CLINICAL PRACTICE

335Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine

Targeted Therapy for Metastatic Renal Cell Carcinoma

Andika Afriansyah, Agus Rizal A.H. Hamid, Chaidir A. Mochtar, Rainy Umbas
Department of Urology, Faculty of Medicine Universitas Indonesia – Cipto Mangunkusumo Hospital, Jakarta,
Indonesia.

Corresponding Author:
Prof. Rainy Umbas, MD., PhD. Department of Urology, Faculty of Medicine Universitas Indonesia – Cipto
Mangunkusumo Hospital. Jl. Diponegoro no. 71, Jakarta 10430, Indonesia. email: rainy.umbas@gmail.com.

ABSTRAK
Pada sepuluh tahun terakhir, perkembangan terapi target pada karsinoma sel renal bermetastasis menjadi

harapan baru dan mampu meningkatkan prognosis penyakit tersebut. Terdapat tiga terapi target yang telah
dikembangkan termasuk multi-targeted tyrosine kinase inhibitors (TKI), penghambat mammalian target of
rapamycin (mTOR) complex-1 kinase, dan antibodi monoklonal humanized antivascular endothelial growth factor
(VEGF). Tujuan artikel ini secara kritis menelaah studi terkini terapi target untuk tatalaksana pasien tersebut.
Pada sebagian besar uji klinis yang mengevaluasi terapi target, pasien distratifikasi berdasakan model yang
dikembangkan oleh Memorial Sloan Kattering Cancer Center (MSKCC) dan rekomendasi terapi berdasarkan
tingkat resiko pasien. Terapi target lini pertama (belum pernah mendapatkan terapi sistemik sebelumnya), sunitinib,
pazopanib, atau bevacizumab ditambah IFN-α merupakan pilihan terapi dengan tingkat resiko menguntugkan dan
sedang serta gambaran histologi sel jernih. Pasien yang mengalami progresifitas pasca terapi sitokin, sorafenib
atau axitinib adalah pilihan yang direkomendasikan. Karsinoma sel ginjal bermetastasis tipe sel jernih dengan
tingkat resiko menguntungkan dan sedang yang gagal pada terapi target lini pertama dapat ditatalaksana dengan
sorafenib, everolimus, temsirolimus atau axitinib. Akan tetapi, studi saat ini menunjukkan tidak ada pilihan terapi
sekuensial terbaik pasca kegagalan terapi lini pertama. Pasien dengan tingkat risiko buruk dan gambaran histologi
bukan sel jernih, temsirolimus merupakan terapi target yang didukung oleh uji klinis fase III. Saat ini, beberapa
obat baru masih dalam tahap uji klinis fase II dan III dan hasil uji klinis tersebut mungkin dapat mengubah terapi
standar pasien karsinoma sel ginjal bermetastasis di masa yang akan datang.

Kata kunci: karsinoma sel ginjal metastasis, sel jernih, terapi target, terapi sekuensial.

ABSTRACT
In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has

provided a new hope and significantly enhanced the prognosis of the disease. Three class of targeted therapy were
developed, including multi-targeted tyrosine kinase inhibitors (TKI), the mammalian target of rapamycin (mTOR)
complex-1 kinase inhibitors, and the humanized antivascular endothelial growth factor (VEGF) monoclonal
antibody. Hence, the objective of this article was to critically examine the current evidence of targeted therapy
treatment for patients with mRCC. In the majority of trials evaluating targeted therapy, patients were stratified
according to Memorial Sloan Kattering Cancer Center (MSKCC) risk model and the recommendation of targeted
treatment based on risk features. In first-line setting (no previous treatment), sunitinib, pazopanib, or bevacizumab
plus IFN-α were recommended as treatment options for patient with favorable- or intermediate- risk features and
clear cell histology. Patients who progressed after previous cytokine therapy would have sorafenib or axitinib as
treatment options. Clear-cell mRCC with favorable- or intermediate- risk features and failure with first-line TKI
therapy might be treated with sorafenib, everolimus, temsirolimus or axitinib. However, the current evidence did

Andika Afriansyah Acta Med Indones-Indones J Intern Med

336

not show the best treatment sequencing after first-line TKI failure. In patients with poor-risk clear-cell and non-
clear cell mRCC, temsirolimus was the treatment option supported by phase III clinical trial. In addition, several
new drugs, nowadays, are still being investigated and waiting for the result of phase II or III clinical trial, and
this might change the standard therapy for mRCC in the future.

Keywords: clear cell, metastatic, non-clear cell, renal cell carcinoma, sequential therapy targeted therapy.

INTRODUCTION
Kidney cancer is one of the most common

malignancies worldwide with 2% of all adult
malignancies, and approximately 271.000 new
cases were diagnosed in 2008.1-3 Approximately
90 % of all renal malignancy are comprised
as renal cell carcinoma (RCC).4 The incidence
of renal tumor differs between countries, with
the highest incidence in Australia, Europe, and
America, and the incidence is low in India, Africa,
and China.5 The mortality was highest in Australia,
New Zealand, North America, and Europe,
whereas the lowest mortality rate was in Africa
and Asia.2 Over the last two decade until recently,
the incidence of RCC increased approximately
2% in Europe and worldwide, though the
incidence decreased in Denmark and Sweden.6
The incidence of kidney cancer in Indonesia is
2.4-3 cases/100.000 population which increased
from the earlier estimation approximately 1.4-
1.8 cases/100.000 population.7 Data from Cipto
Mangunkusumo hospital between 1995 to 2014,
total of 120 patients was diagnosed with RCC.
Among them, 28% of patients were present with
nodal metastasis and 24% of patients were present
with distant metastasis (Mochtar CA, et al, 2015,
unpublished data).

Approximately one third of patients
diagnosed with RCC present with metastatic
diseases, and up to 40% of patients with clinically
localized RCC will develop metastasis.8 Patients
with mRCC face a fatal prognosis, with 5-year
survival rates less than 10%.9 In the past 20 years,
cytokine therapy using interferon-α (IFN-α)
was standard treatment of mRCC and became
the main focus of the research for renal cancer.
The response rate of mRCC patient treated with
IFN-α was less than 10% and median overall
survival (OS) was 13 months. In several trials
evaluated the cytokine, toxicity frequently
occurred and required inpatient administration

for intensive care. The limitations of cytokine
therapy had intensified the research of a new
class of drugs that much more specifics sites
of cellular action than immunotherapy. Recent
development of more specific action, called
targeted therapy, has provided a new hope for the
treatment of mRCC and significantly improved
the perspective of treatment from this disease.10

Three classes of targeted therapy have been
developed including multi-targeted tyrosine
kinase inhibitors (TKI): sorafenib, axitinib,
pazopanib, and sunitinib; the mammalian
target of rapamycin (mTOR) complex 1 kinase
inhibitors: temsirolimus and everolimus; the
humanized antivascular endothelial growth factor
(VEGF) monoclonal antibody: bevacizumab with
interferon (IFN)-α.8,11 Abundance of targeted
agents has been approved for treatment of mRCC,
yet the most effective treatment of mRCC is still
unknown. Systemic targeted treatment may be life
long and expensive, thus financial reason might
be influence the patient compliance.12 In addition,
current Indonesia kidney cancer guideline does
not clearly state the targeted treatment strategy
for mRCC patient.13 In order to improve the
benefits of the targeted therapy, mRCC patients
should be treated based on the risk stratification,
histopathology, and status of previous systemic
treatment. Hence, the aim of this article is to
review the current evidence of targeted treatment
and supplements the treatment strategy for mRCC
patient in our current guideline.

TARGETED THERAPY FOR METASTATIC
CLEAR-CELL RENAL CELL CARCINOMA

Several phase II/III trials evaluated TKI,
VEGF monoclonal antibody, and mTOR
for treating mRCC patients. These trials
predominantly recruited patients with clear-cell
RCC histology. Sunitinib, sorafenib, axitinib,
pazopanib, bevacizumab+ IFNα were attempted

Vol 48 • Number 4 • October 2016 Targeted therapy for metastatic renal cell carcinoma

337

for clear cell mRCC patients with favorable- or
intermediate-risk feature. Temsirolimus was

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evaluated in phase III clinical trial for poor risk
features (Table 1).

Andika Afriansyah Acta Med Indones-Indones J Intern Med

338

Patient Risk Stratification
The Prognostic model to predict survival of

mRCC patients was important for interpreting
and designing a clinical trial. An ideal prognostic
model must be easy to use and included the most
relevant disease characteristics. There were
several prognostic models, which predicted the
patient survival and influenced the choice of
targeted treatment. Memorial Sloan Kattering
Cancer Center (MSKCC) and Groupe Francais
d’Immunotherapie were calculated the prognostic
model based on the outcome of patient treated
with immunotherapy, especially IFN-α and
Interleukin-2 (IL-2).14-16 Since the IFN-α was
a considered as a suitable comparator of a new
drug , the prognostic model that used for clinical
trial should be derived from the population
of mRCC patient treated with IFN-α therapy.
MSKCC model was the first prognostic model
to predict survival of patients in interferon era,
and was used in the majority of trials to evaluate
the targeted treatment. MSKCC risk system
stratified patients with poor-, intermediate-, and
favorable-risk categories based on the number of
clinical features and laboratories (Table 2).14,15

five agents as first line therapy i.e sunitinib,
pazopanib, sorafenib, axitinib, and bevacizumab
+ IFNα (Table 1). Four of these trials were using
IFN-α as comparator, and one trial was using
placebo as comparator, and two trials were using
another TKI as comparator. The majority of
trials included patients without prior systemic
therapy. Three trials included the patients with
prior systemic immunotherapy using IFN-α or
IL-2. Choosing between sunitinib and pazopanib
as the first line therapy was still controversial,
and two trials were performed to evaluate the
efficacy between two agents.

Sunitinib. The first Phase-III trial in 750
showed that patients treated with sunitinib had
longer PFS (11 month vs. 5 month) than IFN-α
group.17 Median OS of this study was 26.4
months for sunitinib group and 21.8 months
in IFN-α group (HR 0.82, 95% CI 0.67 – 1.00,
p= 0.051). Patients included in this study were
predominantly favorable (n=264; 35.2%) or
intermediate (n=421; 56.1%) according to
MSKCC risk features.17,18 Analysis of large
sunitinib global expanded-access study, a
population based study that included a total of
4,543 patients from 50 countries treated with
sunitinib, showed that median OS was 18.4
months and 19.0 months in the patients with
or without prior cytokine therapy, respectively.
The median PFS was 9.3 and 9.7 months in the
patients with or without prior cytokine therapy.19
Other cohort study in different population
setting showed different median OS with 33.1
months and 17.3 months in the Japan and
Canada population.20,21 Data from RenIs (Renal
Information System), a epidemiological database
for patients treated with targeted therapy in
Czech Republic, showed a small difference
of PFS between patient in the population and
clinical trials (10 months vs. 11 months).22

There are many factors that influence the
effects of sunitinib (Table 3). The reduction of
OS was significantly associated with six factors
including Eastern Cooperative Oncology Group
(ECOG) performance status >1, time from
diagnosis to treatment <1 year, hemoglobin
<lower limit of normal (LLN), calcium >upper
limit of normal (ULN), neutrophil count >ULN,
platelet count >ULN. Grassi et al showed that

Table 2. Memorial sloan kattering cancer center (MSKCC)
criteria

Risk factors* Cut-off point used

Karnofsky performance
status

<80

Time from diagnosis to
treatment

<12 months

Hemoglobin <LLN

LDH >1.5 times ULN

Corrected serum calcium >10.0 mg/dl (2.4 mmol/L)

*Favorable (low) risk: no risk factors; Intermediate risk:
one or two risk factors; Poor (high) risk: three or more
risk factors
LDH = lactate dehydrogenase; LLN = lower limit of
normal; ULN = upper limit of normal

Ta r g e t e d T h e r a p y f o r F a v o r a b l e - t o
Intermediate- risk Clear Cell mRCC

First line targeted therapy. Most of the
trials recruited patients with favorable- or
intermediate- risk group based on MSKCC risk
model. Data from 7 randomized controlled trial
(RCT) were used to determine the efficacy of

Vol 48 • Number 4 • October 2016 Targeted therapy for metastatic renal cell carcinoma

339

liver metastasis treated with sunitinib had poor
outcome. From a series of patients treated with
sunitinib in Japan, C-reactive protein (CRP)
≥1 mg/dl, MSKCC poor calcification, liver
metastasis were associated with a decrease of
OS.19,21,23 Izzedine et al showed that OS might
improve when mRCC patient with hypertensive
disease treated with sunitinib and angiotensin
inhibitors.24

Another important thing in patient with
palliative setting beside OS was health-related
quality of life (HRQL). Patient with improvement
OS should have improvement quality of life.
Analysis from Phase III trial compared sunitinib
and IFN-α, the study found that HRQL was
significantly better in the sunitinib group
than IFN-α group. HRQL was measured by
Functional Assessment of Cancer Therapy-
Kidney Symptom Index-15 item (FKSI-15) and

FKSI Disease-Related Symptoms (FKSI-DRS).17
Sunitinib had higher Quality Adjusted Life Years
(QALYs) compared to IFN-α, 1.99 QALYs vs.
1.33 QALYs. However, the incremental cost for
one QALYs was still expensive, approximately
$ 52,593 (IDR 734,618,108).25 When sunitinib
was compared to best supportive care (BSC),
patient treated with sunitinib had higher QALY
than BSC, 1.36 QALYs vs. 0.39 QALYs. For
one extra QALY, there was incremental cost
approximately €34,196 (IDR 523,280,336) per
QALY gained.26

Pazopanib. Strernberg et al performed Phase
III clinical trial and randomized 435 patients
with predominantly favorable- (n=170, 39%)
or intermediate- (n=236; 54%) risk factor. This
trial included the patients who had or had not
been treated with cytokine therapy. The result
of this trial showed that patients treated with

Table 3. Factors associated with reduced OS in mRCC patients treated with Sunitinib

Study Parameters HR 95% CI

Gore et al (2015)31 ECOG PS >1 2.2 1.98-2.44

Time from diagnosis to
treatment < 1 year

1.32 1.21–1.44

Hemoglobin < LLN 1.84 1.68–2.01

Calcium > ULN 1.41 1.25–1.59

Neutrophil count > ULN 2.03 1.83–2.25

Platelet count > ULN 1.36 1.23–1.50

Mizayaki et al (2015)33 Poor MSKCC clasification 1.73 n.p

C-reactive protein ≥1.0mg/dl 2.80 n.p

Liver metastasis 2.37 n.p

Izzedine et al (2015)36 Hypertension patients
treated with angiotensin
inhibitors

0.55 0.35-0.86

Motzer et al (2013)39 White race 0.34 0.13-0.88

Bone metastasis 2.34 1.28-4.29

Baseline corrected Ca > 10
mg/dl

4.36 1.66-11.44

Patil et al (2010)40 ECOG PS > 1 1.52 1.11-2.09

Time from diagnosis to
treatment < 1 year

1.70 1.25-2.33

LDH 2.01 1.54–2.62

Corrected Ca level 1.58 1.30–1.86

Normal hemoglobin level 0.14 0.04-0.44

Bone metastasis 1.46 1.08-1.99

HR = hazard ratio; CI = confident interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; LLN =
lower limit of normal; ULN = upper limit of normal; Ca = calcium; MSKCC = Memorial Sloan Kattering Cancer Center; n.p
= not presented

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340

pazopanib had longer PFS compared with
placebo (median PFS 11.1 vs. 2.8 month).
However, pazopanib treatment did not showed
a statistically significant improvement in median
OS compared with placebo (22.9 months vs.
20.5 months, in pazopanib and placebo arm,
respectively). Diarrhea, hypertension, and nausea
were the most common adverse effects observed
in pazopanib arm.27,28

Sorafenib. In Phase II trial, which evaluated
sorafenib as first line therapy, patient treated
with sorafenib had similar PFS as treated with
IFN-α (approximately 5.7 months). Because of
this findings, there was not any phase III trial
which performed for evaluating sorafenib as
the first-line therapy. However, greater numbers
of patients showed regression of tumor size in
sorafenib arm (68.2% vs. 39.0%).18 Different
result was found when sorafenib was used for
patients with unsuccessful cytokine therapy.
Sorafenib showed effects on prolongs the
median PFS compared to placebo, 5.5 months
in sorafenib arm and 2.8 months in placebo arm.
There was no statistically significant difference
between sorafenib and placebo for prolonged the
median OS.29,30 Propocio et al assessed sorafenib
as first line and second line therapy in community
setting, and found that the efficacy of sorafenib
was generally as good as in clinical trial,
especially when sorafenib was used as second
line. Patients treated with sorafenib as first line
had median OS 17.2 months and the second
line had median OS 16.3 months. This study
suggested that sorafenib might be used as first
line and second line setting, although the result
from clinical trial, which assessed sorafenib as
first line therapy, showed no difference compared
with IFN-α.31

Axitinib. Phase III trial evaluated the efficacy
of axitinib compared with sorafenib in mRCC
patients. In the subgroup analysis of patients
who progressed with cytokine therapy, axitinib
was statistically significant in prolonged median
PFS, 12.1 months in axitinib arm vs. 6.5 months
in sorafenib arm, but there was no statistically
significant in prolong the OS.32,33

Bevacizumab plus IFN-α. There were two
trials that evaluated the efficacy of combination
bevacizumab +IFN-α compared to IFN-α alone.

Rini et al recruited 732 patients who treated with
bevacizumab plus IFN-α or IFN-α alone, and
found better results for PFS in bevacizumab
plus IFN-α group than IFN-α mono-therapy
(8.5 vs. 5.2 month). OS between two groups
was no statistically different (18.3 vs. 17.4
months).34 Other trial from Escudier et al
showed statistically different of PFS outcome
in bevacizumab plus IFN-α arm vs. placebo plus
IFN-α (10.2 vs. 5.4 months).35

Comparison between first-line therapy.
Several studies evaluated the efficacy of targeted
therapy compared with IFN-α or placebo, whereas
just pazopanib and sunitinib was compared
in head-to head trial.17,28,36,37 Two randomized
clinical trial, COMPARZ (Comparing the
Efficacy, Safety and Tolerability of Pazopanib
versus Sunitinib) and PISCES (Patient Preference
Study of Pazopanib versus Sunitinib in Advanced
or Metastatic Kidney Cancer) study, had been
conducted to determine treatment options
between sunitinib and pazopanib as first line
targeted therapy. COMPARZ trial showed
the non-inferiority comparative effectiveness
between pazopanib 800 mg once daily continuing
dose and sunitinib once daily dose of 50 mg for
4 weeks followed by 2 weeks without treatment.
Disease-progression events developed in 60% of
patients (336 of 557) in pazopanib arm and 58%
patients (323 of 553) in sunitinib group. The non-
inferiority of pazopanib compared with sunitinib
are also observed in PFS outcome (median PFS
10.2 months in sunitinib group vs. 10.5 months
in pazopanib group).38 Even tough the survival
rate of sunitinib and pazopanib was similar, these
agents might be different in the incidence of
toxicities that influenced health-related quality-
of-life (HRQoL), and this circumstance should
be considered in palliative setting. The PISCES
study was designed using crossover method to
assess patient’s preference either pazopanib or
sunitinib. This study reported that more patients
were prefer using pazopanib (70% of patients)
than sunitinib (22%), with HRQoL and safety
as independent influencing factors.39

Milis et al40 conducted a meta-analysis of
trial to evaluate the effectiveness of targeted
therapy by using adjusted indirect comparison.
They found the superiority of sunitinib compared

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341

with bevacizumab plus IFN-α (HR 0.75, 95% CI
0.60-0.93, p = 0.001) and sorafenib (HR 0.58,
95% CI 0.38 to 0.36, p = 0.001) to improve the
PFS. In addition, there was no difference between
bevacizumab and sorafenib in prolong the OS.

Hence, we recommended that sunitinib,
pazopanib, and bevacizumab plus IFN-α were
used for mRCC patient in first-line setting
(no previous systemic treatment). In addition,
sorafenib and axitinib were recommended for
patient with previous immunotherapy (with
IFN-α or IL-2).

Sequential treatment after progressed with
first-line therapy. Most patients experienced
disease progression with targeted therapy, and
sequential therapy with different agents might
be clinically benefits. However, choosing the
sequence of TKI remained clinical challenge.
The rationale of using sequential therapy for
treating progressing mRCC was evaluated in
several trial including: RECORD-1 (Renal
Cell cancer treatment with Oral RAD001 given
Daily); INTROSECT (Investigating Torisel As
Second-Line Therapy); SWITCH (Efficacy and
Safety of Sorafenib Followed by Sunitinib Versus
Sunitinib Followed by Sorafenib in the Treatment
of First-Line Advanced mRCC); RECORD-3;
AXIS (Axitinib as Second-Line Therapy for
Metastatic Renal Cell Cancer). (Table 4)

RECORD-1 trial. Motzer et al conducted
the first randomized trial of sequential targeted
therapy in progressing mRCC patients who got
targeted therapy with sunitinib or sorafenib.
They randomized 416 patients to receive oral
everolimus 10 mg per day or placebo. Majority
of patients in this study were favorable- or
intermediate- risk factors. The main outcome was
PFS using RECIST criteria based on radiology
evaluation. This study showed a statistically
difference of PFS between everolimus arm and
placebo arm with median PFS, which was 4.9
months versus 1.9 months respectively (HR 0.33;
p<0.001). However, there was no statistically
significant difference OS in everolimus and
placebo arm. This study concluded the efficacy
and safety of everolimus in patients with mRCC
after progression of sunitinib or sorafenib.41

INTROSECT trial. This trial compared the
efficacy of temsirolimus and sorafenib as second

line therapy after progression on sunitinib. This
study were randomly assigned 512 patients
to receive 25 mg once weekly intravenous
temsirolimus or oral sorafenib 400 mg twice
per day. The trial found that there was no PFS
advantage between temsirolimus and sorafenib,
with median PFS in temsirolimus arm was 4.3
months compared with 3.9 months in sorafenib
arm. However, in OS outcome, there was a
significant difference between median OS of
sorafenib arm compared to temsirolimus arm,
16.6 months vs. 12.3 months, respectively. The
longer OS suggested that the usage of sequence
VEGF inhibitor might have benefits in patients
with mRCC.42

SWITCH trial. This trial was the first
prospective phase III-RCT that evaluated the
sequential therapy with sorafenib-sunitinib (So-
Su) or sunitinib-sorafenib (Su-So) in advanced/
mRCC. From the total of 365 patients included in
this study, 182 patients were randomly assorted
into So-Su arm and 183 patients into Su-So
arm. Median first-line PFS showed similarity
between two groups, but median second-line PFS
was longer in So-Su than Su-So. Total PFS and
OS was no difference between to study group.
The study concluded that both of treatment
options were similarly effective in patients with
advanced/mRCC.43

RECORD-3 trial. This trial evaluated the
sequential therapy with first-line everolimus and
second-line sunitinib versus first-line sunitinib
and second-line everolimus. The total of 471
patients with metastatic clear cell or non-clear
cell RCC enrolled in this Phase-II clinical trial,
238 patients randomly assigned into everolimus-
sunitinib and 233 patients into sunitinib-
everolimus arm. The primary end point of this
study was median OS and PFS. The median
combined PFS was not statistically different
between two arms which the median PFS was
21.1 months for everolimus-sunitinib arm and
25.8 months for sunitinib-everolimus arm (HR
1.3; 95% CI 0.9 – 1.7). There was no statistically
difference between two arms for prolonged OS.44

AXIS trial. Seven hundred twenty three
patients were evaluated after progressed with
first line treatment with sunitinib, temsirolimus,
cytokines, or bevacizumab plus IFN-α. They

Andika Afriansyah Acta Med Indones-Indones J Intern Med

342

Table 4. Sequential therapies and their impact on metastatic renal cell carcinoma

Clinical Trial Treatment groups
Study
design

Study eligibility
N

(patients)
Median PFS

(months)

Median
OS

(months)

RECORD-145,46
Sunitinib/sorafenib-
everolimus vs.
sunitinib/sorafenib-
placebo

Randomized
open label
study

- Clear-cell mRCC
patients

- Progressed on
sunitinib or sorafenib

410 (272
vs. 138)

4.0 vs. 1.9*
14.8 vs.

14.4

INTROSECT47
Sunitinib-
temsirolimus vs.
sunitinib-sorafenib

Randomized
open label
study

- Metastatic RCC
patients (any
histology)

- Progressed after
sunitinib as first line
therapy

512 (259
vs. 253)

4.3 vs. 3.9
12.3 vs.

16.6*

SWITCH48
Sorafenib-sunitinib
vs. sunitinib-
sorafenib

Randomized
open label
study

- Metastatic RCC (all
histology)

- No prior systemic
therapy

365 (182
vs. 183)

12.5 vs. 14.9†
(5.9 vs. 8.5††
g 5.4 vs.
2.8†††)

31.5 vs.
30.2†

RECORD-349
Everolimus-sunitinib
vs. sunitinib-
everolimus

Randomized
open label
study

- Metastatic clear cell or
non-clear cell RCC

- No previous systemic
therapy

471 (238
vs. 233)

25.1 vs. 25.8†
22.4 vs.
23.8†

AXIS26,27
Sunitinib – axitinib
vs. sunitinib -
sorafenib

Double blind-
RCT

- Metastatic clear-cell
RCC

- Progressed after
sunitinib as first line
therapy

389 (94
vs. 195)

4.8 vs. 3.4*
15.2 vs.

16.5

Bevacizumab
– axitinib vs.
bevacizumab -
sorafenib

Double blind-
RCT

- Metastatic clear-cell
RCC

- Progressed after
bevacizumab as first
line therapy

59 (29 vs.
30)

4.2 vs. 4.7
14.7 vs.

19.8

Temsirolimus-
axitinib vs.
temsirolimus -
sorafenib

Double blind-
RCT

- Metastatic clear-cell
RCC Progressed after
temsirolimus as first
line therapy

24 (12 vs.
12)

10.1 vs. 5.3
18.0 vs.

8.5

TKI = tyrosine kinase inhibitors; N = number of patients; PFS = progression free survival; OS = overall survival; vs.= versus;
RCT = randomized controlled trial; *= statistically significant; †= combined median OS/PFS after first-line and second line
†† = median first-line PFS/OS; †††= median second-line PFS/OS.

compared the axitinib 5 mg twice daily with
sorafenib 400 mg twice daily. PFS is the primary
end point using RECIST criteria. The secondary
outcomes were OS, objective respond rate, and
disease progression. Among 723 patients, 361
patients assigned to axitinib arm and 362 patients
assigned to sorafenib arm. The median PFS was
6.7 months in axitinib arm compared with 4.7
months in sorafenib arm (HR 0.665; 95% CI
0.544-0.812; one sided p<0.001). Axitinib was
superior compared to sorafenib for the PFS in
patients with previously treated with sunitinib.
There was no difference in OS data, which
median OS 20.1 months in axitinib arms and
19.2 months in sorafenib arm (HR: 0.969; 95%

CI: 0.800-1.174, p = 0.374). In the subgroup
analysis of patients previously treated with
sunitinib, bevacizumab, and temsirolimus, the
study did not record any statistically significant
difference either in sunitinib or axitinib for
prolong the OS.32

T h e r e f o r e , a c c o r d i n g t o t h e s e t r i a l s
reviewed, it concluded that any sequential
therapy has similar effects on prolong PFS
and OS. Sorafenib, everolimus, temsirolimus,
and axitinib might be useful for patients who
progressed after first line TKI. In addition,
axitinib was superior than sorafenib in term of
prolonged PFS, but not prolonged OS of patients
who progressed after first line targeted treatment.

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Targeted Therapy for Poor-risk Metastatic
Clear Cell Carcinoma

The efficacy of targeted therapy, especially
temsirolimus, in treating mRCC with poor-risk
category was evaluated in Phase-III conducted by
Hudes et al. They randomly assigned 626 patients
to receive 25 mg of intravenous temsirolimus,
3 million U of IFN-α subcutaneous three times
weekly, or the combination therapies with 15 mg
of temsirolimus weekly plus 6 million U of IFN-α
three times weekly. The comparison between
temsirolimus mono-therapy and IFN-α mono-
therapy illustrated that the OS was statistically
significant with median OS 10.9 months in
temsirolimus group versus 7.3 months in IFN-α
group (HR 0.73, 95% CI: 0.58-0.92, p = 0.008).
The combination of temsirolimus and IFN-α did
not show a significant improvement of OS and
showed a greater risk of toxicity than mono-
therapy subgroup. In addition, this study showed
the difference of median PFS in the IFN-α,
temsirolimus, and combination-therapy: 1.9
month, 3.8 month, and 3.7 months, respectively.45

Temsirolimus was better tolerated than IFN-α
with the grade 3 and 4 adverse events lower in
the temsirolimus group (67%) than in the IFN-α
group (78%). Although, grade 3 and 4 metabolic
alteration (hypertriglyceridemia, hyperglycemia,
and hypokalemia) and cutaneous rash were more
common in temsirolimus group compared with
IFN-α. Asthenia, pyrexia, and neutropenia were
more frequent in the IFN-α group. Treatment
discontinuations due to adverse event were lower
in temsirolimus group than IFN-α, 7% and 4 %
respectively.45

Hudes et al45 is the only one Phase-III
randomized clinical trial that evaluated the
efficacy of targeted therapy in naïve poor-
risk mRCC patients. If temsirolimus cannot
be administrated to poor-risk patients, the
alternatives of therapy might be answered from
Phase-III trial that enrolled limited number of
poor-risk patients. In the AVOREN trial assessing
efficacy of bevacizumab, the study included
54 patients from 649 patients who classified
as poor risk according to MSKCC risk score.
Sub-group analysis of patients with poor risk
found that there was no significant differences
between patients treated with bevacizumab and

bevacizumab plus IFN-α (HR: 0.87; 95% CI:
0.48-1.56).37 The same results was reported from
other studies evaluating the sunitinib for patients
with poor risk group. There was no significant
difference between OS comparing sunitinib and
IFN-α (5.3 months in sunitinib vs. 4.0 months
in IFN-α; HR 0.660; 95%CI: 0.360-1.207). In
conclusion, bevacizumab plus IFN-α or sunitinib
might be used for poor-risk mRCC patients when
temsirolimus could not be used.17

TARGETED THERAPY FOR METASTATIC
NON-CLEAR CELL CARCINOMA

Because of diversity in the molecular and
genetic basis of non-clear cell type, the trial
was performed for clear cell mRCC, might
not be extrapolated to other histology type of
RCC. There was no current consensus about
appropriate first line treatment due to lack of
level 1 evidence. Targeted treatment in non-clear
cell RCC focused on temsirolimus, everolimus,
sorafenib, and sunitinib.

I n t h e A R C C ( A d v a n c e R e n a l C e l l
Carcinoma) trial, temsirolimus was evaluated
in 73 patients with mRCC non clear-cell type
(37 randomized to temsirolimus and 36 patients
to IFN-α arm).45 This study found that the
differences OS between temsirolimus arm and
IFN-α arm were 11.6 months and 4.3 months
with HR 0.49; 95% CI 0.29-0.85. They also
observed that PFS was longer in temsirolimus
arm than IFN-α arm with median PFS in
temsirolimus arm 7.0 months vs. 1.8 months in
IFN-α arm (HR 0.38, 95% CI 0.23-0.62). This
study concluded that temsirolimus had clinically
benefits compared to IFN-α in non-clear cell
histology.46

Escudier et al47 performed phase II trial to
evaluate the efficacy of other mTOR inhibitor,
everolimus, for treating 92 patients with
metastasis non-clear cell RCC. There were 59%
of patients receiving everolimus that had non-
progressing disease within 6 months. Median OS
was 21 months and median PFS was 7.6 months
with grade ≥3 adverse events including asthenia
(10.9%), fatigue (5.4%), and anemia (5.4%).

The ESPN (Everolimus Versus Sunitinib
Prospective Evaluation in Metastatic Non-Clear
Cell Renal Cell Carcinoma) trial conducted

Andika Afriansyah Acta Med Indones-Indones J Intern Med

344

by Tannir et al48 was performed to evaluate
the efficacy of everolimus or sunitinib to treat
metastatic non-clear RCC. This study was
multicenter randomized clinical trial with cross
over design and used PFS as primary outcome.
The study reported that OS and PFS showed
advantage of sunitinib group compared with
everolimus (16.2 months vs. 14.9 months;
p=0.01, and 6.1 months vs. 4.1 months; p=0.25,
respectively).

INVESTIGATIONAL AGENTS
With the advancement of knowledge of

the molecular mechanism about RCC, several
agents of new-targeted treatment were being
developed for improving the survival of mRCC
patients.49,50 Recently, the majority of phase
II or phase III clinical trial included VEGF
inhibition as mechanism of action to inhibit
tumor progression. Resistance to inhibition of
VEGF was being suggested as a reason for tumor
progression after therapy of VEGF inhibitor, and
dual (or multiple) pathway inhibition was being
developed for overcoming resistance to VEGF.51
Lenvatinib, an agent that inhibit both VEGFR
and FGFR, has been granted by Food and Drug
Administration (FDA) as a potential treatment
of advance RCC based on phase II clinical
trial conducted by Motzer et al.52 Lenvatinib
monotherapy showed improvement of median
PFS by 39% compared with everolimus (HR
0.61; 95% CI 0.38-0.98; p =0.048). OS analysis
showed better outcome in the combination
of lenvatinib and everolimus compared with
everolimus monotherapy.53

In the past decade, immunotherapy has been
less studied due to the extensive development of
VEGF- and mTOR- directed therapy. However,
enthusiasm has been directed to immune
surveillance due to dramatic response of
anti PD-1 antibody in the patient of RCC.54
Nivolumab was the most extensively studied
PD-1 inhibitor in mRCC. Clinical phase II trial
showed a promising efficacy of nivolumab in
treating mRCC patients with previous anti-
angiogenic treatment. We are still waiting for the
recent phase III trial which comparing between
Nivolumab and everolimus in mRCC patient
with previously treated by systemic therapy.55,56

Cabozantinib, a TKI with potent activity
against MET gene and VEGFR 2 receptors, has
showed clinical benefits in patients with advanced
clear-cell RCC in a single arm trial. Phase III
METEOR (Cabozantinib vs. Everolimus in
Subjects With Metastatic Renal Cell Carcinoma)
trial evaluated the efficacy of 60 mg cabozantinib
compared with 10 mg temsirolimus, yet this trial
is still on going.57 Other, several clinical trials
of phase II or III such as AGS-003 (autologous
dendritic cell immunotherapy) and MPDL3280A
(an engineered anti-PDL1 antibody) are still in
progress.58,59

CONCLUSION
The development of targeted therapy has

significantly improved the perspective of
mRCC treatment. Sunitinib, pazopanib, and
bevacizumab have demonstrated significant
improvement of PFS as a first line targeted
therapy in metastatic clear cell type RCC patients
with favorable- and intermediate- risk category.
Clear cell mRCC patients with favorable- and
intermediate-risk category who progressed after
prior cytokine therapy, sorafenib, axitinib, and
pazopanib showed improvement of PFS. There
was no difference on prolonged PFS and OS
between sequential therapies. Temsirolimus
showed benefit in prolonged PFS and OS in
clear-cell poor risk category and non-clear
cell mRCC. Several new drugs are still being
investigated and waiting for the results of phase
II or III clinical trial.

REFERENCES
1. Parkin DM, Bray F, Ferlay J, et al. Global cancer

statistics, 2002. CA Cancer J Clin. 2005;55(2):74-108.
2. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide

burden of cancer in 2008: GLOBOCAN 2008. Int J
Cancer. 2010;127(12):2893-917.

3. Ljungberg B, Campbell SC, Choi HY, et al. The
epidemiology of renal cell carcinoma. Eur Urol.
2011;60(4):615-21.

4. Gupta K, Miller JD, Li JZ, et al. Epidemiologic
and socioeconomic burden of metastatic renal cell
carcinoma (mRCC): a literature review. Cancer Treat
Rev. 2008;34(3):193-205.

5. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates
of cancer incidence and mortality in Europe in 2008.
Eur J Cancer. 2010;46(4):765-81.

6. Karim-Kos HE, de Vries E, Soerjomataram I, et

Vol 48 • Number 4 • October 2016 Targeted therapy for metastatic renal cell carcinoma

345

al. Recent trends of cancer in Europe: a combined
approach of incidence, survival and mortality for
17 cancer sites since the 1990s. Eur J Cancer.
2008;44(10):1345-89.

7. Umbas R, Safriadi F, Mochtar CA, et al. Urologic
cancer in Indonesia. Jpn J Clin Oncol. 2015;45(8):708-
12.

8. Flanigan RC, Campbell SC, Clark JI, et al. Metastatic
renal cell carcinoma. Curr Treat Options Oncol.
2003;4(5):385-90.

9. Patil S, Manola J, Elson P, et al. Improvement in overall
survival of patients with advanced renal cell carcinoma:
prognostic factor trend analysis from an international
data set of clinical trials. J Urol. 2012;188(6):2095-100.

10. Pal SK, Nelson RA, Vogelzang N. Disease-specific
survival in de novo metastatic renal cell carcinoma
in the cytokine and targeted therapy era. PLoS One.
2013;8(5):e63341.

11. Molina AM, Motzer RJ. Clinical practice guidelines for
the treatment of metastatic renal cell carcinoma: today
and tomorrow. Oncologist. 2011;16 Suppl 2:45-50.

12. Lesmana LA, Gani RA, Hasan I, et al. Influence of
the sorafenib patients assistance program on treatment
compliance and overall survival of unresectable
hepatocellular carcinoma patients. Acta Med Indones.
2012;44(3):228-32.

13. Umbas R, Hardjowijoto S, Safriadi F, et al. Panduan
penanganan kanker ginjal (Guidelines on renal
malignant tumour). Jakarta: Ikatan Ahli Urologi
Indonesia; 2012.

14. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa
as a comparative treatment for clinical trials of new
therapies against advanced renal cell carcinoma. J Clin
Oncol. 2002;20(1):289-96.

15. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and
prognostic stratification of 670 patients with advanced
renal cell carcinoma. J Clin Oncol. 1999;17(8):2530-
40.

16. Negrier S, Escudier B, Gomez F, et al. Prognostic
factors of survival and rapid progression in 782 patients
with metastatic renal carcinomas treated by cytokines:
a report from the Groupe Francais d’Immunotherapie.
Ann Oncol. 2002;13(9):1460-8.

17. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib
versus interferon alfa in metastatic renal-cell carcinoma.
N Engl J Med. 2007;356(2):115-24.

18. Escudier B, Szczylik C, Hutson TE, et al. Randomized
phase II trial of first-line treatment with sorafenib
versus interferon Alfa-2a in patients with metastatic
renal cell carcinoma. J Clin Oncol. 2009;27(8):1280-9.

19. Gore ME, Szczylik C, Porta C, et al. Final results
from the large sunitinib global expanded-access
trial in metastatic renal cell carcinoma. Br J Cancer.
2015;113(1):12-9.

20. Heng DY, Chi KN, Murray N, et al. A population-based
study evaluating the impact of sunitinib on overall
survival in the treatment of patients with metastatic

renal cell cancer. Cancer. 2009;115(4):776-83.
21. Miyazaki A, Miyake H, Harada KI, et al. Prognostic

outcome in patients treated with tyrosine kinase
inhibitors as first-line molecular-targeted therapy
for metastatic renal cell carcinoma: Experience in
real-world clinical practice in Japan. Mol Clin Oncol.
2015;3(3):601-6.

22. Poprach A, Bortlicek Z, Buchler T, et al. Patients with
advanced and metastatic renal cell carcinoma treated
with targeted therapy in the Czech Republic: twenty
cancer centres, six agents, one database. Med Oncol.
2012;29(5):3314-20.

23. Grassi P, Verzoni E, Porcu L, et al. Sites of disease
as predictors of outcome in metastatic renal cell
carcinoma patients treated with first-line sunitinib or
sorafenib. Ther Adv Urol. 2015;7(2):59-68.

24. Izzedine H, Derosa L, Le Teuff G, et al. Hypertension
and angiotensin system inhibitors: impact on outcome
in sunitinib-treated patients for metastatic renal cell
carcinoma. Ann Oncol. 2015;26(6):1128-33.

25. Remak E, Charbonneau C, Negrier S, et al. Economic
evaluation of sunitinib malate for the first-line
treatment of metastatic renal cell carcinoma. J Clin
Oncol. 2008;26(24):3995-4000.

26. Paz-Ares L, del Muro JG, Grande E, et al. A cost-
effectiveness analysis of sunitinib in patients with
metastatic renal cell carcinoma intolerant to or
experiencing disease progression on immunotherapy:
perspective of the Spanish National Health System. J
Clin Pharm Ther. 2010;35(4):429-38.

27. Sternberg CN, Hawkins RE, Wagstaff J, et al. A
randomised, double-blind phase III study of pazopanib
in patients with advanced and/or metastatic renal cell
carcinoma: final overall survival results and safety
update. Eur J Cancer. 2013;49(6):1287-96.

28. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib
in locally advanced or metastatic renal cell carcinoma:
results of a randomized phase III trial. J Clin Oncol.
2010;28(6):1061-8.

29. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for
treatment of renal cell carcinoma: Final efficacy and
safety results of the phase III treatment approaches
in renal cancer global evaluation trial. J Clin Oncol.
2009;27(20):3312-8.

30. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in
advanced clear-cell renal-cell carcinoma. N Engl J
Med. 2007;356(2):125-34.

31. Procopio G, Derosa L, Gernone A, et al. Sorafenib as
first- or second-line therapy in patients with metastatic
renal cell carcinoma in a community setting. Future
Oncol. 2014;10(10):1741-50.

32. Rini BI, Escudier B, Tomczak P, et al. Comparative
effectiveness of axitinib versus sorafenib in advanced
renal cell carcinoma (AXIS): a randomised phase 3
trial. Lancet. 2011;378(9807):1931-9.

33. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib
versus sorafenib as second-line treatment for advanced

Andika Afriansyah Acta Med Indones-Indones J Intern Med

346

renal cell carcinoma: overall survival analysis and
updated results from a randomised phase 3 trial. Lancet
Oncol. 2013;14(6):552-62.

34. Escudier B, Pluzanska A, Koralewski P, et al.
Bevacizumab plus interferon alfa-2a for treatment of
metastatic renal cell carcinoma: a randomised, double-
blind phase III trial. Lancet. 2007;370(9605):2103-11.

35. Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial
of bevacizumab plus interferon alfa versus interferon
alfa monotherapy in patients with metastatic renal
cell carcinoma: final results of CALGB 90206. J Clin
Oncol. 2010;28(13):2137-43.

36. Motzer RJ, Hutson TE, Tomczak P, et al. Overall
survival and updated results for sunitinib compared
with interferon alfa in patients with metastatic renal
cell carcinoma. J Clin Oncol. 2009;27(22):3584-90.

37. Escudier B, Bellmunt J, Negrier S, 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.
2010;28(13):2144-50.

38. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus
sunitinib in metastatic renal-cell carcinoma. N Engl J
Med. 2013;369(8):722-31.

39. Escudier B, Porta C, Bono P, et al. Randomized,
controlled, double-blind, cross-over trial assessing
treatment preference for pazopanib versus sunitinib in
patients with metastatic renal cell carcinoma: PISCES
Study. J Clin Oncol. 2014;32(14):1412-8.

40. Mills EJ, Rachlis B, O’Regan C, et al. Metastatic renal
cell cancer treatments: An indirect comparison meta-
analysis. BMC Cancer. 2009;9:34.

41. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial
of everolimus for metastatic renal cell carcinoma :
final results and analysis of prognostic factors. Cancer.
2010;116(18):4256-65.

42. Hutson TE, Escudier B, Esteban E, et al. Randomized
phase III trial of temsirolimus versus sorafenib
as second-line therapy after sunitinib in patients
with metastatic renal cell carcinoma. J Clin Oncol.
2014;32(8):760-7.

43. Eichelberg C, Vervenne WL, De Santis M, et al.
SWITCH: A Randomised, Sequential, Open-label
Study to Evaluate the Efficacy and Safety of Sorafenib-
sunitinib Versus Sunitinib-sorafenib in the Treatment
of Metastatic Renal Cell Cancer. Eur Urol. 2015;doi:
10.1016/j.eururo.2015.04.017.

44. Motzer RJ, Barrios CH, Kim TM, et al. Phase II
randomized trial comparing sequential first-line
everolimus and second-line sunitinib versus first-
line sunitinib and second-line everolimus in patients
with metastatic renal cell carcinoma. J Clin Oncol.
2014;32(25):2765-72.

45. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus,
interferon alfa, or both for advanced renal-cell
carcinoma. N Engl J Med. 2007;356(22):2271-81.

46. Dutcher JP, de Souza P, McDermott D, et al. Effect of

temsirolimus versus interferon-alpha on outcome of
patients with advanced renal cell carcinoma of different
tumor histologies. Med Oncol. 2009;26(2):202-9.

47. Escudier BJ, Bracarda S, Maroto Rey JP, et al. Open-
label, phase II raptor study of everolimus (EVE)
for papillary mRCC: Efficacy in type 1 and type 2
histology. ASCO Meeting Abstracts. 2014;32(4_
suppl):410.

48. Tannir NM, Jonasch E, Altinmakas E, et al. Everolimus
versus sunitinib prospective evaluation in metastatic
non-clear cell renal cell carcinoma (The ESPN Trial):
A multicenter randomized phase 2 trial. ASCO Meeting
Abstracts. 2014;32(15_suppl):4505.

49. Randall JM, Millard F, Kurzrock R. Molecular
aberrations, targeted therapy, and renal cell carcinoma:
current state-of-the-art. Cancer Metastasis Rev.
2014;33(4):1109-24.

50. Thomas JS, Kabbinavar F. Metastatic clear cell renal
cell carcinoma: A review of current therapies and novel
immunotherapies. Crit Rev Oncol Hematol. 2015.

51. Ciamporcero E, Miles KM, Adelaiye R, et al.
Combination strategy targeting VEGF and HGF/c-met
in human renal cell carcinoma models. Mol Cancer
Ther. 2015;14(1):101-10.

52. Motzer R, Hutson T, Glen H, et al. Randomized phase
II, three-arm trial of lenvatinib (LEN), everolimus
(EVE), and LEN+EVE in patients (pts) with metastatic
renal cell carcinoma (mRCC). ASCO Meeting
Abstracts. 2015;33(15_suppl):4506.

53. Sonpavde G, Willey CD, Sudarshan S. Fibroblast
growth factor receptors as therapeutic targets in clear-
cell renal cell carcinoma. Expert Opin Investig Drugs.
2014;23(3):305-15.

54. Pal SK, Haas NB. Adjuvant therapy for renal cell
carcinoma: Past, present, and future. Oncologist.
2014;19(8):851-9.

55. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab
for Metastatic Renal Cell Carcinoma: Results
of a Randomized Phase II Trial. J Clin Oncol.
2015;33(13):1430-7.

56. Xu KY, Wu S. Update on the treatment of metastatic
clear cell and non-clear cell renal cell carcinoma.
Biomark Res. 2015;3:5.

57. Exiles. A Study of Cabozantinib (XL184) vs Everolimus
in Subjects With Metastatic Renal Cell Carcinoma
(METEOR). In: ClinicalTrials.gov [internet] Bethesda
(MD): National Library of Medicine (US). 2015 [cited
2015 Sept 2] Available from: https://clinicaltrials.
gov/ct2/show/NCT01865747 NLM Identifier:
NCT01865747.

58. Hoffmann-La Roche. A Phase 2 Study of MPDL3280A
(an Engineered Anti-PDL1 Antibody) as Monotherapy
or in Combination With Avastin (Bevacizumab)
Compared to Sunitinib in Patients With Untreated
Advanced Renal Cell Carcinoma. In: ClinicalTrials.
gov [Internet]. Bethesda (MD): National Library of
Medicine (US). 2015 [cited 2015 Sept 1] Available

Vol 48 • Number 4 • October 2016 Targeted therapy for metastatic renal cell carcinoma

347

from: http://clinicaltrials.gov/show/NCT01984242
NLM Identifier: NCT01984242.

59. Argos Therapeutics. Phase 3 Trial of Autologous
Dendritic Cell Immunotherapy (AGS-003) Plus
Standard Treatment of Advanced Renal Cell Carcinoma
(RCC) (ADAPT). In: ClinicalTrials.gov [Internet].
Bethesda (MD): National Library of Medicine (US).
2015 [cited 2015 Sept 2] Available from: https://
clinicaltrials.gov/ct2/show/NCT01582672 NLM
Identifier: NCT01582672.