Journal of Cancer Therapy, 2013, 4, 22-29
http://dx.doi.org/10.4236/jct.2013.49A2004 Published Online October 2013 (http://www.scirp.org/journal/jct)
Treatment Efficacy of Targeted Therapies for Metastatic
Renal Cell Carcinoma—A Review after Seven Years
of Experience
Hartmut Kirchner1, Axel Heidenreich2, Bernhard Brehmer2*
1Department of Oncology, Siloah Hospital, Hannover, Germany; 2Department of Urology, RWTH Aachen University, Aachen, Ger-
many.
Email: *bbrehmer@ukaachen.de
Received July 12th, 2013; revised August 10th, 2013; accepted August 18th, 2013
Copyright © 2013 Hartmut Kirchner et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Renal cell carcinoma (RCC) is the 10th leading cause of deaths from cancer in the Western world. During the last two
decades this type of malignancy was difficult to treat with limited treatment options using cytokines like interferon al-
pha (IFN) or interleukin-2 (IL-2). The development of targeted therapies that interfere with specific pathways of tumor
angiogenesis and proliferation has profoundly changed this situation and improved the prognosis for patients diagnosed
with metasatic renal cell carcinoma (mRCC) considerably. To date, seven targeted therapies have been approved for the
first- and second-line treatment of metastatic renal cell carcino ma. In addition, recent data suggest that sequential treat-
ment with these modern drugs is feasable and effective and leads to extended overall survival compared to historical
data. As more progress is being made, the variety of therapeutic options makes it challenging in clinical practice to
choose the best treatment option for the individual mRCC patient. This review revisits results from the pivotal trials of
currently approved therapeutic agents (in chronological order of their approval) in context with latest results from cur-
rent clinical trials.
Keywords: Kidney Cancer; Systemic Therapy; Review
1. Introduction
Renal cell carcinoma (RCC) is a malignancy whose glo-
bal incidence has been steadily increasing over the past
decades. One third of patients present with advanced
stages of disease, and another third develop metastases in
the follow-up. This leads to the high mortality-to-inci-
dence ratio [1,2].
Until recently, the prognosis for most patients diag-
nosed with mRCC was poor. Because mRCC is widely
resistant to chemotherapy, systemic treatment options
were restricted to immune modulation with cytokines
that resulted in rather low response rates combined with
high toxicity. This situ ation chang ed with the approval of
sorafenib and sunitinib, the first targeted therapies for the
treatment of mRCC in 2006. To date, seven new drugs
for the treatment of mRCC patients are available (Ta ble
1). Since their introduction, targeted therapies prolonged
significantly the median overall survival time of mRCC
patients. They have established a promising new treat-
ment paradigm by interfering with specific pathways of
tumor angiogenesis and pro liferation.
These agents typically exert their therapeutic effects
either by inhibiting angiogenetic signalling cascades me-
diated by vascular endothelial growth factor receptors
(VEGFR) or by blocking the mammalian target of rapa-
mycin (mTOR), an important downstream switchboard
of intracellular communication. The first group com-
prises the monoclonal antibody bevacizumab and the
receptor tyrosine kinase inhibitors (TKIs) sorafenib,
sunitinib, pazopanib and axitinib. The mTOR inhibitors
temsirolimus and everolimus belong to the second group
[3,4].
2. Approved Targeted Therapies
2.1. Sorafenib
In the prospective randomized phase 3 TARGET trial
903 patients who had previously been treated with cyto-
kines were randomly assigned to receive either sorafenib
*Corresponding a uthor.
Copyright © 2013 SciRes. JCT
Treatment Effi cacy of Targeted Therapies for Metastatic Renal Cell Carcinoma—A Review
after Seven Years of Experience 23
Table 1. Approval trials mRCC.
PFS (months) OS (months) Response rate
Sorafenib (vs. p la ce bo ) 5.5 vs. 2.8 17.8 vs. 14.3 (censo red) PR 10% vs. 2% DCR 62% vs. 37%
Sunitinib (vs. IFN-
) 11 vs. 5 26.4 vs. 21. 8 ORR 47% vs. 12%
Bevacizumab + IFN-
(vs. placebo + IFN-
) 10.2 vs. 5.4 18.3 vs. 17.4 ( C A L G B )
23.3 vs. 21.3 (AVOREN) ORR 31% vs. 13%
Temsirolimus (vs. TEM + IFN vs. TEM) 5.5 vs. 4.7. vs. 3.1 10.9 vs. 8.4 vs. 7.3 ORR 8.6% vs. 8.1% vs. 4.8%
Everolimus (vs. placebo 2:1) 4.0 vs. 1.9 mOS in Ev group not yet reached;
8.8 mo. in placebo gro u p PR 3% vs. 0%
Pazopanib (vs. pl ac eb o 2: 1) 9.2 vs. 4.2 22.9 vs. 20.5 ORR 30% vs. 3%
Axitinib (vs. s orafenib open-label ) 6.7 vs. 4.7 20.1 vs. 19.2 ORR 19% vs. 9%
or placebo [5,6]. Overall survival (OS) was the primary
endpoint of the TARGET study. When a pre-planned
analysis of OS revealed a 28% reduction in the risk of
death among patients receiving sorafenib, patients from
the placebo group were allowed to cross over to the
sorafenib group to benefit from active treatment. When
post-cross-over survival data of placebo patients were
censored, sorafenib demonstrated a significant improve-
ment in OS (17.8 vs. 14.3 months; HR 0.78; p = 0.0287).
Progression-free survival (PFS) was prolonged by soraf-
enib to 5.5 months compared with 2.8 months in the pla-
cebo group. Based on these data, sorafenib has been ap-
proved for the treatment of patients who are not suited
for or have progressed on a cytokine-based therapy.
Large expanded access trials with 2.504 patients in North
America and 1.159 patients in Europe have confirmed
the efficacy and tolerability of sorafenib in first- and
second-line-settings in daily routine treatment with a
median PFS of 8.1 and 6.6 months, respectively [7,8].
2.2. Sunitinib
Sunitinib received its approval as a first-line therapy for
mRCC after a phase 3 study with 750 patients who were
randomized into two groups: one treated with sunitinib
and the other with IFN-
[9]. PFS was defined as the
primary endpoint. It was significantly longer in the sunit-
inib group (11 vs. 5 months; HR 0.42; p 0.001). Overall
survival in the appro val study was longer in the sunitinib
group than in th e IFN-
group (26.4 vs. 21.8 months; p =
0.051), although statistically insignificant. Significance
was reached, however, when the confounding effects of
cross-over and poststudy cancer treatment were censored
(28.1 vs. 14.1 months; p = 0.003) [10]. A large expanded
access trial with 4.564 patients in 52 countries has con-
firmed the results of the approval study for sunitinib in
terms of efficacy and tolerability with a median PFS of
9.4 and OS of 18.7 months, respectively [11].
2.3. Bevacizumab plus Interferon
In combination with IFN-
, bevacizumab was clinically
tested in two phase 3 trials. Their primary endpoint was
overall survival. Both trials did not meet the predefined
criteria for its statistical significance, although OS data of
23.3 and 18.3 months for the combination therapy were
reported. However, both trials successfully demonstrated
a significant extension of PFS, which led to the approval
of bevacizumab plus IFN-
for the first-line treatment of
mRCC in 2009. The AVOREN trial randomized 649
first-line patients to receive IFN-
and bevacizumab or
IFN-
and placebo. PFS increased to 10.2 months for the
combination therapy versus 5.4 months for IFN-
(HR
0.63; p = 0.0001) [12,13]. The similarly designed CALG B
study randomized 732 patients to receive either the com-
bination or IFN-
alone. PFS was significantly longer in
patients receiving the combination therapy (8.5 vs. 5.2
months; p < 0.001; HR 0.71) [14,15].
2.4. Temsirolimus
In 2009, the intravenously applied mTOR inhibitor tem-
sirolimus has been approved for the first-line treatment
of mRCC patients with a poor prognosis based on the
results of the phase 3 trial ARCC. This trial randomized
626 previously untreated mRCC patients with a poor risk
(MSKCC score, modified by Hudes) to receive temsi-
rolimus, IFN-
, or a combination of temsirolimus and
IFN-
. The primary endpoint was OS, which was sig-
nificantly longer in the temsirolimus group compared
with the IFN-
group (10.9 vs. 7.3 months; HR 0.73; p =
0.008). Median OS in the combination group did not dif-
fer significantly from the IFN-
group (8.4 vs. 7.3
months; HR 0.96; p = 0.70). Median PFS times in the
ARCC study reached 5.5, 4.7 and 3.1 months in patients
receiving temsirolimus, the combination therapy, or IFN-
alone [16].
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Treatment Effi cacy of Targeted Therapies for Metastatic Renal Cell Carcinoma—A Review
after Seven Years of Experience
24
2.5. Everolimus
The orally administered mTOR inhibitor Everolimus has
been approved in 2010 for the second- or third-line ther-
apy of mRCC patients after failure of TKIs. The approval
is based on the results of the phase 3 RECORD-1 trial.
416 patients with mRCC who had progressed on sunit-
inib, sorafenib, or both, were randomized in a two to one
ratio to receive either everolimus or placebo. The pri-
mary endpoint was PFS. The trial was halted early after
the second interim analysis had shown a significant dif-
ference between the two groups: Median PFS in the
everolimus group was 4.9 months vs. 1.9 months in the
placebo group (HR 0.33; p 0.001). OS did not differ
significantly between the two groups (14.8 vs. 14.4
months; HR 0.87; p = 0.16) [17,18].
2.6. Pazopanib
The TKI Pazopanib was evaluated in a phase 3 trial with
435 mRCC patients who were previously untreated or
had failed on a cytokine based therapy. These patients
were randomized in a two to one ratio to receive either
pazopanib or placebo. PFS was defined as the primary
endpoint. It was significantly longer in the pazopanib
group (9.2 vs. 4.2 months; HR 0.46; p < 0.0001). The
objective response rate was 30% with pazopanib in
comparison to 3% with placebo. OS did not differ sig-
nificantly between the two groups (22.9 vs. 20.5 months;
HR 0.91; p = 0.224) [19,20].
Based on these results, pazopanib has been approved
in 2010 under the condition that its efficacy and safety be
tested in direct comparison to sunitinib. This comparison
in the COMPARZ trial whose results were presented at
the ESMO 2012 (see 3.1.2.) supported the positive opin-
ion on Pazopanib [21] .
2.7. Axitinib
Axitinib is a TKI proven in second-line therapy of
mRCC in direct comparison to sorafenib. In the open-
label phase 3 trial AXIS 723 patients who had progressed
on first-line therapy with sunitinib, bevacizumab plus
IFN-
, temsirolimus, or cytokines were randomized to
receive axitinib or sorafenib. PFS was defined as the
primary endpoint. It was significantly longer for axitinib
(6.7 vs. 4.7 months; HR 0.665; p < 0.0001) [22]. Median
OS did not significantly differ between the axitinib arm
and the sorafenib arm of the trial (20.1 vs. 19.2 months;
HR 0.969; p = 0.3744) [23,24]. Based on the results of
the AXIS trial, axitinib achieve d market authorization for
second-line therapy of mRCC in 2012.
3. Current Prospective Trials
Eight studies and subgroup analyses have been recently
published regarding the field of first-line and second-line
treatment in mRCC (Tables 2 and 3). The purpose of
most of these studies was to define the optimal sequ ential
treatment with the new drugs.
Table 2. First-line therapy mRCC.
Drugs tested ORR (%) PFS (months) OS (months)
EFFECT Phase II (n = 292) Sunitinib (4/2) vs. Sunitinib (cont.) 32.2 vs. 28.1 8.5 vs. 7.0 23.1 vs. 23.5
COMPARZ Phase III (n = 1110) Pazopanib vs. Sunitinib 31 vs. 25 8.4 vs. 9.5 28.4 vs. 29.3
AMG 386 Phase II (n = 152) Sorafenib + AMG 386 (10 mg) vs. Sorafenib
+ AMG 386 (3 mg) vs. Sorafenib + Placebo 38 vs. 37 vs. 259.0 vs. 8.5 vs. 9.0 n.p.
TIVO-1 Phase III (n = 517) Tivozanib vs. Sorafenib 33 vs. 23 11.9 vs. 9.1 28.8 vs. 29.3
NCT00920186 Phase III (n = 288) Axitinib vs. Sorafenib 32.3 vs. 14.6 10.1 vs. 6.5 n.p.
INTORACT Phase III (n = 791) Bevacizumab + IFN-α vs.
Bevacizumab + Temsirolimus 28 vs. 27 9.3 vs. 9.1 25.5 vs. 25.8
n.p.: not published.
Table 3. Data sequential therapy.
Sequences tested ORR (%) PFS (months) OS (months)
AXIS Phase III (n = 723) SunitinibSorafenib vs. SunitinibAxitinib
---
IFN-αSorafenib vs. IFN-αAxitinib 3.4 vs. 4.8
---
6.5 vs. 12.1
16.5 vs. 15.2
---
27.8 vs. 29.4
INTORSE CT Phase III (n = 512) SunitinibSorafenib vs. SunitinibTemsirolimus8 vs. 8 3.91 vs. 4.28 16.64 vs. 12.27
Copyright © 2013 SciRes. JCT
Treatment Effi cacy of Targeted Therapies for Metastatic Renal Cell Carcinoma—A Review
after Seven Years of Experience 25
3.1. First-Line Therapies
3.1.1. EFFECT
The approved dosing schedule of sunitinib calls for four
weeks on treatment (50 mg per day) followed by two
weeks off treatment. A continuous daily dosing of 37.5
mg sunitinib has shown antitumor activity, too. In the
phase 2 EFFECT trial, 292 previously untreated mRCC
patients were randomized to receive sunitinib in one of
both schedules in order to compare their safety and effi-
cacy. Time to tumor progression (TTP) was defined as
the primary endpoint. While there was a trend towards an
inferior TTP and PFS (estimated as a sensitivity analysis
for TTP) with contin u ou s dosing, both param e t ers did not
differ significantly between the treatment groups. Median
PFS reached 8.5 months on schedule 4 weeks on/2 weeks
off compared with 7.0 months on co ntinuous dosing (HR
0.77; p = 0.070). Kaplan Meier estimates of OS sug-
gested a slight yet insignificant advantage for continuous
dosing (23.1 vs. 23.5 months; HR 1.09; p = 0.615). In
their conclusion, the study investigators recommend to
adhere to the approv ed sunitinib dose and schedule [25].
3.1.2. CO MPARZ
The open-label phase 3 COMPARZ was a head-to-head
analysis between pazopanib and sunitinib in first-line
treatment of mRCC. 1110 patients were randomized to
receive pazopanib on a continuous schedule or sunitinib
on the 4 weeks on/2 weeks off schedule. PFS as the pri-
mary endpoint showed no statistical significant superior-
ity for either of the two treatments (8.4 months for pa-
zopanib vs. 9.5 months for sunitinib). An in terim analysis
revealed a median OS of 28.4 months in the pazopanib
group compared with 29.3 months in the sunitinib group
(HR 0.908; p = 0.275). Both treatments elicited similar
objective respon se rates with 31% an d 25%, resp ectively.
In conclusion, COMPARZ has proven the non-inferiority
of pazopanib’s efficacy compared with sunitinib [21].
3.1.3. AM G 3 86
AMG 386 is an investigational biological drug, a pepti-
body, whose antitumor activity was tested in a double-
blind phase 2 trial in comparison with sorafenib. 152
previously untreated patients were randomized to receive
sorafenib daily plus AMG 386 at 10 mg/kg (group A ), or
sorafenib p lus AMG 386 at 3 mg/kg (grou p B), or soraf-
enib plus placebo (group C) once weekly. Median PFS
did not differ significantly between the three groups and
reached 9.0, 8.5 and 9.0 months, respectively. The objec-
tive response rate was 38%, 37%, and 25%, respectively
[26].
3.1.4. TIVO-1
Tivozanib is an investigational TKI that has been evalu-
ated in direct comparison to sorafenib as a first-line
treatment for mRCC. In the phase 3 TIVO-1 trial 517
patients were randomized to receive either tivozanib or
sorafenib. First results demonstrate a significant longer
PFS in the tivozanib group (11.9 vs. 9.1 months; HR
0.797; p = 0.042). In treatment-naïve patients (70% of
total study population) median PFS in the tivozanib
group reached 12.7 months versus 9.1 months in the
sorafenib group (HR 0.756; p = 0.037). The objective
response rate for tivozanib was 33% compared with 23%
for sorafenib (p = 0.014) [27]. While median PFS dif-
fered considerably in patients with an ECOG 0 perform-
ance status (14.8 months in the tivozanib versus 9.1
months in the sorafenib group; HR 0.617; p = 0.004), it
was almost equal in ECOG 1 patients (9.1 vs. 9.0 months;
HR 0.920; p = 0.588). A similar observation emerged
from a subgroup analysis according to the MSKCC score.
For patients with a favorable risk, median PFS was 16.7
versus 10.7 months (HR 0.590; p = 0.018), while it
reached 9.4 versus 7.4 months (HR 0.786; p = 0.076) for
intermediate risk patients [28]. Median OS data showed
no significant difference between both arms (29.3 vs.
28.8 months; HR 1.25; p = 0.105) [29].
3.1.5. NCT 00920186
In a first-line comparison b etween axitinib and so rafenib,
288 previously untreated mRCC patients were random-
ized at a 2:1 ratio to receive either of the two drugs. Me-
dian PFS was 10.1 months in the axitinib versus 6.5
months in the sorafenib group (stratified HR 0.77; 1-
sided p = 0.038). In contrast, in ECOG 1 patients, both
treatments yielded a similar PFS of 6.5 and 6.4 months,
respectively. Overall, the study did not reach its primary
endpoint, which had called for a hazard ratio of under
0.56 and a 1-sided p of 0.02 5 [30].
3.1.6. INTORACT
The phase 3 trial INTORACT compared bevacizumab
plus interferon with bevacizumab plus temsirolimus as a
first-line treatment for mRCC. 791 patients, predomi-
nantly with clear cell histology, were randomized to re-
ceive one of the two combination therapies. No superior-
ity for the combination with temsirolimus could be dem-
onstrated. Patients receiving bevacizumab plus IFN-
showed a median progression-survival time of 9.3 mon t h s ,
a median OS time of 25.5 months, and an objective re-
sponse rate of 28% compared with 9.1 months, 25.8
months, and 27% in the group that received the combina-
tion with temsirolimus [31].
3.2. Sequential Therapies
None of the new drugs available is able to completely
block all angiogen ic or proliferative signalling pathways.
Copyright © 2013 SciRes. JCT
Treatment Effi cacy of Targeted Therapies for Metastatic Renal Cell Carcinoma—A Review
after Seven Years of Experience
26
Ultimately, tumor cells will adapt to this incomplete in-
hibition and develop resistance. Yet because there is no
absolute cross-resistance between TKIs such as sorafenib
and sunitinib, as retrospective studies suggest, sequential
therapies have the potential to prolong the life of mRCC
patients. This assumption is confirmed by data from cur-
rent prospective trials.
3.2.1. AXIS
The AXIS trial compared axitinib and sorafenib in a
second-line setting. Stratification of the overall study
population by prior first-line treatment allowed for sub-
group analyses of different therapeutic sequences. In fact,
AXIS was the first prospective phase 3 trial proving a
benefit for TKI-TKI treatment sequences. Second-line
PFS in patients with a previous sunitinib regimen was
longer in the axitin ib than in the sorafenib group (4.8 vs .
3.4 months; HR 0.741; p = 0.0107). Yet second-line me-
dian OS was shorter for patients treated with a sunit-
inib-axitinib sequence than for those receiving sorafenib
after sunitinib, although with no statistical significance
(15.2 vs. 16.5 months; HR 0.997; p = 0.4902). The ob-
jective response rate in the second line treatment was
19% in the axitinib and in 9% the sorafenib arm. The
patients treated with cytokines prior to TKI showed the
longest PFS (12.1 months for axitinib; and 6.5 months
for sorafenib; HR 0.464; p < 0.0001) [22]. Their median
OS reached 29.4 months in the axitinib and 27.8 months
in the sorafenib group (HR 0.813; p = 0.1435). While
axitinib’s efficacy was superior to sorafenib as a sec-
ond-line treatment in most subgroups, sorafenib patients
with an intermediate prognosis according to the MSKCC
risk score had a clear advantage in OS (23.9 vs. 18.8
months) [ 2 3,24].
3.2.2. INTORSECT
The INTORSECT trial was another second phase 3 trial
prospectively proving the efficacy of sequential TKI
therapies. Its primary objective was to compare safety
and efficacy of temsirolimus and sorafenib in a second-
line setting for mRCC patients after failure on prior
sunitinib. 512 patients were randomized to receive either
temsirolimus or sorafenib. Patients in both groups ex-
perienced a prolongation of their PFS time, slightly
longer yet with no statistical significance in the temsi-
rolimus group (4.28 vs. 3.91 months; HR 0.87; p =
0.193). The OS, however, was significantly shorter in the
temsirolimus than in the sorafenib group (12.27 vs. 16.64
months; HR: 1.31; p = 0.014) [32].
4. Comment
Sorafenib and sunitinib have been the first targeted
therapies for the treatment of mRCC, and their safety and
efficacy has extensively been evaluated and confirmed
since their approval by the FDA in December 2005 and
January 2006, respectively. While sunitinib was initially
regarded as the standard systemic therapy for treatment-
naïve mRCC patients, sorafenib was also approved as a
first-line treatment only for those patients who do not
tolerate a cytokine-based therapy. It is noteworthy that
both the TIVO-1 and the AMG 386 trial reported a much
longer median PFS for first-line Sorafenib treatment (9.1
and 9.0 months, respectively) compared to the presented
data from Escudier et al. with PFS of 5.7 months [33].
Sorafenib appears to exert its optimal efficacy in patients
with an intermediate prognosis and/or limited perform-
ance status [23,24,28,30]. Sunitinib, on the other hand,
showed a shorter PFS in the EFFECT and the COM-
PARZ trials than in the phase III approval trial (8.5 and
9.5 months, respectively, vs. 11 months) [9,21,25]. The
longest median PFS reported to date in treatment-naïve
mRCC patients has been reache d with 12.7 months in the
TIVO-1 trial by tivozanib in direct comparison to soraf-
enib [27].
The extended PFS upon treatment with the new TKIs
is certainly a breakthrough in the management of mRCC.
Even if it is probably true, though, that PFS can be re-
garded as a surrogate marker for OS, it is questionable
whether a linear correlation between both parameters
exists [34]. With the exception of sorafenib, all phase 3
trials for the currently approved TKIs did define PFS as
their primary endpoint. This shortened the time to regis-
tration and avoid ed the risk o f missing OS as th e primary
endpoint—like Sorafenib initially did in its pioneering
TARGET trial. Because it turned out in the interim
analysis that the disease was controlled significantly by
sorafenib, patients from the placebo group were allowed
to cross over to the verum group. This crossover of 48%
confounded the trial data and subsequently made it im-
possible to determine a statistically significant advantage
in OS for sorafenib on an intention-to-treat basis. The
phase III trial ARCC with the mTOR inhibitor temsi-
rolimus was the only mRCC approval study so far that
succeeded in meeting OS as the primary endpoint with-
out censoring data [16].
It is remarkable that the head-to-head comparison of
temsirolimus and sorafenib in a second-line setting re-
vealed a significant longer OS in t he sorafenib group [32].
Crossover effects are not the only confounding source
for the correct determination of OS; post-study tumor
treatments also play an important role in this respect. In
case of the approval study for su nitinib it was possible to
analyze the subgroups of patients with no post-study
cancer treatment separately and thus to calculate a sig-
nificant OS compared with the IFN-
group (28.1 vs.
14.1 months) [10]. Similar OS data were presented in the
interim analysis of the COMPARZ trial with sunitinib in
Copyright © 2013 SciRes. JCT
Treatment Effi cacy of Targeted Therapies for Metastatic Renal Cell Carcinoma—A Review
after Seven Years of Experience 27
a first-line setting is estimated to reach 29.3 months
compared with 28.4 months for Pazopanib [21]. Also in
the AXIS trial comparing axitinib and sorafenib as sec-
ond-line therapies in patients previously treated with cy-
tokines the OS was 29.4 and 27.8 months, respectively
[22].
Sequential therapies with the new drugs may permit
mRCC patients to survive even longer, but the optimal
sequence is still unknown. In several retrospective stud-
ies the question of optimal TKI sequencing was investi-
gated [35-40]. In a study with 90 patients at four French
academic centers Sablin et al. reported a significant dif-
ference in OS between the Sor-Sun and the Sun-Sor
group of patients (135 vs. 82 weeks; HR 0.49; p = 0.04)
[35]. In a meta-analysis of Sablin’s and 21 further studies
Stenner et al. conclude that the Sor-Sun sequence trans-
lates into a longer overall PFS than the Sun-Sor seq uence
[38]. Calvani supposes that the higher affinity of sunit-
inib for certain receptor kinases may lead to an overcome
of drug resistance emerging after initial first-line treat-
ment [37. In first-line treatment this potency might in-
duce an aggressive tumor phenotype and make first-line
sunitinib an independent predictor of inferior OS in se-
quential therapies. Yet subgroup analyses of the RE-
CORD-1 study send mixed messages in this regard: The
group who received sorafenib prior to everolimus as only
previous TKI experienced a longer PFS than the one who
received sunitinib (5.9 and 3.9 months, respectively).
With a HR of 1.97 it was discussed that sunitinib pre-
treatment could be a negative prognostic factor for OS
(p < 0.001) [18].
5. Conclusion
In spite of these data the optimal sequence of targeted
therapies remains unclear. As the European Association
of Urology emphasizes in its current guidelines on renal
cell carcinoma, no recommendations in this regard can be
given yet, although it suggests levels of evidence for
each targeted therapy. Second-line options after prior
TKI are axitinib, sorafenib and everolimus. The only
mentioned third-line therapy is everolimus [41]. Further
randomized trials are needed to evaluate sequential the-
rapies for mRCC, especially those in which alternative
sequences are evaluated in a head-to-head comparison.
The results of the currently ongoing prospective SWIT CH
study that randomizes 355 treatment-naïve patients to
receive a sequence of sorafenib followed by sunitinib or
vice versa are expected to shed a clearer light on what is
the optimal TKI-TKI sequence [42].
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