Targeted therapy in metastatic renal carcinoma
Jane Mattei, Rodrigo Donalisio da Silva, David Sehrt, Wilson R. Molina, Fernando J. Kim⇑
Chief of Urology, Denver Health Medical Center, 777 Bannock Street, Denver, CO 80204, United States
a r t i c l ei n f o
Received 27 August 2013
Received in revised form 23 September 2013
Accepted 26 September 2013
Renal cell carcinoma
a b s t r a c t
Background: Advanced renal cell carcinoma is one of the most treatment-resistant malignancies to con-
ventional cytotoxic chemotherapy. The development of new targeted therapy was result of understand-
ing biological pathways underlying renal cell carcinoma. Our objective is to provide an overview of
current therapies in metastatic renal cell carcinoma.
Methods: MEDLINE/PUBMED was queried in December 2012 to identify abstracts, original and review
articles. The research was conducted using the following words: ‘‘metastatic renal cell carcinoma’’ and
‘‘target therapy’’. Phase II and Phase III clinical trials were included followed FDA approval. Total of 40
studies were eligible for review.
Conclusion: The result of this review shows benefit of these target drugs in tumor burden, increase pro-
gression-free and overall survival and improvement the quality of life compared with previous toxic
immunotherapy, although complete response remains rare.
Published by Elsevier Ireland Ltd.
Metastatic renal cell carcinoma is highly resistant to chemo-
therapy. Although a higher incidence of small renal masses are
being detected, approximately one in three patients still present
with metastases disease [1,2]. Immunotherapy including IL-2 and
IFN-a had long been the main stay of treatment of advanced renal
cell carcinoma (RCC) with responses only in a small subset of pa-
tients resulting in a 5-year survival of 6% [3,4]. Significant advances
in the understanding of renal cell tumor biology have led to the
development of molecular therapies targeting the vascular endo-
thelial growth factor (VEGF) and mammalian target of rapamycin
(mTOR) pathways resulting in significant improvement in overall
survival and quality of life .
This aim of this systematic review is to provide a summary of
contemporary and investigational therapies for the treatment of
metastatic renal cell carcinoma.
2.1. Search strategy and study selection
The systemic review of targeted therapies in metastatic RCC was performed
according to the Preferred Reporting Items for Systematic Reviews and Meta-Anal-
yses (PRISMA) guidelines. The search strategy was aimed at finding relevant studies
and clinical trials from PUBMED/MEDLINE (1966–2013). Targeted therapies were
identified by researching ‘‘target therapy and ‘‘metastatic renal cell carcinoma’’.
The terms identified included names of following therapies; ‘Sunitinib’, ‘Sorafenif’,
‘Pazopanib’, ‘Axitinib’, ‘Cediranib’, ‘Everolimus’, ‘Temsirolimus’, ‘Bevacizumab’, and
Study inclusion criteria included contemporary articles published after 2000,
were published in English, reported data of the Phase II and III Clinical Trials and
of outcomes following FDA approval, one reviewer identified all studies that
appeared to fit the inclusion criteria for full review. Total of 40 studies were eligible
for review (see Fig. 1).
2.2. Data extraction and analysis
Studies relevant to the targeted therapy of metastatic renal cell carcinoma were
included. The following variables were extracted from each study: study name, per-
iod of the study, molecular targets of the drug, FDA approval status, and indication
of treatment, recommended dosage of the drug, safety and efficacy of the drug.
Efficacy was evaluated by the Overall survival (OS), progression free survival
(PFS), and time to progression (TTP) as defined by the FDA Center for Drug Evalua-
tion and Research. Safety was evaluated by the severity of adverse events defined
by the Common Toxicity Criteria (CTC) (see Table 1).
3. Evidence synthesis
3.1. VEGF targeted therapies
Renal cell carcinomas are among the most vascularized of all
solid tumors and angiogenesis is critical for tumor growth and pro-
gression. Vascular endothelial growth factor and its receptor-
VEGF/VEGFR mediate VEGFR regulation of vessel permeability,
endothelial cell activation, survival, proliferation, invasion and
migration. Receptors for VEGFR and PDGFR exhibit tyrosine kinase
activity and, upon ligand binding, activate downstream signaling
pathways as the Raf/MEK/ERK . Raf is a key in regulating
endothelial cell survival, during angiogenesis, via effects on
0304-3835/$ - see front matter Published by Elsevier Ireland Ltd.
⇑Corresponding author. Tel.: +1 303 436 6575.
E-mail address: email@example.com (F.J. Kim).
Cancer Letters 343 (2014) 156–160
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/canlet
intrinsic and extrinsic apoptosis pathways [6–8]. A number of
drugs have been developed to target this pathway.
Sorafenib was the first antiangiogenic multikinase inhibitor for
mRCC approved by the FDA (2005). It is an oral multikinase inhib-
itor with activity against RAS family, VEGFR-1-3 and PDGFR 7.
Sorafenib is considered a second line therapy and recommended
dose is 400 mg twice a day.
The TARGET trial (Phase III) evaluated the efficacy of sorafenib
vs. placebo in 903 patients who had failed previous standard ther-
apy. 8 Interim analysis showed a significantly longer PFS with
sorafenib compared to placebo (5.5 vs. 2.8 months; p < 0.001).
Partial responses were reported in 10% of patients receiving sorafe-
nib and in 2% of those receiving placebo (p < 0.001). The placebo
patients were allowed to cross over at that time that sorafenib
showed to reduce the risk of death. After 16 months after cross-
over, the overall survival time in the sorafenib treated cohort
was 17.8 months compared with 15.2 months for the placebo
group (p < 0.146). After censoring of the crossover patients, the
estimated overall survival for the placebo-treated patients was
14.3 months. Common adverse events were skin rash/desquama-
tion, hand-foot skin reaction, and fatigue; 9% of patients discontin-
ued therapy, and no patients died from toxicity [7–9].
Sunitinib soon followed and was approved by the FDA in 2006.
Sunitinib also is an inhibitor of VEGFR1-3 and PDGFR. It has also
direct antitumor effects on ligands which promotes the prolifera-
tion and differentiation of hematopoietic cells as the Fms-like
tyrosine kinase 3 (FLT3), stem-cell factor receptor (c-KIT) [10,11].
Sunitinib is considered a primary option for the treatment of
mRCC. It is orally administered with the recommended daily dose
of 50 mg/day by a schedule 4/2.
The Phase III trial of sunitinib enrolled 750 patients and
compared sunitinib to interferon. Sunitinib doubled progression-
free survival (11 months vs. 5 months). The objective response
rates were 47% and 12% for sunitinib and interferon-a, respec-
tively(p < 0.001) andthe median
26.4 months for sunitinib and 21.8 months for interferon-alfa
(p = 0.051) . Moreover, a global expanded access Phase III
study with 4564 patients was conducted to provide sunitinib on
relatively unselected or trial-ineligible patients with brain metas-
tases and with poor ECOG performance status. Results showed a
median progression-free survival of 10.9 months and median
overall survival of 18.4 months with similar overall survival in
patients with and without prior cytokine therapy. Adverse events
related with sunitinib included hypertension, fatigue, diarrhea
and hand-foot syndrome, but none of these adverse events were
graded with high severity. When applied Q-TWiST (quality-ad-
justed time without symptoms of disease progression or toxicity
of treatment) score, sunitinib resulted better clinical efficacy and
quality-of-life outcomes compared with IFN-alfa for mRCC pa-
Pazopanib was approved by the FDA in 2009 and is a second
generation of multi-target tyrosine kinase receptor. It is an orallyan
orally bioavailable, multi-targeted TKI that inhibits the function of
multiple receptor kinases including VEGFR1-3, RET and c-kit [14–
16]. It is recommended as a first-line treatment and an option as
a second line in previously cytokine-treated patients [17,18]. The
drug is administered orally with 800 mg once daily.
The Phase III trial showed a significant improvement in PFS and
RR in treatment-naive and cytokine-pretreated patients with
advanced and/or metastatic RCC. Of 435 patients enrolled, the
Fig. 1. Therapeutic biological pathways in renal-cell carcinoma.
J. Mattei et al./Cancer Letters 343 (2014) 156–160
PFS in the overall study population was a median 9.2 vs.
4.2 months (p < 0.0001); the treatment-naive subpopulation was
a median was 11.1 vs. 2.8 months (p < 0.0001) and cytokine-pre-
treated subpopulation was a median of 7.4 vs. 4.2 months. Treat-
ment-naive pazopanib-treated patients had a RR of 32%, while
cytokine-pretreated patients had a RR of 29%. The final OS results
showed a median OS of 22.9 vs. 20.5 months, which were not sig-
nificantly different (p = 0.224).
Pazopanib demonstrated acceptable safety and tolerability,
even though it has been associated with liver toxicity. Adverse
events were hair color changes, nausea, anorexia, vomiting and
the Grade 3–4 toxicity were hypertension and diarrhea .
In 2012, the FDA approved axitinib and it is another second-
generation multi-target tyrosine kinase inhibitor, target in VEGFR-
1–3, c-Kit and PDGFR. Its potency is 50–450 times greater than the
first-generation VEGFR inhibitors [20,21]. Axitinib is an option as a
second-line therapy option in cytokine-refractory metastatic RCC.
The recommended dose schedule of axitinib is 5.0 mg twice daily
. A total of 723 patients were enrolled in the Phase III trial com-
paring the efficacy of axitub to sorafenib. The median PFS was
6.7 months with axitinib compared to 4.7 months with sorafenib
(p < 0.0001). In the Phase II trial the OS was 29.9 months and a
TTP of 15.7 months. The overall response rate was 22.6%, and the
median duration of response was 17.5 months.
Axitinib presented adverse events which were similar to sorafe-
nib, including diarrhea, hypertension, fatigue, and dysphonia and
hand-foot syndrome23. Toxicities in the Phase II trial were mild
to moderate and were manageable. Grade 3–4 adverse events
included hand-foot syndrome, fatigue, hypertension, dyspnea,
diarrhea, dehydration and hypotension.
Cediranib is an investigational drug under the FDA. It is an ATP-
competitive inhibitor of receptor tyrosine kinases (RTKs) members’
related family of VEGF1-3 in nanomolar concentration . The
drug is being evaluated as a first-line therapy. The recommend
dose is 45 mg/day A Phase II compared the efficacy of cediranib
with placebo in patients with metastatic or recurrent clear cell re-
nal cell carcinoma who had not previously received a VEGF signal-
ing inhibitor 34% patients on Cediranib patients achieved a partial
response and 47% experienced stable disease. Cediranib treatment
prolonged PFS significantly compared with placebo with median
12.1 vs. 2.8 months (p = 0.017). In addition, more than half of pa-
tients who achieved a partial response with cediranib experienced
responses lasting more than a year.
The most common adverse events for patients were diarrhea,
fatigue, hypertension and dysphonia. These events were manage-
able by supportive care or dose reductions reductions [23,24].
Bevacizumab is a human recombinant IgG monoclonal antibody
who target VEGF-2, occurring increase of vascular permeability
and reducing proliferation and migration of endothelial cells .
FDA approved in 2009 at 10 mg/kg IV every 2 weeks in combina-
tion with interferon alfa.
A phase III (CALGB 90206)  randomized trial of bev-
acizumab (10 mg/kg each 2 weeks) plus IFN-alfa (9 million U/3
times weekly) vs. IFN-alfa monotherapy was conducted in a 732
metastatic RCC previously untreated. ORR with bevacizumab plus
IFN-alfa wasalfa was higher compared to IFN monotherapy (25.5
vs. 13.1% p < 0.0001). The median OS was 18.3 months for bev-
acizumab plus IFN-alfa and 17.4 months for IFN-alfa monotherapy
Molecular targeting agent clinical trial outcomes in the treatment of renal cell carcinoma.
MechanismTherapyAverage Cost of Medication
TargetLine of therapyStudyPFS
Sorafenib $2831.18VEGFR2-3; PDGFR; RAF; c-
VEGFR1-3; PDGFR; KIT;
VEGFR1-3; PDGFR, c-kit
Sorafenib vs. Placebo 5.5 vs.
11 vs. 5*
Sunitinib$3029.50First lineSunitinib vs. IFN
Pazopanib vs. Sunitinib
Pazopanib vs. Placebo
8.4 vs. 9.5
9.9 vs. 8.5
Second linePazopanib vs. Placebo
Axitinib $11,339.33VEGFR1-3; c-Kit; PDGFR–
First lineAxitinib vs. Sorafenib
Axitinib vs. Sorafenib
VEGFR1-2; c-Kit First lineCediranib vs. Placebo
VEGF First lineBevacizumab-IFN vs. IFN
Bevacizumab-IFN vs. IFN
$4864.58EGFR tyrosine kinase First lineBevacizumab-Erlontinib vs
Temsirolimus$4167.95 mTOR; HIF1-2; VEGFFirst lineTemsirolimus vs. IFN10.9 vs.
4.3 vs. 3.9
Temsirolimus vs. Sorafenib
Everolimus vs. Placebo
Everolimus $4866.67mTOR; HIF1; VEGF
PFS – prgression free survival; i – investigational drug; cyto – Post-cytokine; vegf – Post-VEGF; mtor – Post-mTORi; + excludes cost of IFN; costs are based on our institutional
J. Mattei et al./Cancer Letters 343 (2014) 156–160
(p = 0 .097). There was significantly more Grade 3–4 hypertension
(HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFN-
Another Phase III trial (AVOREN) with 649 patients previously
untreated were randomized to receive bevacizumab (10 mg/kg
every 2 weeks) plus IFN-alfa (9 MUI) or placebo and IFN-alfa.
Rates of overall response and stable disease in the bevacizumab
plus IFN-alfa vs. placebo plus IFN-alfa arms were 31% and 46%
vs. 13% and 50%, respectively. Compared to the control group,
the median PFS was significantly longer in the bevacizumab and
IFN-alfa (10.2 vs. 5.4 months; p < 0.0001). The combination of bev-
acizumab and interferon resulted a significant improvement in
progression-free survival compared with interferon-alfa. Fatigue,
asthenia and proteinuria were the most common grade 3 toxici-
Erlotinib is an orally available and inhibits the tyrosine kinase
domain of epidermal growth factor receptor (EGFR) leading to
the inhibition of EGFR autophosphorylation and downstream sig-
naling . Erlotinib is waiting awaiting FDA approval, but the rec-
ommend dose is 150 mg/day.
Erlotinib demonstrated encouraging activity in renal cell
carcinoma when was associated with bevacizumab in a Phase II
trial 63 patients with metastatic clear-cell renal carcinoma were
treated withbevacizumab 10 mg/kg/2 weeks
150 mg/daily. From 59 assessable patients, 25% had objective
responses and 61% had a stable disease after 8 weeks and survival
at 18 months was 60% . However, a randomized, double-blind,
Phase II trial of erlotinib and bevacizumab compared with
bevacizumab alone was not superior than to only bevacizumab.
The treatment was well tolerated and the most common toxicity
was skin rash .
Other Phase II evaluated erlotinib combined with sirulimus in
metastatic RCC 25 patients previously treated with sunitinib and/
or sorafenib were evaluated. No complete or partial responses
were observed, but stable disease was noted in 21.8% of patients
in 46 months. The progression-free survival and overall survival
were 12 and 40 weeks respectively. This study did not show advan-
tage in a combination of erlotinib and sirolimus over a single-agent
as second line therapy .
4. Mammilian target of rapamycin (mTOR) inhibitors
Another underlying signaling pathways in RCC is the mamma-
lian target of rapamycin (mTOR) pathway, which has a critical role
in the regulation of cell growth, proliferation and angiogenesis and
angiogenesis . This pathway is under influence of important
ant growth factors as EGF, IGF-1, PDGFR and MAPK pathway. Has
been demonstrated that mTOR pathway is more significantly al-
tered in clear-cell RCC, high-grade and tumors with poor prognos-
tic features [32,33].
Everolimus is a specific mTOR inhibitor, a downstream member
of the RAS/PI3K/PKB pathway. It was approved by FDA in 2009 as
an option in advanced RCC patients who had failed treatment with
VEGF therapy. Usual dose is 10 mg once daily .
Phase II trial demonstrated antitumor activity in 41 metastatic
RCC who had received at maximum one previous therapy.
Everolimus dose was 10 mg daily/28-day cycle. Results showed a
median progression-free survival of 11.2 months and the median
overall survival of 22.1 months. Partial responses were observed
in 5 patients, stable disease lasting 3 months was reported in 27
patients and stable disease lasting 6 months was reported in 21 pa-
tients. Nausea, diarrhea, stomatitis, pneumonitis and rash were the
main Grade 3–4 side effects of everolimus .
Antitumoral activity was demonstrated in a Phase II trial at
combination of everolimus and bevacizumab. Metastatic renal cell
carcinoma patients without previous therapy or who had failure to
sunitinib and/or sorafenib were eligible 80 patients, 50 untreated
and 30 previously treated, received bevacizumab 10 mg/kg intra-
venously every 2 weeks and everolimus 10 mg orally daily. The
median progression-free survivals in previously untreated were
9.1 months and previously treated were 7.1 months. Proteinuria
was the most important adverse event .
A Phase III trial, controlled by placebo, with everolimus as a
second-line therapy for advanced clear cell carcinoma refractory
to sunitinib, sorafenib or both agents 410 patients were random-
ized to receive everolimus 10 mg or placebo in addition to best
(Memorial Sloan-Kettering Cancer Center) prognostics score as
favorable, intermediate or poor risk, and whether they had
previously received one or two VEGF receptor tyrosine kinase
4.9 months compared with placebo, 1.87 months . Stomatitis,
rash, diarrhea and non-infectious pneumonitis were the most
stratified according MSKCC
prolonged for everolimus
Temsirolimus is another specific mTOR inhibitor and inhibits
tumor angiogenesis by reducing synthesis of VEGF 14. Temsiroli-
mus was approved by FDA in 2007 for advanced/metastatic RCC
patients with three or more poor prognostic features. The standard
dose is 25 mg i.v/weekly.
A combination of temsirolimus and interferon-alfa was per-
formed in a Phase I/II trial  for advanced RCC in ascending-dose
to up 25 mg/once a week combined with IFN-6 or 9 million U three
times per week. 71 RCC were eligible and the recommended doses
for temsirolimus was 15 mg and for IFN-a 6 million U. Among pa-
tients who received the recommended dose, 8% achieved partial re-
sponse, 36%stable diseasefor 24 weeks and
progression-free survival for all patients was 9.1 months. Adverse
events were stomatitis, fatigue, nausea/vomiting and grade 3 tox-
icities included leukopenia and hypophosphatemia.
A multicenter Phase III  trial enrolled 626 advanced and
poor prognosis patients and confirmed that temsirolimus plus
interferon did not improve survival. Patients with no previous
treatment received 25 mg of intravenous temsirolimus weekly,
3–18 million U of interferon alfa/3x week or a combination of
15 mg of temsirolimus weekly plus 6 million U of interferon alfa/
3x week. Patients on temsirolimus alone had longer overall sur-
vival and progression-free survival (p < 0.001) than patients who
received interferon only (p < 0.001). The combination showed in-
creased toxicity with no significant improvement in OS when com-
pared to IFN-alfa alone. Median overall survivals in the interferon,
temsirolimus and combination groups were 7.3, 10.9, and
8.4 months, respectively. A OS of temsirolimus monotherapy was
longer compared to IFN-a monotherapy (medians, 10.9 vs.
7.3 months) and median PFS time for the temsirolimus was
5.5 months comparedwith 3.1 months
(p = 0.001).
The most common adverse events were rash, peripheral edema,
hyperglycemia and hyperlipidemia in the temsirolimus group,
whereas asthenia was more significant in the interferon group.
Grade 3–4 toxicity occurred in almost 90% of patients in a combi-
J. Mattei et al./Cancer Letters 343 (2014) 156–160
4.3. Cytoreductive nephrectomy in target therapy era Download full-text
Cytoreductive nephrectomy has been shown to extent overall
patients survival in the multimodal treatment of metastatic RCC.
For targeting agents there is no current knowledge whether cyto-
reductive surgery is advocated before or after successful medical
therapy. In target therapy era it’s likely to remain part of the treat-
ment and it’s recommended when possible. Completed remove of
metastasis contributes to improved clinical prognosis and should
be considered when feasible .
In recent years, the clarification of molecular mechanisms of
RCC has permitted a tremendous progress in development and ap-
proval of multiple targeted agents for treatment of advanced RCC.
Therapy targeted at the vascular endothelial growth factor (VEGF)
and mammalian target of rapamycin (mTOR) pathways now repre-
sents the standard of care in metastatic RCC. The third generation
of tyrosine kinases inhibitors appears has similar efficacy or supe-
rior than existing agents, but with more acceptable toxicity. How-
ever, more studies need to be performed comparing patient
populations in both groups.
Each of these therapies offers a very evident clinical benefit as
reduction in tumor burden, increasing progression-free, overall
survival and improves the quality of life compared with previous
therapy. On the other hand, complete responses have been only
rarely noted, necessitating continual therapy for most patients.
Therefore, considerable challenges still face this field and sev-
eral questions remain to be answered. It is unknown if any clinical
benefit is added in initiating a second targeted therapy before pa-
tients experience disease progression. Also, is not clear about the
most favorable sequencing therapies and whether they have a role
in the adjuvant setting. These are important questions for future
studies in order to eradicating or increase survival and quality of
life of renal cell carcinoma patients.
Conflicts of Interest
Fernando J. Kim is a principal investigator for Olympus, Covidi-
en, and Healthtronics. Wilson R. Molina has a fellowship grant with
 Y. Najjar, B. Rini, Novel agents in renal carcinoma: a reality check, Ther. Adv.
Med. Oncol. 4 (4) (2012) 183–194.
 W. Stadler, Targeted agents for the treatment of advanced renal cell carcinoma,
Cancer 104 (11) (2005) 2323–2333.
 W. Berg, C. Divgi, D. Nanus, R. Motzer, Novel investigative approaches for
advanced renal cell carcinoma, Semin. Oncol. 27 (2) (2000) 234–239.
 T. Dorff, A. Goldkorn, D. Quinn, Targeted therapy in renal cancer, Ther. Adv.
Med. Oncol. 1 (3) (2009) 183–205.
 R. Janusz, S. Robert, Rasregulation of vascular endothelial growth factor and
angiogenesis, Methods Enzymol. 333 (2001) 267–283.
 R. Hilger, M. Scheulen, D. Strumberg, The Ras–Raf–MEK–ERK pathway in the
treatment of cancer, Onkologie 25 (6) (2002 December) 511–518.
 Rini B. Sorafenib, Expert. Opin. Pharmacother. 7 (4) (2006) 453–461.
 B. Escudier, T. Eisen, W.M. Stadler, et al., Sorafenib in advanced clear-cell renal-
cell carcinoma, New Engl. J. Med. 356 (2) (2007) 125–134.
 M.J. Ratain, T. Eisen, W.M. Stadler, et al., Phase II placebo-controlled
randomized discontinuation trial of sorafenib in patients with metastatic
renal cell carcinoma, J. Clin. Oncol. 24 (16) (2006) 2505–2512.
 R. Motzer, B. Rini, R. Bukowski, et al., Sunitinib in patients with metastatic
renal cell carcinoma, JAMA 295 (21) (2006) 2516–2524.
 Rini B. Sunitinib, Expert. Opin. Pharmacother. 8 (14) (2007) 2359–2369.
 R. Motzer, T. Hutson, P. Tomczak, et al., Sunitinib versus interferon alfa in
metastatic renal-cell carcinoma, New Engl. J. Med. 356 (2) (2007) 115–124.
 D. Cella, J. Li, J. Cappelleri, et al., Quality of life in patients with metastatic renal
cell carcinoma treated with sunitinib or interferon alfa: results from a phase III
randomized trial, J. Clin. Oncol. 26 (22) (2008) 3763–3769.
 B. Vakkalanka, R. Bukowski, Novel drugs for renal cell carcinoma, Expert Opin.
Investig. Drugs 17 (10) (2008) 1501–1516.
 M. Al-Marrawi, B. Rini, Pazopanib for the treatment of renal cancer, Expert
Opin. Pharmacother. 12 (7) (2011) 1171–1189.
 N.S. Vasudev, J.M. Larkin, Tyrosine kinase inhibitors in the treatment of
advanced renal cell carcinoma: focus on pazopanib, Clin. Med. Insights Oncol.
5 (2011) 333–342.
development in advanced renal cell carcinoma, Front Oncol. 2 (2012) 13.
 S. Keisner, S. Shah, Pazopanib: the newest tyrosine kinase inhibitor for the
treatment of advanced or metastatic renal cell carcinoma, Drugs 71 (4) (2011)
 C. Sternberg, I. Davis, J. Mardiak, et al., Pazopanib in locally advanced or
metastatic renal cell carcinoma: results of a randomized phase III trial, J. Clin.
Oncol. 28 (6) (2010 February 20) 1061–1068. Epub 2010 January 25.
 G. Sonpavde, T. Hutson, B. Rini, Axitinib for renal cell carcinoma, Expert Opin.
Investig. Drugs 17 (5) (2008) 741–748.
 C. Carmichael, C. Lau, D. Josephson, S. Pal, Comprehensive overview of axitinib
development in solid malignancies: focus on metastatic renal cell carcinoma,
Clin. Adv. Hematol. Oncol. 10 (5) (2012) 307–314.
 O. Rixe, R. Bukowski, M. Michaelson, et al., Axitinib treatment in patients with
cytokine-refractory metastatic renal-cell cancer: a phase II study, Lancet
Oncol. 8 (11) (2007) 975–984.
 B. Rini, B. Escudier, P. Tomczak, et al., Comparative effectiveness of axitinib
versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase
3 trial, Lancet 378 (9807) (2011) 1931–1939.
 P. Mulders, R. Hawkins, P. Nathan, et al., Cediranib monotherapy in patients
with advanced renal cell carcinoma: results of a randomised phase II study,
Eur. J. Cancer 48 (4) (2012) 527–537.
 B. Rini, S. Halabi, J. Rosenberg, et al., Bevacizumab plus interferon alfa
compared with interferon alfa monotherapy in patients with metastatic renal
cell carcinoma: CALGB 90206, J. Clin. Oncol. 26 (33) (2008) 5422–5428.
 B. Escudier, J. Bellmunt, S. Négrier, et al., Phase III trial of bevacizumab plus
interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN):
final analysis of overall survival, J. Clin. Oncol. 28 (13) (2010) 2144–2150.
 Tang P, Tsao M, Moore M, A review of erlotinib and its clinical use, Expert Opin.
(7) (February 2006) 177–193.
 J. Hainsworth, J. Sosman, D. Spigel, D. Edwards, C. Baughman, A. Greco,
Treatment of metastatic renal cell carcinoma with a combination of
bevacizumab and erlotinib, J. Clin. Oncol. 23 (2005) 7889–7896 (? 2005 by
American Society of Clinical Oncology).
 R.M. Bukowski, F.F. Kabbinavar, R.A. Figlin, et al., Randomized phase II study of
erlotinib combined with bevacizumab compared with bevacizumab alone in
metastatic renal cell cancer, J. Clin. Oncol. 25 (2007) 4536–4541 (? 2007 by
American Society of Clinical Oncology).
 T. Flaig, L. Costa, D. Gustafson, et al., Safety and efficacy of the combination of
erlotinib and sirolimus for the treatment of metastatic renal cell carcinoma
after failure of sunitinib or sorafenib, Br. J. Cancer 103 (2010) 796–801.
 G. Sonpavde, T. Choueiri, Biomarkers: the next therapeutic hurdle in
metastatic renal cell carcinoma, Br. J. Cancer 107 (7) (2012) 1009–1016.
 D. Cho, M. Atkins, Future directions in renal cell carcinoma: 2011 and beyond,
Hematol. Oncol. Clin. North Am. 25 (4) (2011) 917–935.
 M. Pinto, S. Redondo, A. Espinosa, A. Zamora, F. Castelo, B. González, mTOR
pathway inhibition in renal cell carcinoma, Urol. Oncol. 30 (4) (July–August
2012) 356–361 (Epub 2010 March 5).
 M. Voss, A. Molina, R. Motzer, MTOR inhibitors in advanced renal cell
carcinoma, Hematol. Oncol. Clin. North Am. 25 (4) (2011) 835–852.
 R. Amato, Everolimus for the treatment of advanced renal cell carcinoma,
Expert Opin. Pharmacother. 12 (7) (2011) 1143–1155.
 D.R. Spigel, F. Anthony Greco, D.M. Waterhouse, et al., Phase II trial of
bevacizumab and everolimus in patients with advanced renal cell carcinoma, J.
Clin. Oncol. 28 (13) (May 1 2010) 2131–2136 (Epub 2010 April 5).
 R. Motzer, B. Escudier, S. Oudard, et al., Efficacy of everolimus in advanced
renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III
trial, Lancet 372 (9637) (2008) 449–456.
 R. Motzer, G. Hudes, B. Curti, D. McDermott, B. Escudier, Negrier Sea. Phase I/II
trial of temsirolimus combined with interferon alfa for advanced renal cell
carcinoma, J. Clin. Oncol. 25 (25) (2007) 3958–3964.
 G. Hudes, M. Carducci, P. Tomczak, et al., Temsirolimus, interferon alfa, or both
for advanced renal-cell carcinoma, New Engl. J. Med. 356 (22) (2007) 2271–
 B. Ljungberg, N.C. Cowan, D.C. Hanbury, M. Hora, M.A. Kuczyk, A.S.
Merseburger, J.J. Patard, P.F. Mulders, I.C. Sinescu, EAU guidelines on renal
cell carcinoma: the 2010 update, Eur. Urol. 58 (3) (2010) 398–406.
tyrosine kinaseinhibitors andtheir
J. Mattei et al./Cancer Letters 343 (2014) 156–160