Targeted Therapies for the

Treatment of Metastatic Renal

Cell
Carcinoma: Clinical Evidence

Di bacakan oleh
Yose Rinaldi

 systemic therapy for patients with

metastaticrenal cell carcinoma (mRCC)
was limited to cytokines :
- interleukin-2 and interferon (IFN)
for first- and second-line
These include:
sorafenib,sunitinib, bevacizumab
(plus IFN-), temsirolimus,everolimus,
and, most recently, pazopanib

INTRODUCTION
In the past 5 years, treatment
options have expanded for patients
with metastatic renal cell
carcinoma(mRCC),
systemic treatment was limited to
cytokine therapy with interleukin (IL)2 or interferon(IFN), because mRCC is
largely resistant to chemotherapy

 Cytokine use is based on the rationale that

immune system stimulation kills cancer
cells.
Cytokine therapy is low rates of response
and high rates of toxicity in the first-line.
In the second-line setting (in patients who
have progressedon one cytokine), while
toxicity remains similar to that of first-line
new therapies were needed to improve
outcomes in patients with mRCC.

six targeted therapies have been evaluated

randomized, controlled phase III clinical
trials of patients with mRCC
objectives of this article are to review the
clinical evidence supporting the benefits
of these agents, discuss the survival
endpoints used in their pivotal clinical
trials, and identify future research
directions with these targeted therapies.

EFFICACY OF CURRENTLY APPROVED

MOLECULAR-TARGETED AGENTS FOR
MRCC

The six molecular-targeted agents approved

in the U.S. for the treatment of mRCC :
sorafenib,
sunitinib,
bevacizumab
(in combination with IFN-),
temsirolimus,
everolimus and pazopanib

Sorafenib
Sorafenib is an oral multikinase inhibitor
that inhibits signaling, VEGF receptors
(VEGFRs), and platelet derived growth
factor receptors (PDGFRs).
Approved by the U.S. Food and Drug
Administration (FDA)in December 2005
and by the European Medicines
Agency(EMA) in July 2006 for patients with
cytokine-refractory, advanced RCC or
mRCC.

Pasien that group of Treatment Approaches in Renal

Cancer Global Evaluation Trial (TARGET)
Memorial Sloan-Kettering Cancer Center (MSKCC) risk
score [6, 17].
They received continuous oral sorafenib, 400 mg twice daily
(n 451), or placebo (n 452) in 6-week cycles for the first
24 weeks and in 8-week cycles thereafter; treatment was
continued until disease progression or patient withdrawal
from the study.
The primary endpoint was OS, and the secondary endpoint
was PFS.
The study design included assessments of OS at two
planned interim analyses and one final analysis and an
assessment of PFS.

 The interim analysis of PFS, carried out in

January2005
with sorafenib, than with placebo, 5.5
months versus 2.8 months, respectively (p
.001).
The PFS time was longer with sorafenib
regardless of age, MSKCC risk score, prior
cytokine therapy, the presence of lung or
liver metastases at baseline, and time
since diagnosis.

However, a preplanned secondary

analysis that accounted for the
confounding effects of crossover
showed that the OS time was
significantly longer with sorafenib
than with placebo (17.8 months
versus 14.3 months, respectively; p .
0287).

Sunitinib
Sunitinib is an oral multitargeted receptor tyrosine
kinase inhibitor (RTKI) that inhibits signaling by
VEGFRs, PDGFRs, and c-Kit.
The FDA approval in January 2006 and full approval
in January 2007 from the EMA.
Patients received oral sunitinib, 50 mg, once daily in
6-week cycles (4 weeks of treatment and 2 weeks of
no treatment; n 350) or IFN- three times weekly,
escalated in weekly increments from 3 MU to 6 MU to
9MU per dose (n 350). Treatment was continued
until disease progression, unacceptable toxicity, or
consent withdrawal. PFS was the primary endpoint.
OS was a secondary endpoint.

 the second analysis, the median PFS interval

was significantly longer with sunitinib than
with IFN- (11 months versus 5 months; p .
001), and this result was unaffected by
patient age, sex, or MSKCC risk score.
The ORRs at the second analysis were 31%
In addition, QOL was superior with sunitinib
than with IFN-; scores indicated clinically
meaningful differences in kidney cancer
related symptoms and overall QOL (p .001).

The confounding effects showed that the

OS time was significantly longer with
sunitinib than with IFN- (26.4 months
versus 20.0 months, respectively p .036)
Patients who did not receive poststudy
cancer treatment showed that the median
OS time with sunitinib was double that
with IFN- (28.1 months versus 14.1
months, respectively p .003).

Bevacizumab plus IFN Bevacizumab is an i.v. administered anti-VEGF monoclonal

antibody given in combination with injected IFN.
This combination was approved by the EMA in November 2007
and by the FDA in August 2009 for the first-line treatment of
patients with advanced RCC or mRCC.
The pivotal trials, were a randomized, double-blind study of
bevacizumab plus IFN- versus placebo plus IFN-(Avastin and
Roferon in Renal Cell Carcinoma [AVOREN] and a randomized,
openlabel study of bevacizumab plus IFN- versus IFN- (Cancerand
Leukemia Group B [CALGB] 90206; n732).
Both evaluated the same doses of bevacizumab (10mg/kg every
2 weeks) and IFN- (9 MU three times weekly) and had OS as the
primary endpoint.
treatment was continued until disease progression, unacceptable
toxicity, or consent withdrawal administered for a maximum of 52
weeks.

 analyses showed that median interval was

significantly longer with bevacizumab plus IFNthan with the comparator (AVOREN: 10.2 months
versus 5.4 months, respectively; p .0001; CALGB
90206: 8.5 months versus 5.2 months,
respectively; p .0001). In both trials, bevacizumab
plus IFN- showed trends toward a longer OS time
than with the comparator, but the differences were
not statistically significant. However, the OS
results of both trials were likely confounded.

In addition, more than half the

patients in each arm who
discontinued because of disease
progression or other reasons
received subsequent therapy, which
included sorafenib and sunitinib.

Temsirolimus
Temsirolimus is an mTOR inhibitor.
was approved by the FDA in May 2007 and by the EMA in November
2007 for the first-line treatment of patients with poor-prognosis mRCC.
The pivotal trial of temsirolimus was a randomized phase III study that
compared temsirolimus or temsirolimus plus IFN- with IFN- alone in 626
patients newly diagnosed with mRCC who had at least three of six
predictors of short survival.
These predictors serum lactate dehydrogenase 1.5 the upper limit of
normal, hemoglobin level below the lower limit of normal, corrected
serum calcium level 10 mg/dl, 1 year from initial diagnosis to
randomization, Karnofsky performance status score of 60 or 70, and
multiple organ metastases.
Patients received a 30-minute i.v. infusion of 25 mg temsirolimus
(temsirolimus-only group) or 15 mg temsirolimus plus IFN- three times
weekly (3 MU for the first week, 6 MU thereafter) (combination therapy
group.
Treatment was continued until disease progression, symptomatic
deterioration, or unacceptable toxicity.

the median PFS intervals were 3.8 months with

temsirolimus alone, 1.9 months with IFN- alone,
and 3.7 months with the combination.
The ORR was 4.8% with IFN- alone, 8.6% with
temsirolimu alone, and 8.1% with the combination.
The median OS time was significantly longer with
temsirolimus alone than with IFN- alone (10.9
months versus 7.3 months, respectively p .008),
and combination therapy with temsirolimus and
IFN- did not lead to a significantly longer median
OS time than with IFN- alone (8.4 months versus
7.3 months, respectively).

Everolimus
Everolimus is an oral mTOR inhibitor
was approved by the FDA in March 2009 for the
treatment of patients withadvanced RCC after failure
of sorafenib or sunitinib, and by the EMA inMay 2009
for the treatment of patients with advanced RCC that
has progressed on or after treatment with VEGFtargeted therapy.
The pivotal trial, was a randomized, double-blind,
placebo-controlled phase III study of single agen
everolimus versus placebo in 416 patients with mRCC.
Patients received continuous oral everolimus, 10 mg (n
277), or placebo (n 139) once daily. Treatment was
continued until disease progression, unacceptable
toxicity, death, or discontinuation.

 The double-blind phase of the study was

terminated early (February 2008) after results of
the second interim analysis of data collected
through mid-October 2007 showed that the
median PFS interval was significantly longer with
everolimus (4.0 months) than with placebo (1.9
months; p .0001).
The PFS time was significantly longer with
everolimus regardless of previous treatment,
MSKCC risk score, age, or sex.
The final analysis was carried out with data
collected through February 2008, when the
double-blind phase was terminated; OS data
were collected through November 2008.

Pazopanib
Pazopanib is an oral multikinase angiogenesis inhibitor that
inhibits signaling by VEGFRs, PDGFRs, and c-Kit.
It was approved by the FDA in October 2009 for the first-line
treatment of patients with advanced RCC.
The pivotal trial was a randomized, double-blind, placebocontrolled phase III study of single-agent pazopanib in 435
cytokine-pretreated or treatment-nave patients with locally
advanced RCC and/or mRCC .
Patients received continuous oral pazopanib, 800 mg (n 290), or
placebo (n 145) once daily. Treatment continued until disease
progression, death, unacceptable toxicity, or consent withdrawal.
The median PFS duration was significantly longer with pazopanib
than with placebo in the entire population (9.2 months versus 4.2
months, respectively; p .0001)
Pazopanib led to a significantly longer PFS time regardless of
MSKCC risk score, age, sex, or performance status.

Other Agents
Axitinib (AG-013736)

Axitinib is an orally bioavailable VEGFR TKI

axitinib monotherapy was evaluated in 52
patients with cytokine-refractory mRCC,
The ORR was 44.2%. The median time to
progression was 15.7 months and the
median OS time was 29.9 month. The ORR
was 22.6%, median PFS time was 7.4
months, 18 Clinical Evidence for Targeted
Therapies in mRCC

Tivozanib
Tivozanib, also an orally bioavailable
VEGFR TKI, was investigated in a phase II
randomized, placebo-controlled, trial of
272 patients.
subgroup analysis of these data
suggested that patients with clear cell
RCC and prior nephrectomy appear to
respond best to tivozanib, with an ORR of
29.6% and a median PFS time that was
not reached.

Dovitinib (TKI258)
Dovitinib is a selective oral inhibitor
of fibroblast growth
patients indicated that the ORR was
10% and the preliminary median PFS
duration was 5.5 months.
The maximum-tolerated dose for
further study in the phase II portion
of the trial was 500 mg daily.

FUTURE DIRECTIONS: COMBINATION THERAPY

WITH TARGETED AGENTS
Sequential therapy with targeted agents is the current
standard of care
the strategy of combination therapy with targeted
agents is under active investigation.
Combination therapy provides the potential for
additive or synergistic effects as a result of a more
complete blockade of aberrant signaling.
it has the potential to delay or circumvent the
development of resistance that would
The goal is to use each agent at its full dose, but
efficacy gains, must be balanced with the potential for
greater toxicity

Sorafenib Combinations
Sorafenib was investigated in
combination with cytokine therapy in
several phase II trials. Sorafenib (400
mgtwice daily) plus IL-2 (4.5 MU five
times weekly) for six consecutive weeks
was safe, feasible, and more active
than monotherapy with sorafenib (400
mg twice daily) in a phase II trial of 128
previously untreated patients with mRCC.

Sunitinib Combinations
sunitinib plus downstreammTORinhibition
with temsirolimus resulted in substantial
toxicity at low starting doses of both
agents (sunitinib, 25 mg daily;
temsirolimus, 15 mg once weekly), causing
trial termination Sunitinib Combinations
in substantial toxicity at low starting doses
of both agents (sunitinib, 25 mg daily;
temsirolimus, 15 mg once weekly), causing
trial termination

Temsirolimus Combinations
Combination therapy with full doses
of i.v. temsirolimus(25 mg weekly)
and bevacizumab (10 mg/kg every 2
week in 4-week cycles) was active
and well tolerated.

Everolimus Combinations
Combination therapy with everolimus
and the VEGFR TKIs is showing
promise in initial studies. Everolimus
(5mg daily) plus sorafenib (400 mg
daily) was safe and feasible in a
phase I trial of patients with
advanced RCC.

CONCLUSIONS
The development of molecular-targeted therapies
has greatly increased the treatment options
available for and outcomes achieved by patients
with mRCC.
Since 2005, six targeted agents have been
approved by regulatory authorities for various uses
in advanced RCC or mRCC patients.
Clinical trial data demonstrate better prognoses
with these agents, because the PFS and OS times
achieved with targeted agents have been shown to
be superior to those seen with IFN- in head-to-head
compare

 At present, combination therapy strategies have not

been proven to be beneficial, with many combinations
showing excessive toxicity with marginal or inferior
efficacy to that seen with the sequential use of agents.
Combination therapy strategies that incorporate new
agents that target pathways important in drug
resistance are undergoing early evaluation in clinical
trials.
As more information regarding mechanisms of disease
and drug resistance becomes available, new targets,
new targeted agents, and new combinations will be
studied with the goal of providing maximal efficacy with
manageable toxicity

THANK YOU..