was the finding that tumor regression occurred in
68% of patients receiving sorafenib 400 mg orally (PO)
BID compared with 39% of patients receiving IFN-!, and
sorafenib was associated with a longer time to health
status deterioration than IFN-!, as determined using the
Functional Assessment of Cancer Therapy - Biological
Response Modifiers scale (HR, 0.50; 95% CI, 1.43-2.85;
p=0.0001) (Figure 2) (Szczylik et al, 2007).
The effects of sorafenib dose-escalation and
switching from IFN-! to sorafenib were also assessed in
patients with disease progression in this trial. No objective
responses were noted in 44 patients who were doseescalated from sorafenib 400 mg BID to 600 mg BID, but
there was an additional PFS benefit of 4.1 months
following escalation from the 400 mg to the 600 mg dose,
and the higher dose was well tolerated. Among the 41
patients who switched from IFN-! to sorafenib therapy,
22% demonstrated objective responses by independent
assessment, with a median PFS of 5.7 months (Szczylik et
al, 2007).
Figure 1. Hazard ratios for overall survival by patient subgroup in patients with metastatic renal cell carcinoma receiving temsirolimus
or interferon-alpha. Reproduced from Dutcher et al, 2007 with kind permission from Journal of Clinical Oncology.
427
Figure 2. Time to health status deterioration in patients with metastatic renal cell carcinoma treated with sorafenib versus interferon-alfa
(IFN-!), as determined using the Functional Assessment of Cancer Therapy - Biological Response Modifiers (FACT-BRM) scale.
Reproduced from Szczylik et al, 2007 with kind permission from Journal of Clinical Oncology.
with favorable (11.1 versus 5.7 months, respectively;
p=0.0012) and intermediate (8.4 versus 5.3 months,
respectively; p=0.0017) MSKCC risk status, while nonsignificant improvements were observed in the poor-risk
subgroup (3.3 versus 2.6 months, respectively; p=0.25).
ORR was 25.5% with combination therapy versus 13.1%
with IFN-! monotherapy (p<0.0001). The most common
serious AEs in both arms of the trial were fatigue (37%
versus 30%) and anorexia (17% versus 8%), with
combination or single-agent therapy, respectively.
Findings from the large AVOREN and CALBG
90206 trials indicate that bevacizumab, in combination
with IFN-!, is associated with a statistically significant
improvement in PFS and tumor response when
administered in the first-line setting. In a smaller
randomized phase II trial, the addition of erlotinib to
bevacizumab was well tolerated but did not provide
additional clinical benefit compared with bevacizumab
alone (Bukowski et al, 2007a). However, data from the
trial support the clinical benefit of bevacizumab in patients
with previously untreated mRCC.
D. Bevacizumab
Randomized clinical trials have reported beneficial
effects with bevacizumab in patients with advanced RCC
(Yang et al, 2003b; Bracarda et al, 2007; Bukowski et al,
2007a; Escudier et al, 2007a; Melichar et al, 2007; Rini et
al, 2008). Data on the efficacy and safety of bevacizumab
(10 mg/kg intravenously [IV] every 2 weeks) in
combination with IFN-! versus IFN-! alone in the firstline setting were reported in the randomized, controlled,
multicenter, phase III AVOREN trial in 649 patients with
advanced RCC (Bracarda et al, 2007; Escudier et al,
2007a; Melichar et al, 2007). Bevacizumab plus IFN-!
significantly increased PFS compared with IFN-! plus
placebo, as determined by investigator assessment (10.2
versus 5.4 months; HR, 0.63, p<0.0001) (Escudier et al,
2007a). PFS benefits with bevacizumab plus IFN-! were
achieved regardless of baseline prognostic factors
(Bracarda et al, 2007) or IFN-! dose reductions (Melichar
et al, 2007). Furthermore, ORR was significantly higher in
the bevacizumab/IFN-! group than in the IFN-! plus
placebo group (31% versus 13%; p<0.0001); however, OS
could not be determined due to a lack of mature data. The
most common serious (grade 3-4) AEs associated with
bevacizumab/IFN-! versus IFN-! plus placebo were
fatigue and hypertension (23% versus 15%, and 3.9%
versus 0.7%, respectively). Hemorrhage was reported in
11 patients (3.3%) receiving bevacizumab plus IFN-!
versus 1 patient (0.3%) receiving IFN-! plus placebo.
More recently, interim data from the similar CALBG
90206 study were reported at the ASCO 2008
Genitourinary Cancers Symposium. In this study, patients
with clear-cell mRCC were randomized to receive firstline bevacizumab and IFN-! (n=369) or IFN-! alone
(n=363) at the same doses as in the AVOREN trial (Rini et
al, 2008). Overall, patients achieved a median PFS of 8.5
months (95% CI, 7.5-9.7) with bevacizumab plus IFN-!
versus 5.2 months (95% CI, 3.1-5.6) with IFN-! alone
(HR, 0.71; 95% CI, 0.61-0.83; p<0.0001). Compared with
monotherapy, significant improvements in PFS were also
achieved with combination therapy in patient subgroups
E. Atrasentan
A phase II trial of the selective endothelin-A receptor
antagonist (SERA), atrasentan (Xinlay™; Abbott
Laboratories, IL, USA), has recently been completed in
patients with mRCC (Manola et al, 2007). Atrasentan
inhibits the activity of endothelin-1, a protein implicated in
stimulating the spread of cancer cells. The phase II trial
showed that atrasentan (10 mg/day PO) was well tolerated
but findings from the trial did not support its use as a firstline monotherapy in patients with mRCC (Manola et al,
2007). The data revealed a median PFS with atrasentan of
2.3 months (95% CI, 2.0-3.5 months), and a percentage of
patients remaining progression-free at 6 months, stratified
according to disease status and prior immunotherapy, of
between 0% and 17%.
428
use of this agent in the second-line setting (Gore et al,
2007a,b). In the program, antitumor activity with sunitinib
was reported across a diverse patient population, and
safety and tolerability outcomes were similar to those
observed in previous clinical trials with sunitinib (Motzer
et al, 2006a,b). In 3997 evaluable patients, the ORR was
11.4%, with a further 44.6% of patients exhibiting stable
disease (SD) at #3 months. Sunitinib was associated with
acceptable tolerability in specific patient subgroups,
including patients with poor performance status (PS #2),
older patients (aged >65 years), and patients with brain
metastases (Gore et al, 2007b).
Sunitinib also demonstrated substantial antitumor
activity in 61 bevacizumab-refractory patients in a phase
II, single-arm, open-label study (George et al, 2007a;
Hutson et al, 2007). Partial responses (PRs) were observed
in 23% of patients (n=14) and SD in 59% of patients
(n=36), with a median PFS of 30.4 weeks (95% CI, 18.336.7). The positive findings from this study in patients
who had received previous treatment with bevacizumab
indicate an absence of cross-resistance between these two
agents that target the VEGF pathway (George et al, 2007a;
Hutson et al, 2007). This suggests that the therapeutic
activity of sunitinib in RCC may be mediated via multiple
pathways, and sunitinib may even inhibit signaling
pathways involved in bevacizumab resistance.
III. Recent advances in second-line
treatment of RCC
National and international treatment guidelines
support several targeted agents that have been associated
with improved patient outcomes compared with historical
therapies as second-line treatments in mRCC (Ljungberg
et al, 2007; National Comprehensive Cancer Network,
2008). Currently recommended targeted therapies include
sorafenib, sunitinib, temsirolimus, and bevacizumab in
patients with cytokine-refractory mRCC. Data presented at
the 2007 ASCO and ECCO congresses concerning the use
of targeted agents in the second-line treatment of mRCC
are discussed below.
A. Sunitinib
Clinical benefit with sunitinib in the second-line
setting was confirmed in an updated, pooled efficacy
analysis of two phase II trials that reported substantial
antitumor activity in patients with cytokine-refractory
mRCC (Rosenberg et al, 2007). In 168 evaluable patients,
investigator-assessed ORR was 45% (95% CI, 39-54) and
PFS was 8.4 months (95% CI, 7.9-10.7). Median OS was
19.9 months for the pooled population, which compared
favorably with historical experience of other agents in the
second-line setting, in which median OS of 12.7 months
was reported (Motzer et al, 2004). Prognostic factors for
survival were similar to those previously identified in
association with cytokine therapy, including performance
status, time from diagnosis to treatment, and serum
hemoglobin level (Table 1) (Motzer et al, 2004;
Rosenberg et al, 2007). Updated data from the larger of
these two trials in 105 evaluable patients, showed an ORR
of 33% (95% CI, 24-43%) with a median duration of
response of 14.0 months. Median TTP and PFS were 10.7
and 8.8 months, respectively, and median survival was
23.9 months; 43 patients remained alive at a median
follow-up of 29.7 months (Motzer et al, 2007d).
Efficacy and safety data from an international
expanded access program of sunitinib in mRCC were
presented at both the 2007 ASCO and ECCO meetings;
these data provide a practical clinical perspective on the
B. Sorafenib
Final data from the phase III TARGET trial (Target
Approaches in Renal Cancer Global Evaluation Trial) of
second-line sorafenib versus placebo with best supportive
care in advanced RCC showed no statistically significant
difference in OS between sorafenib and placebo (median
OS, 17.8 versus 15.2 months; HR, 0.88; p=0.146)
(Escudier et al, 2007b; Bukowski et al 2007b). However,
some clinicians consider that sorafenib may offer
clinically important benefits, and it seems likely that the
crossover of placebo patients to the sorafenib treatment
arm, due to significant improvements in PFS with
sorafenib, may have confounded the final analysis.
Table 1. Pretreatment predictors of overall survival as determined by multivariate analysis from a pooled analysis of 168
patients with metastatic renal cell carcinoma treated with sunitinib as second-line therapy in two single-arm phase II
clinical trials. Reproduced from Rosenberg et al, 2007 with kind permission from Journal of Clinical Oncology.
Variable
Time interval from diagnosis to treatment
#1 year vs <1 year
Hemoglobin*
#13/11.5 g/dL vs <13/11.5 g/dL
Baseline ECOG PS
0 vs 1 or 2
Number of metastatic sites
0 or 1 vs 2 or #3
Hazard ratio
0.384
95% CI
0.255-0.580
P-value
<0.0001
0.427
0.280-0.651
<0.0001
0.552
0.363-0.840
0.0056
0.445
0.218-0.906
0.0257
*Cut point is 13 g/dL for males and 11.5 g/dL for females
CI = confidence interval, ECOG PS = Eastern Cooperative Oncology Group performance status
429
In the open-label ARCCS (Advanced Renal Cell
Carcinoma Sorafenib Expanded Access Program-North
America) trial, sorafenib treatment was evaluated in 2502
patients with advanced RCC who would not otherwise
have been eligible for inclusion in clinical trials (Knox et
al, 2007). Fifty percent (n=1255) of these patients received
sorafenib as a second-line treatment. Of 936/1255 secondline patients, one patient had a PR (3%) and 161 patients
(17%) showed unconfirmed responses. SD was observed
in 759 patients (81%), and clinical benefit was achieved in
84% of patients. Similar results were observed in the 1247
patients in the program who received sorafenib as a firstline treatment. More than 1150 patients have been
recruited into EU-ARCCS, the European arm of this openlabel study, and analyses are ongoing in these patients
(Beck et al, 2007). Despite the positive results achieved in
this program to date, the trial is limited by its non-rigorous
design and short duration of follow-up (~12 weeks).
phase, and targeting VEGF, thus inhibiting angiogenesis
(Jac et al, 2007). In a phase II, single-arm trial,
administration of everolimus at an oral dose of 10 mg/day
by continuous daily dosing (CDD) in a 28-day cycle to 37
evaluable patients with progressive mRCC in the secondline setting resulted in a PR in 12 patients (32.4%) and SD
for >3 months in 19 patients (51.4%). Median OS in the
trial was >11.5 months (range 1->20) (Jac et al, 2007).
Treatment-related AEs included mucositis, skin rash,
pneumonitis, thrombocytopenia, anemia, laboratory
abnormalities, and decreased metabolic activity (Jac et al,
2007). Following positive early results, studies are
ongoing in patients in whom prior sunitinib or sorafenib
therapy failed.
B. Axitinib
Axitinib is a potent small molecule RTK inhibitor of
VEGFRs, PDGFR-", and c-KIT (Rugo et al, 2005) that
has been shown to be active in cytokine-refractory mRCC
(Rini, 2005). Activity of axitinib as a second-line therapy
in patients with mRCC that is refractory to tyrosine kinase
inhibitors, such as sunitinib and sorafenib, is of clinical
interest (Rini et al, 2007a). An open-label, multicenter,
phase II trial was recently undertaken to investigate oral
axitinib administered twice daily at a dose of 5 mg in this
setting (Rini et al, 2007a,b). In 62 evaluable patients who
had received prior treatment with sorafenib or sorafenib
and sunitinib, axitinib therapy was associated with PR in
15% of patients (n=9) and SD in 37% of patients (n=23),
with some level of tumor shrinkage in 51% of patients
(Figure 3). Median PFS was not reached, but preliminary
data indicated an overall median PFS of >7.7 months (Rini
et al, 2007a,b). Based on these data, axitinib appears to
exhibit substantial antitumor activity in patients with
sorafenib-refractory mRCC, and a tolerability profile that
is manageable and characteristic of this class of agents.
IV. Novel targeted agents in the
second-line treatment of RCC
Promising data with several newer targeted agents in
the second-line setting in mRCC were presented at the
2007 ASCO and ECCO meetings, including data from
trials of the mTOR inhibitor, everolimus (RAD001;
Certican, Novartis International AG, Basel, Switzerland),
and the novel agents axitinib (AG-013736; Pfizer Inc.,
New York, NY, USA) and volociximab (M200; Biogen
Idec, Zug, Switzerland; PDL Biopharma Inc., Redwood
City, CA, USA).
A. Everolimus
Like temsirolimus, everolimus is an oral mTOR
inhibitor that is believed to exert anti-tumor activity by
shutting down tumor cell responses to nutrients and
growth factors, arresting the cell cycle in the late G1
Figure 3. Tumor regression, measured as maximum percent reduction in target lesions, in 42 evaluable patients with TKI-refractory
metastatic renal cell carcinoma receiving axitinib monotherapy in the second-line setting. Reproduced from Rini et al, 2007 with kind
permission from Journal of Clinical Oncology.
430
with an overall median PFS of 11.3 months. The most
common grade 3 treatment-related AEs were diarrhea,
which occurred in 14% of patients (n=6), and nausea and
rash, each in 5% of patients (n=2 each); no grade 4
treatment-related AEs were observed (Redman et al,
2007).
Combined inhibition of mTOR and PDGFR may
prevent tumor growth and angiogenesis through vertical
blockade of the PI3K/AKT pathway and its stimulatory
effects on VEGF (Arsham et al, 2004; Chan et al, 2007).
The therapeutic potential of such blockade provided the
rationale for a phase II study of combination therapy with
everolimus (2.5 mg/day PO) and imatinib mesylate (IM;
Glivec®; Novartis, Basel, Switzerland; 600 mg/day PO) in
patients with previously treated advanced RCC (Chan et
al, 2007). Among the 10 patients who were evaluable for
the primary endpoint (PFS), three patients were
progression-free at 3 months. Nine patients were evaluable
for best response by RECIST, among whom SD was the
best response in seven patients and PD occurred in two
patients. The combination of everolimus and IM was
associated with moderate toxicity. Grade 3 AEs included
fatigue, thrombocytopenia, peripheral edema, rash, and
abdominal pain. In addition, two cases of grade 3
pneumonitis and angioedema (n=1 each) were considered
as potential everolimus-related toxicities (Chan et al,
2007).
In a similar phase I-II, single-arm study, PTK/ZK
(PTK787/ZK222584; Novartis, Basel Switzerland;
Schering, Berlin, Germany; 1000 or 1250 mg/day PO), a
novel orally active multitargeted kinase inhibitor against
VEGFR and PDGFR, was evaluated in combination with
everolimus (5 or 10 mg/day PO) in 27 patients with
advanced solid tumors who may have received prior
VEGF inhibitor therapy (Speca et al, 2007). Preliminary
data from 13 mRCC patients who were evaluable for
response showed PR in two patients (15%) and SD for >3
months in eight patients (62%); median TTP in these
patients was 6 months. DLTs included grade 3 asthenia
and mucositis, and grade 4 hypertension (Speca et al,
2007). The investigators concluded that the combination
of PTK/ZK 1,000 mg plus everolimus 5 mg was well
tolerated and was associated with clinical activity in
patients with advanced RCC, despite prior treatment with
VEGF pathway inhibitors in some cases (Speca et al,
2007).
C. Volociximab
Volociximab is a chimeric monoclonal antibody that
blocks the binding of fibronectin in the extracellular
matrix to integrin a5"1, and thus induces apoptosis in
proliferating endothelial cells (Yazji et al, 2007). The
efficacy and safety of volociximab was assessed in a
multicenter, open-label, phase II study in 40 evaluable
patients with refractory or relapsed clear-cell mRCC.
Patients received intravenous volociximab at a dose of 10
mg/kg every 2 weeks until disease progression. PR was
confirmed in one patient, with SD in 32 patients (80%).
Median TTP was 4 months, and median OS had not been
reached at 22 months, with 68% of patients remaining
alive at 22 months (Yazji et al, 2007). Most frequently
reported side effects included grade 1-2 fatigue, nausea,
dyspnea, and arthralgia. The investigators concluded that
volociximab was well tolerated and was associated with
anti-tumor effects in a large percentage of patients. Further
studies of this novel agent are planned.
V. Combination therapy with targeted
agents in RCC
Combination therapy with targeted agents is a logical
next step in optimizing the treatment of patients with
mRCC. Combinations of targeted agents may offer more
complete inhibition of a single pathway (vertical blockade)
or may inhibit several pathways to mediate a range of
therapeutic effects (horizontal blockade); however, this
type of treatment has raised concerns regarding increased
risks of toxicities compared with single-agent treatments.
Data from several phase I/II trials of combination therapies
with targeted agents were presented at the 2007 ASCO and
ECCO meetings (Chan et al, 2007; Feldman et al, 2007;
Merchan et al, 2007; Patel et al, 2007; Patnaik et al, 2007;
Redman et al, 2007; Speca et al, 2007).
Temsirolimus in combination with bevacizumab was
evaluated in a phase I study in 12 patients with stage 4
mRCC, in which patients could receive full doses of each
agent in monthly cycles (temsirolimus 25 mg/week IV;
bevacizumab 10 mg/kg once every 2 weeks) (Merchan et
al, 2007). This combination demonstrated clinical activity,
including PR in 7 patients, without enhanced toxicity
(Merchan et al, 2007). In contrast, however, data from a
similar phase I study of temsirolimus (15 or 25 mg/week
IV) in combination with sorafenib (200 or 400 mg BID) in
patients with advanced solid tumors revealed significant
mucocutaneous toxicity when full doses of sorafenib were
given. PR was observed in 2/24 patients and prolonged SD
was noted in one patient. Evaluations of this combination
at revised dose levels are ongoing (Patnaik et al, 2007).
The combination of oral sunitinib (37.5 or 50 mg/day
on Schedule 4/2) and gefitinib (Iressa; AstraZeneca,
London, UK; 250 mg/day), an orally active selective
epidermal growth factor receptor (EGFR) inhibitor, was
assessed in a phase I/II trial based on preclinical data,
which suggested that simultaneous inhibition of VEGFR
and EGFR may act synergistically to inhibit tumor growth
(Patel et al, 2007; Redman et al, 2007). Among 42 patients
with mRCC who were evaluable for a response, PR was
noted in 17 patients (40%) and SD in 19 patients (45%),
VI. Sequential treatment of targeted
agents in RCC
Until recently, few data have been available on the
use of sequential targeted therapies in patients with mRCC
in whom antiangiogenic treatments have failed. The 2007
ASCO and ECCO meetings highlighted several studies
that have begun to address this important clinical question.
Anecdotal reports have suggested that patients
respond to sunitinib treatment following sorafenib failure
and vice versa (Dham and Dudek, 2007; Sablin et al,
2007). A study presented at ASCO 2007 evaluated the
efficacy of sequential therapy with sorafenib or sunitinib
in 37 patients who had switched treatment due to disease
progression (n=32) or unacceptable toxicity (n=5)
431
following first-line sunitinib or sorafenib (Dham and
Dudek, 2007). The study showed that disease control was
achieved with both sequential treatments; however,
median duration of SD was longer in patients who
received sorafenib followed by sunitinib rather than vice
versa (sorafenib followed by sunitinib, 32 weeks [range 637]; sunitinib followed by sorafenib, 8 weeks [range 410]) (Dham and Dudek, 2007).
A retrospective analysis in France assessed
sequential therapy in 90 patients who received sorafenib
followed by sunitinib (n=68) or sunitinib followed by
sorafenib (n=22) over a 3-year period in clinical studies or
extended-access programs (Sablin et al, 2007). Overall,
PR rates were 17.6% for sorafenib followed by sunitinib
and 22.7% for sunitinib followed by sorafenib. PD
occurred in only six patients receiving both drugs, all of
whom were of intermediate or poor risk, with 3 or more
metastatic sites. These data support the sequential use of
sorafenib and sunitinib and suggest no cross-resistance
between the two therapies (Sablin et al, 2007).
A subsequent study, presented at ECCO 2007,
assessed the comparative toxicity of sunitinib and
sorafenib by self-reported questionnaire in patients who
received the two treatments sequentially, 17 patients
receiving sorafenib first and 10 patients receiving sunitinib
first (Plantade et al, 2007). Patients reported fatigue as a
more important side-effect of sunitinib than sorafenib,
irrespective of the order of administration. Stomatitis was
more common with sunitinib, regardless of treatment
sequence, while diarrhea and hand-foot syndrome were
more common with sorafenib. Anorexia occurred with
similar frequency with both drugs, and patients reported
similar effects on quality of life (QoL) with both agents.
Overall, treatment with sunitinib was more acceptable to
patients than sorafenib therapy (Plantade et al, 2007).
Data from studies such as these highlight the
potential of sequential targeted therapies, indicating that
responses to treatment can be achieved in mRCC patients
who receive targeted agents following the failure of an
initial RTK inhibitor. Findings from the studies suggest
that improved responses are achieved in patients who
receive sunitinib following sorafenib failure, and that
sunitinib is more acceptable to patients (Dham and Dudek,
2007; Plantade et al, 2007; Sablin et al, 2007).
the use of alternate doses and schedules with sunitinib and
sorafenib in mRCC.
Following favorable phase III trials with second-line
sorafenib (400 mg BID) showing efficacy in mRCC
patients, a single-arm, phase II, dose-escalation study in 44
evaluable patients with mRCC demonstrated that the
majority of patients were able to tolerate much higher
doses of sorafenib (Amato et al, 2007). Patients underwent
monthly dose-escalation from 400 mg BID to 600 and then
800 mg BID, and received treatment for a median duration
of #6 months. Doses were escalated to 600 mg BID in 41
of 44 patients (93%) and to 800 mg BID in 32 of 44
patients (73%). The investigators reported that treatment
was well tolerated, with AEs including hand-foot
syndrome, skin rash, diarrhea, alopecia, fatigue,
hypertension, hypophosphatemia, and elevated amylase
and lipase levels, as might be expected with this regimen.
ORR was a considerable 55%, with complete response
noted in 16% of patients and PR in 39% of patients; 20%
of patients exhibited SD for #6 months (Amato et al,
2007).
In addition to the wealth of available data regarding
the use of sunitinib 50 mg/day PO administered on
Schedule 4/2, a recent study showed that CDD with
sunitinib 37.5 mg PO had comparable efficacy to
intermittent dosing with sunitinib 50 mg PO in 107
patients with cytokine-refractory mRCC (Srinivas et al,
2007; Escudier et al, 2007c). The study investigated the
efficacy and tolerability of CDD and compared morning
and evening dosing regimens. In total, a PR was confirmed
in 22% of patients, while 48% of patients exhibited SD for
>3 months; median PFS was 8.3 months (95% CI, 6.58.8). The study showed no differences between morning
and evening dosing. The investigators concluded that
administration of sunitinib by CDD is associated with a
manageable tolerability profile and additional flexibility in
terms of dose scheduling (Escudier et al, 2007c). This
dosing regimen may offer a useful alternative to existing
intermittent treatment schedules and may be explored in
future combination studies.
Findings from a pharmacokinetic/pharmacodynamic
analysis of the exposure-response profile of sunitinib in
mRCC, based on data from three phase II trials in 237
patients, supported the benefits of CDD with sunitinib
(Houk et al, 2007a,b). The meta-analysis showed greater
efficacy in patients with the greatest exposure to the drug,
and revealed that increased exposure was associated with a
higher probability of PR, greater OS, and longer TTP.
Higher exposure was also associated with greater changes
in tumor volume. Comparable efficacy was observed when
sunitinib was administered as an oral dose of 37.5 mg by
CDD and when it was given at a dose of 50 mg/day PO on
Schedule 4/2 (Figure 4) (Houk et al, 2007a,b).
VII. Refining existing therapies using
alternate schedules and doses
As our clinical understanding of existing RTKs and
other targeted agents increases, so also does our interest in
optimizing currently available treatment regimens in order
to improve patient outcomes. Several research groups
presented data at the ASCO and ECCO 2007 meetings on
432
Figure 4. Comparison of time to progression and overall survival in patients with metastatic renal cell carcinoma receiving sunitinib at
50 mg/day following a 4/2 Schedule (4 weeks on treatment followed by 2 weeks off treatment in a 6-week cycle; n=188) or at a dose of
37.5 mg/day by continuous daily dosing (CDD) (n=49). Reproduced from Houk et al, 2007 with kind permission from Journal of
Clinical Oncology.
Choueiri et al, 2007); however, variation in treatment
outcomes occurs and the association remains unclear
(Choueiri et al, 2007). To address this issue, Choueiri and
colleagues used polymerase chain reaction analysis to
assess VHL mutational status in 123 mRCC patients who
had received prior treatment with anti-VEGF therapy
(sunitinib, sorafenib, axitinib, or bevacizumab); findings
were correlated with clinical and laboratory features and
treatment outcomes. Loss of function (LOF) mutations
(p=0.03), normal hemoglobin levels (p=0.01), and the
absence of prior radiotherapy (p=0.04) were identified as
independent predictors of response in a multivariate
analysis. The presence of a LOF mutation was associated
with an ORR of 52% versus 31% for those without the
mutation. Of the four treatments, sunitinib was associated
with the greatest ORR in patients with VHL mutations or
promoter hypermethylation, while axitinib conferred the
greatest ORR in patients with wild-type VHL status.
However, PFS and OS were not affected by VHL status.
The researchers concluded that certain types of VHL
mutation - such as LOF mutations, which have been
correlated with poor patient prognosis (Kim et al, 2005) may be associated with greater responses to VEGFtargeted therapies (Choueiri et al, 2007).
VIII. Prognostic and predictive factors
The identification of prognostic or predictive factors
for individual patient outcomes is important in order to
develop tailored treatments that reduce the risk of relapse
and enhance the chance of successful management.
Prognostic and predictive factors for survival were the
focus of a number of publications and presentations at the
2007 ASCO and ECCO meetings.
Motzer and colleagues undertook an analysis of
prognostic risk factors based on data from the phase III
trial of first-line sunitinib versus IFN-! in mRCC (Motzer
et al, 2007a). They observed improvements in PFS with
sunitinib versus IFN-!, irrespective of MSKCC prognostic
risk factor group (favorable, intermediate, or poor),
indicating that sunitinib is an effective treatment for a
range of mRCC patient populations (Motzer et al,
2007b,c). Using a multivariate analysis, the researchers
identified three baseline prognostic factors predictive of
prolonged PFS with sunitinib (Eastern Cooperative
Oncology Group PS 0 versus 1 [p=0.007], time from
diagnosis to treatment #1 year versus <1 year [p<0.001],
and corrected calcium level $10 versus >10 mg/dL
[p=0.0084]). Median PFS was 14.9 months (95% CI, 13.417.4) with sunitinib versus 8.4 months (95% CI, 7.8-11.0)
with IFN-! in patients with favorable risk; 10.7 months
(95% CI, 8.3-11.4) versus 3.8 months (95% CI, 3.7-5.1),
respectively, in patients with intermediate risk; and 3.9
months (95% CI, 2.5-13.5) versus 1.2 months (95% CI,
1.0-5.1), respectively, in patients with poor-risk mRCC
(Motzer et al, 2007c).
Von Hippel-Lindau (VHL) tumor suppressor gene
inactivation through mutation is strongly associated with
clear-cell RCC in a majority of cases (Kaelin, 2002; Rini
and Small, 2005). VHL inactivation is thought to be
associated with a greater objective response to VEGFtargeted therapy (Kaelin, 2002; Rini and Small, 2005;
IX. QoL and cost-effectiveness
As newer targeted therapies in oncology offer
patients longer disease-free periods, there is an increasing
need to understand the effects of these therapies on patient
QoL and management costs.
At both the ASCO and ECCO 2007 meetings, Cella
and colleagues (Cella et al, 2007a,b) examined the
correlation between baseline QoL variables and PFS in the
previously reported phase III trial comparing sunitinib
with IFN-! as first-line therapy in patients with mRCC
(Motzer et al, 2007). The analyses showed that baseline
433
QoL score was predictive of PFS, regardless of treatments
and other demographic and clinical characteristics at
baseline (Cella et al, 2007a). The superior treatment effect
of sunitinib on PFS in comparison with IFN-! remained
when QoL and other baseline variables were controlled
(Cella et al, 2007a). However, treatment advantages with
sunitinib versus IFN-! were greater in European,
Australian, and Canadian patients than in US patients
(Cella et al, 2007b).
In another phase III study, QoL was compared in
poor-prognosis mRCC patients receiving first-line
temsirolimus and IFN-! versus either agent alone
(Parasuraman et al, 2007). The study investigated QoL in
terms of quality-adjusted time without symptoms of
progression or toxicity (TWiST), and found that survival
benefits with temsirolimus were correlated with
improvements in QoL. Patients receiving temsirolimus
alone exhibited 38% greater TWiST than those receiving
IFN-! alone (6.5 versus 4.7 months, p=0.0005,
respectively). However, there was no significant
difference in TWiST values between the combination and
IFN-! monotherapy treatment arms (P=0.1288)
(Parasuraman et al, 2007).
Data from the international phase III trial of first-line
sunitinib in the mRCC setting (Motzer et al, 2007a) have
also been used to evaluate the cost-effectiveness of
sunitinib in comparison with IFN-! in mRCC patients
from a US societal perspective (Rémak et al, 2007;
Négrier et al, 2007). Markov models were used to project
survival and costs over 5- and 10-year time horizons based
on data from the trial. The evaluation showed that the
probability of sunitinib providing a cost-effective
alternative to IFN-! was 45.9% with a threshold of
$50,000 per quality-adjusted life-year (QALY), and 64.9%
with a threshold of $100,000 per QALY. Furthermore,
when compared with multiple therapies, sunitinib was the
optimal treatment above a threshold of $55,000 per
QALY. These data suggest that sunitinib represents a costeffective first-line treatment for mRCC, with costeffectiveness ratios within the established cost thresholds
that society is willing to pay for health benefits (Rémak et
al, 2007; Négrier et al, 2007).
cytokines and/or targeted agents. Sunitinib and sorafenib
have shown efficacy in this setting, while novel agents,
such as axitinib, have yielded positive data in patients with
RTK-refractory disease. As in first-line treatment, solid
clinical evidence supports the efficacy of sunitinib in this
setting, including poor-prognosis patients and those who
would not normally be eligible for enrolment in clinical
trials. Recent studies have demonstrated clinical efficacy
with sunitinib in patients aged over 65 years, patients with
brain metastases, and those with poor PS. Improved
outcomes in a range of patient populations have lead to
investigations of sunitinib, sorafenib, and other targeted
agents using alternative treatment strategies, including
CDD, and as a part of combination and sequential
therapies, in order to optimize treatment efficacy. The
publication of long-term survival data for sunitinib in the
mRCC setting is anticipated at ASCO 2008, and these data
and the subsequent release of mature survival data for
other targeted agents is likely to strengthen the robust
body of evidence supporting their use in this setting.
Historically, mRCC is a highly treatment-resistant
malignancy for which few therapeutic options have been
available until recently. The ongoing development of
novel targeted therapies, greater understanding of
prognostic factors, and the investigation of alternative
dosing schedules and treatment combinations are
continuing to improve our ability to treat patients with
mRCC. Such advances may assist clinicians in tailoring
treatment strategies to individual patients and combating
problems of treatment resistance and treatment-related
toxicities in order to prolong PFS and improve QoL.
Acknowledgements
Editorial support was provided by ACUMED®
(Tytherington, UK) with funding from Pfizer Inc.
References
Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM
(2003) SU11248 inhibits KIT and platelet-derived growth
factor receptor beta in preclinical models of human small cell
lung cancer. Mol Cancer Ther 2, 471-478.
Amato RJ, Harris P, Dalton M, Khan M, Alter R, Zhai Q, Brady
JR, Jac J, Hauke R, Srinivas S (2007) A phase II trial of
intra-patient dose-escalated sorafenib in patients (pts) with
metastatic renal cell cancer (MRCC) (Abst 5026). J Clin
Oncol, 2007 ASCO Annual Meeting Proceedings Part I. Vol
25, No 18S. Oral presentation.
Arsham AM, Plas DR, Thompson CB, Simon MC (2004) Akt
and hypoxia-inducible factor-1 independently enhance tumor
growth and angiogenesis. Cancer Res 64, 3500-3507.
Beck J, Bajetta E, Escudier B, Négrier S, Keilholz U, Szczylik C,
Mersmann S, Burock K, Erlandsson F, Huber C on behalf of
the EU-ARCCS study investigators (2007) A large openlabel, non-comparative, phase III study of the multi-targeted
kinase inhibitor sorafenib in European patients with
advanced renal cell carcinoma (Abst 4506). Eur J Cancer
Suppl, Abstract Book.Vol 5, No 4. Oral presentation.
Bracarda S, Koralewski P, Pluzanska A, Ravaud A, Szczylik
C, Chevreau C, Filipek M, Melichar B, Moore N, Escudier B
(2007)
Bevacizumab/interferon-alpha2a
provides
a
progression-free survival benefit in all prespecified patient
subgroups as first-line treatment of metastatic renal cell
X. Conclusions
In recent years, greater understanding of the
mechanisms involved in mRCC growth and angiogenesis
have prompted the development and evaluation of a
number of targeted antitumor agents that have been
associated with improved clinical outcomes in this setting.
Randomized clinical trials have shown that sunitinib,
temsirolimus, and bevacizumab are effective in the firstline treatment of mRCC. Robust clinical trial data support
sunitinib as the current standard of care in this patient
population, while clinical findings suggest a potential role
for temsirolimus in poor-risk patients. Bevacizumab, in
combination with IFN-!, has been shown to confer
clinical benefit in patients with previously untreated
mRCC. However, there is little evidence to support
sorafenib as a first-line treatment for mRCC.
A host of agents is available for use in the secondline setting in patients with mRCC that is refractory to
434
carcinoma (AVOREN) (Abst 4008). Eur J Cancer Suppl,
Abstract Book. Vol 5, No 4. Poster.
Bukowski RM, Kabbinavar F, Figlin RA, Flaherty K, Srinivas S,
Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q,
Scappaticci FA, McDermott D (2007a) Randomized phase II
study of erlotinib combined with bevacizumab compared
with bevacizumab alone in metastatic renal cell cancer. J
Clin Oncol 25, 4536-4541.
Bukowski RM, Eisen T, Szczylik C, Stadler WM, Simantov R,
Shan M, Elting J, Pena C, Escudier B (2007b) Final results
of the randomized phase III trial of sorafenib in advanced
renal cell carcinoma: Survival and biomarker analysis (Abst
5023). J Clin Oncol, 2007 ASCO Annual Meeting
Proceedings Part I. Vol 25, No 18S. Oral presentation.
Cella D, Li JZ, Cappelleri JC, Bushmakin A, Charbonneau C,
Kim ST, Chen I, Michaelson MD, Motzer RJ (2007a)
Quality of life (QOL) predicts for progression-free survival
(PFS) in patients with metastatic renal cell carcinoma
(mRCC) treated with sunitinib compared to interferon-alfa
(IFN ! ) (Abst 6594). J Clin Oncol, 2007 ASCO Annual
Meeting Proceedings Part I. Vol 25, No 18S. Poster.
Cella D, Li JZ, Bushmakin AG, Cappelleri JC, Kim ST, Chen I,
Charbonneau C, Motzer RJ (2007b) Health-related quality of
life (HRQOL) and kidney cancer-related symptoms in
patients with metastatic renal cell carcinoma (mRCC) treated
with sunitinib versus interferon (IFN)-alfa: Results for
European and US subsample analyses in a randomized,
multinational phase III trial (Abst 1108). Eur J Cancer
Suppl, Abstract Book. Vol 5, No 4. Poster.
Chan JS, Vuky J, Besaw LA, Beer TM, Ryan CW (2007) A
phase II study of mammalian target of rapamycin (mTOR)
inhibitor RAD001 plus imatinib mesylate (IM) in patients
with previously treated advanced renal carcinoma (RCC)
(Abst 15600). J Clin Oncol, 2007 ASCO Annual Meeting
Proceedings Part I. Vol 25, No 18S. Publication only.
Choueiri TK, Vaziri SA, Rini BI, Elson P, Bhalla I, Jaeger E,
Weinberg V, Waldman FM, Zhou M, Bukowski RM,
Ganapathi R (2007) Use of Von-Hippel Lindau (VHL)
mutation status to predict objective response to vascular
endothelial growth factor (VEGF)-targeted therapy in
metastatic renal cell carcinoma (RCC) (Abst 5012). J Clin
25, No 18S. Clinical Science Symposium.
De Souza P, Maart K, Laurell A, Hawkins RE, Berkenblit A,
Galand L, Thiele A, Strahs A, Feingold J, Hudes G (2007)
Results of a phase 3, randomized study of patients with
advanced renal cell carcinoma (RCC) and poor prognostic
features treated with temsirolimus, interferon-! or the
combination of temsirolimus + interferon-! (Abst 4011).
Eur J Cancer Suppl, Abstract Book. Vol 5, No 4. Poster.
Dham A and Dudek AZ (2007) Sequential therapy with sorafenib
and sunitinib in renal cell carcinoma (Abst 5106). J Clin
25, No 18S. Poster.
Dutcher JP, Szczylik C, Tannir N, Benedetto P, Ruff P, Hsu A,
Berkenblit A, Thiele A, Strahs A, Feingold J (2007)
Correlation of survival with tumor histology, age, prognostic
risk group for previously untreated patients with advanced
renal cell carcinoma (adv RCC) receiving temsirolimus
(TEMSR) or interferon-alpha (IFN) (Abst 5033). J Clin
25, No 18S. Poster discussion.
Escudier B, Koralewski P, Pluzanska A, Ravaud A, Bracarda S,
Szczylik C, Chevreau C, Filipek M, Melichar B, Moore N on
behalf of the AVOREN Investigators (2007a) A randomized,
controlled, double-blind phase III study (AVOREN) of
bevacizumab/interferon-!2a vs placebo/interferon-!2a as
first-line therapy in metastatic renal cell carcinoma (Abst 3).
J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part
I. Vol 25, No 18S. Plenary presentation.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels
M, Négrier S, Chevreau C, Solska E, Desai AA, Rolland F,
Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B,
Shan M, Simantov R, Bukowski RM for the TARGET Study
Group (2007b) Sorafenib in advanced clear-cell renal-cell
carcinoma. N Engl J Med 356, 125-134.
Escudier B, Srinivas S, Roigas J, Gilessen S, Harmenberg U, De
Mulder PH, Fountzilas G, Vogelzang N, Peschel C, Flodgren
P (2007c) A phase II study of continuous daily
administration of sunitinib in patients with cytokinerefractory metastatic renal cell carcinoma (mRCC) - final
results (Abst 4504). Eur J Cancer Suppl, Abstract Book.
Vol 5, No 4. Oral presentation.
Feldman DR, Kondagunta GV, Ronnen EA, Fischer P, Chang R,
Baum M, Ginsberg MS, Ishill N, Patil S, Motzer RJ (2007)
Phase I trial of bevacizumab plus sunitinib in patients (pts)
with metastatic renal cell carcinoma (mRCC) (Abst 5099). J
Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I.
Vol 25, No 18S. Poster.
George DJ, Michaelson MD, Rosenberg JE, Bukowski R,
Sosman JA, Stadler WM, Margolin K, Hutson TE, Rini BI
(2007a) Phase II trial of sunitinib in bevacizumab-refractory
metastatic renal cell carcinoma (mRCC): Updated results and
analysis of circulating biomarkers (Abst 5035). J Clin
George DJ, Michaelson MD, Rosenberg JE, Redman BG, Hudes
GR, Bukowski RM, Kim ST, Chen I, Wilding G, Motzer RJ
(2007b) Sunitinib in patients with cytokine-refractory
metastatic renal cell carcinoma (mRCC) (Abst 4517). Eur J
Cancer Suppl, Abstract Book. Vol 5, No 4. Poster.
Godley PA and Taylor M (2001) Renal cell carcinoma. Curr
Opin Oncol 13, 199-203.
Gore ME, Porta C, Oudard S, Bjarnason G, Castellano D,
Szczylik C, Mainwaring PN, Schöffski P, Rini BI, Bukowski
RM (2007a) Sunitinib in metastatic renal cell carcinoma
(mRCC): preliminary assessment of toxicity in an expanded
open access trial with subpopulation analysis (Abst 5010). J
Vol 25, No 18S. Clinical Science Symposium.
Gore M, Szczylik C, Porta C, Bracarda S, Hawkins R, Bjarnason
G, Oudard S, Lee SH, Carteni G, Eberhardt W (2007b)
Sunitinib in metastatic renal cell carcinoma (mRCC):
preliminary assessment of safety and efficacy in an expanded
access trial with subpopulation analysis (Abst 4503). Eur J
Cancer Suppl, Abstract Book. Vol 5, No 4. Oral
presentation.
Houk BE, Bello CL, Michaelson MD, Bukowski RM, Redman
BG, Hudes GR, Wilding G, Motzer RJ (2007a) Exposureresponse of sunitinib in metastatic renal cell carcinoma
(mRCC): A population pharmacokinetic/pharmacodynamic
(PK/PD) approach (Abst 5027). J Clin Oncol, 2007 ASCO
Annual Meeting Proceedings Part I. Vol 25, No 18S. Oral
presentation.
Houk BE, Bello CL, Michaelson MD, Bukowski RM, Redman
B, Hudes GR, Wilding G, Motzer RJ (2007b) A population
pharmacokinetic/pharmacodynamic (PK/PD) analysis of
exposure-response for sunitinib in metastatic renal cell
carcinoma (mRCC) (Abst 4505). Eur J Cancer Suppl,
Abstract Book. Vol 5, No 4. Oral presentation.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor
A, Staroslawska E, Sosman J, McDermott D, Bodrogi I,
Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O,
Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ
for the Global ARCC Trial (2007) Temsirolimus, interferon
435
alfa, or both for advanced renal-cell carcinoma. N Engl J
Med 356, 2271-2281.
Hutson TE, George DJ, Michaelson MD, Rosenberg JE,
Bukowski RM, Sosman JA, Stadler WM, Margolin K, Rini
BI (2007) A phase 2 trial of sunitinib in bevacizumabrefractory metastatic renal cell carcinoma (mRCC): Updated
results and analysis of circulating biomarkers (Abst 4510).
Jac J, Giessinger S, Khan M, Willis J, Chiang S, Amato R
(2007). A phase II trial of RAD001 in patients (Pts) with
metastatic renal cell carcinoma (MRCC) (Abst 5107). J Clin
25, No 18S. Poster.
Kaelin WG Jr. (2002) Molecular basis of the VHL hereditary
cancer syndrome. Nat Rev Cancer 2, 673-682.
Kim JH, Jung CW, Cho YH, Lee J, Lee SH, Kim HY, Park J,
Park JO, Kim K, Kim WS, Park YS, Im YH, Kang WK, Park
K (2005) Somatic VHL alteration and its impact on
prognosis in patients with clear cell renal cell carcinoma.
Oncol Rep 13, 859-864.
Kim DW, Jo YS, Jung HS, Chung HK, Song JH, Park KC, Park
SH, Hwang JH, Rha SY, Kweon GR, Lee SJ, Jo KW, Shong
M (2006) An orally administered multi-target tyrosine kinase
inhibitor, SU11248, is a novel potent inhibitor of thyroid
oncogenic RET/papillary thyroid cancer kinases. J Clin
Endocrinol Metab 91, 4070-4076.
Knox JJ, Figlin RA, Stadler WM, McDermott DF, Gabrail N,
Miller WH Jr, Hainsworth J, Ryan CW, Cupit L, Bukowski
RM on behalf of the ARCCS Investigators (2007) The
Advanced Renal Cell Carcinoma Sorafenib (ARCCS)
expanded access trial in North America: Safety and efficacy
Proceedings Part I. Vol 25, No 18S. Clinical Science
Symposium.
Kondagunta GV, Hudes GR, Figlin R, Wilding G, Hariharan S,
Kempin SN, Fayyad R, Hoosen S, Motzer RJ (2007a)
Sunitinib malate (SU) plus interferon (IFN) in first-line
metastatic renal cell cancer (mRCC): Results of a dosefinding study (Abst 5101). J Clin Oncol, 2007 ASCO
Annual Meeting Proceedings Part I. Vol 25, No 18S. Poster.
Kondagunta GV, Hudes G, Figlin R, Wilding G, Hariharan S,
Kempin S, Fayyad R, Hoosen S, Motzer RJ (2007b)
Sunitinib plus interferon-alfa in the first-line treatment for
metastatic renal cell carcinoma (mRCC): Results of a dosefinding study (Abst 4520). Eur J Cancer Suppl, Abstract
Book. Vol 5, No 4. Poster.
Krause DS and Van Etten RA (2005) Tyrosine kinases as targets
for cancer therapy. N Engl J Med 353, 172-187.
Lilleby W and Fosså SD (2005) Chemotherapy in metastatic
renal cell cancer. World J Urol 23, 175-179.
Ljungberg B, Hanbury DC, Kuczyk MA, Merseburger AS,
Mulders PF, Patard JJ, Sinescu IC; European Association of
Urology Guideline Group for renal cell carcinoma (2007)
Renal cell carcinoma guideline. Eur Urol 51, 1502-1510.
Manola J, Carducci M, Nair S, Liu G, Rousey S, Wilding G
(2007) Phase II ECOG trial of atrasentan in advanced renal
cell carcinoma (Abst 5102). J Clin Oncol, 2007 ASCO
McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR,
Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff
MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier
JW, Gollob JA, Dutcher JP, Atkins MB (2005) Randomized
phase III trial of high-dose interleukin-2 versus subcutaneous
interleukin-2 and interferon in patients with metastatic renal
cell carcinoma. J Clin Oncol 23, 133-141.
Melichar B, Koralewski P, Pluzanska A, Ravaud A, Bracarda S,
Szczylik C, Chevreau C, Filipek M, Moore N, Escudier B
(2007) First-line bevacizumab improves progression-free
survival with lower doses of interferon[alpha]2a in the
treatment of patients with metastatic renal cell carcinoma
(AVOREN) (Abst 4518). Eur J Cancer Suppl, Abstract
Book. Vol 5, No 4. Poster.
Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G,
Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ,
Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J,
Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon
G, Cherrington JM (2003) In vivo antitumor activity of
SU11248, a novel tyrosine kinase inhibitor targeting vascular
endothelial growth factor and platelet-derived growth factor
receptors:
determination
of
a
pharmacokinetic/pharmacodynamic
relationship.
Clin
Cancer Res 9, 327-337.
Merchan JR, Liu G, Fitch T, Picus J, Qin R, Pitot HC, Maples W,
Erlichman C (2007) Phase I/II trial of CCI-779 and
bevacizumab in stage IV renal cell carcinoma: Phase I safety
and activity results (Abst 5034). J Clin Oncol, 2007 ASCO
Annual Meeting Proceedings Part I Vol 25, No 18S. Poster
discussion.
Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S,
Mazumdar M (2004) Prognostic factors for survival in
previously treated patients with metastatic renal cell
carcinoma. J Clin Oncol 22, 454-463.
Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding
G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo
SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006a)
Activity of SU11248, a multitargeted inhibitor of vascular
endothelial growth factor receptor and platelet-derived
growth factor receptor, in patients with metastatic renal cell
carcinoma. J Clin Oncol 24, 16-24.
Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes
GR, Redman BG, Margolin KA, Merchan JR, Wilding G,
Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD
(2006b) Sunitinib in patients with metastatic renal cell
carcinoma. JAMA 295, 2516-2524.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski
RM, Rixe O, Oudard S, Négrier S, Szczylik C, Kim ST,
Chen I, Bycott PW, Baum CM, Figlin RA (2007a) Sunitinib
versus interferon-alfa in metastatic renal-cell carcinoma. N
Engl J Med 356, 115-124.
Motzer RJ, Figlin RA, Hutson TE, Tomczak P, Bukowski RM,
Rixe O, Bjarnason GA, Kim ST, Chen I, Michaelson D
(2007b) Sunitinib versus interferon-alfa (IFN-!) as first-line
treatment of metastatic renal cell carcinoma (mRCC):
updated results and analysis of prognostic factors (Abst
5024). J Clin Oncol, 2007 ASCO Annual Meeting
Proceedings Part I. Vol 25, No 18S. Oral presentation.
Motzer RJ, Michaelson MD, Hutson TE, Tomczak P, Bukowski
RM, Rixe O, Négrier S, Kim ST, Chen I, Figlin RA (2007c)
Sunitinib versus interferon (IFN)-alfa as first-line treatment
of metastatic renal cell carcinoma (mRCC): updated efficacy
and safety results and further analysis of prognostic factors.
Motzer RJ, Michaelson MD, Rosenberg J, Bukowski RM, Curti
BD, George DJ, Hudes GR, Redman BG, Margolin KA,
Wilding G (2007d) Sunitinib efficacy against advanced renal
cell carcinoma. J Urol 178, 1883-1887.
Murray LJ, Abrams TJ, Long KR, Ngai TJ, Olson LM, Hong W,
Keast PK, Brassard JA, O’Farrell AM, Cherrington JM,
Pryer NK (2003) SU11248 inhibits tumor growth and CSF1R-dependent osteolysis in an experimental breast cancer
bone metastasis model. Clin Exp Metastasis 20, 757-766.
National Comprehensive Cancer Network Clinical practice
guidelines in oncology (2008) Kidney cancer. Version 1.
Available
from:
http://www.nccn.org/professionals/physician_gls/PDF/kidne
y.pdf (Accessed April 2008).
436
Négrier S, Escudier B, Lasset C, Douillard JY, Savary J,
Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M,
Philip T, Tursz T (1998) Recombinant human interleukin-2,
recombinant human interferon alfa-2a, or both in metastatic
renal-cell carcinoma. Groupe Francais d'Immunotherapie. N
Engl J Med 338, 1272-1278.
Négrier S, Remák E, Brown R, Kim ST, Charbonneau C, Motzer
RJ (2007) Economic evaluations of sunitinib vs. interferonalfa (IFN-!) in first-line metastatic renal cell carcinoma
(mRCC) (Abst 4514). Eur J Cancer Suppl, Abstract Book.
Vol 5, No 4. Poster.
Nexavar® (Sorafenib) Prescribing Information (2007). Bayer
Healthcare AG, Leverkusen, Germany.
O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee
KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD,
Manning WC, Murray LJ, Heinrich MC, Cherrington JM
(2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor
with potent activity in vitro and in vivo. Blood 101, 35973605.
Parasuraman S, Hudes G, Levy D, Strahs A, Moore L,
DeMarinis R, Zbrozek AS (2007) Comparison of qualityadjusted survival in patients with advanced renal cell
carcinoma receiving first-line treatment with temsirolimus
(TEMSR) or interferon-! (IFN) or the combination of
IFN+TEMSR (Abst 5049). J Clin Oncol, 2007 ASCO
Annual Meeting Proceedings Part I. Vol 25, No 18S. Poster
discussion.
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer
statistics, 2002. CA Cancer J Clin 55, 74-108.
Patel PH, Kondagunta GV, Redman BG, Hudes GR, Kim ST,
Chen I, Motzer RJ (2007). Phase I/II study of sunitinib
malate in combination with gefitinib in patients (pts) with
metastatic renal cell carcinoma (mRCC) (Abst 5097). J Clin
25, No 18S. Poster.
Patnaik A, Ricart A, Cooper J, Papadopoulos K, Beeram M, Mita
C, Mita MM, Hufnagel D, Izbicka E, Tolcher AW, the
National Cancer Institute (2007) A phase I, pharmacokinetic
and pharmacodynamic study of sorafenib (S), a multitargeted kinase inhibitor in combination with temsirolimus
(T), an mTOR inhibitor in patients with advanced solid
malignancies (Abst 3512). J Clin Oncol, 2007 ASCO
Annual Meeting Proceedings Part I. Vol 25, No 18S. Clinical
Science Symposium.
Plantade A, Leborgne S, Massard C, Fizazi K, Escudier B (2007)
Self evaluation of side-effects of patients treated sequentially
with sunitinib and sorafenib in kidney cancer (Abst 4525).
Ravaud A (2007) Targeted therapy in metastatic renal cell
carcinoma: efficacy, adverse-event management and key
considerations. Eur J Cancer Suppl 5, 1-3.
Redman BG, Hudes GR, Kondagunta GV, Patel PH, Kim ST,
Chen I, Motzer RJ (2007) Phase I/II study of sunitinib in
combination with gefitinib in patients with metastatic renal
cell carcinoma (mRCC) (Abst 4513). Eur J Cancer Suppl,
Abstract Book. Vol 5, No 4. Poster.
Remák E, Mullins CD, Akobundu E, Charbonneau C, Woodruff
K (2007) Economic evaluations of sunitinib versus
interferon-alfa (IFN-!) in first-line metastatic renal cell
carcinoma (mRCC) (Abst 6607). J Clin Oncol, 2007 ASCO
Rini BI (2005) SU11248 and AG013736: current data and future
trials in renal cell carcinoma. Clin Genitourin Cancer 4,
175-80.
Rini BI and Small EJ (2005) Biology and clinical development of
vascular endothelial growth factor-targeted therapy in renal
cell carcinoma. J Clin Oncol 23, 1028-1043.
Rini BI, Wilding GT, Hudes G, Stadler WM, Kim S, Tarazi JC,
Bycott PW, Liau KF, Dutcher JP (2007a) Axitinib (AG013736; AG) in patients (pts) with metastatic renal cell
cancer (RCC) refractory to sorafenib (Abst 5032). J Clin
Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J,
Bycott P, Liau K, Dutcher J (2007b) Axitinib (AG013736;
AG) in patients (pts) with metastatic clear cell renal cell
cancer (RCC) refractory to sorafenib (Abst 4507). Eur J
Cancer Suppl, Abstract Book. Vol 5, No 4. Oral
presentation.
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Tanguay S, Dutcher J, Small
EJ (2008) CALGB 90206: A phase III trial of bevacizumab
plus interferon-alpha versus interferon-alpha monotherapy in
metastatic renal cell carcinoma (Abst 350). Poster and oral
presentation presented at the American Society of Clinical
Oncology 2008 Genitourinary Cancers Symposium, San
Francisco, CA, February 14-16.
Rohrmann K, Staehler M, Haseke N, Bachmann A, Stief CG,
Siebels M (2005) Immunotherapy in metastatic renal cell
carcinoma. World J Urol 23, 196-201.
Rosenberg JE, Motzer RJ, Michaelson MD, Redman BG, Hudes
GR, Bukowski RM, George DJ, Kim ST, Baum CM,
Wilding G (2007) Sunitinib therapy for patients (pts) with
metastatic renal cell carcinoma (mRCC): Updated results of
two phase II trials and prognostic factor analysis for survival
Proceedings Part I. Vol 25, No 18S. Poster.
Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM,
Pithavala YK, Reich SD, Freddo JL, Wilding G (2005) Phase
I trial of the oral antiangiogenesis agent AG-013736 in
patients with advanced solid tumors: Pharmacokinetic and
clinical results. J Clin Oncol 2005;23:5474-5483.
Sablin MP, Bouaita L, Balleyguier C, Gautier J, Celier C,
Balcaceres JL, Oudard S, Ravaud A, Négrier S, Escudier B
(2007) Sequential use of sorafenib and sunitinib in renal
cancer: Retrospective analysis in 90 patients (Abst 5038). J
Vol 25, No 18S. Poster.
Schöffski P, Dumez H, Clement P, Hoeben A, Prenen H, Wolter
P, Joniau S, Roskams T, Van Poppel H (2006) Emerging role
of tyrosine kinase inhibitors in the treatment of advanced
renal cell cancer: a review. Ann Oncol 17, 1185-1196.
Speca JC, Mears AL, Creel PA, Yenser SE, Bendell JC, Morse
MA, Hurwitz HI, Armstrong AJ, George DJ (2007) Phase I
study of PTK787/ZK222584 (PTK/ZK) and RAD001 for
patients with advanced solid tumors and dose expansion in
renal cell carcinoma patients (Abst 5039). J Clin Oncol,
2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No
18S. Poster discussion.
Srinivas S, Roigas J, Gillessen S, Harmenberg U, De Mulder PH,
Fountzilas G, Vogelzang N, Peschel C, Flodgren P, Escudier
B (2007) Continuous daily administration of sunitinib in
patients with cytokine-refractory metastatic renal cell
carcinoma (nRCC): Updated results (Abst 5040). J Clin
Szczylik C, Demkow T, Staehler M, Rolland F, Négrier S,
Hutson TE, Bukowski RM, Scheuring UJ, Burk K, Escudier
B (2007) Randomized phase II trial of first-line treatment
with sorafenib versus interferon in patients with advanced
renal cell carcinoma: Final results (Abst 5025). J Clin
25, No 18S. Oral presentation.
SUTENT® (sunitinib) Prescribing Information (2007) Pfizer Inc.,
New York, NY, USA.
437
Torisel™ (temsirolimus) Prescribing Information (2007) Wyeth
Pharmaceuticals Inc, Philadelphia, PA, USA.
US National Institutes of Health (2006) Surveillance,
Epidemiology and End Results (SEER) Cancer Statistics
Review. Kidney and renal pelvis cancer. 5-year relative
survival
rates,
1996-2002.
Available
from:
http://seer.cancer.gov/cgibin/csr/1975_2003/search.pl#results (Accessed September
2006).
Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith
RA, Schwartz B, Simantov R, Kelley S (2006) Discovery
and development of sorafenib: a multikinase inhibitor for
treating cancer. Nat Rev Drug Discov 5, 835-844.
Yang JC, Sherry RM, Steinberg SM, Topalian SL,
Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L,
Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg
SA (2003a) Randomized study of high-dose and low-dose
interleukin-2 in patients with metastatic renal cancer. J Clin
Oncol 21, 3127-3132.
Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ,
Topalian SL, Steinberg SM, Chen HX, Rosenberg SA
(2003b). A randomized trial of bevacizumab, an antivascular endothelial growth factor antibody, for metastatic
renal cancer. N Engl J Med 349, 427-434.
Yazji S, Bukowski R, Kondagunta V, Figlin R (2007) Final
results from phase II study of volociximab, an !5"1 antiintegrin antibody, in refractory or relapsed metastatic clear
cell renal cell carcinoma (mCCRCC) (Abst 5094). J Clin
25, No 18S. Poster.
Robert J. Motzer
438

Highlights from ASCO and ECCO 2007: Update

Transcription

Similar documents

Join us tonight for: Message in the Music Josh Kingcade Giving

Daniel Zelac, MD Scripps Clinic

Oral Pathology

ADENOMYOSIS OF THE GALLBLADDER

Algunas aportaciones de patólogos mexicanos a la Anatomía

Part 3a

Carcinomas renales quísticos

Uncommon Signs of Malignancy