Treatment Efficacy of Targeted Therapies for Metastatic Renal Cell Carcinoma—A Review after Seven Years of Experience

doi:10.4236/jct.2013.49A2004

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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: *[email protected]

Received July 12th, 2013; revised August 10th, 2013; accepted August 18th, 2013

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.

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].

Treatment Effi cacy of Targeted Therapies for Metastatic Renal Cell Carcinoma—A Review

after Seven Years of Experience

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) SunitinibSorafenib vs. SunitinibAxitinib

---

IFN-αSorafenib vs. IFN-αAxitinib 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) SunitinibSorafenib vs. SunitinibTemsirolimus8 vs. 8 3.91 vs. 4.28 16.64 vs. 12.27

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.

Treatment Effi cacy of Targeted Therapies for Metastatic Renal Cell Carcinoma—A Review

after Seven Years of Experience

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

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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