Pazopanib for the treatment of patients with advanced renal cell carcinoma.

Abstract

Dramatic advances in the care of patients with advanced renal cell carcinoma have occurred over the last ten years, including insights into the molecular pathogenesis of this disease, that have now been translated into paradigm-changing therapeutic strategies. Elucidating the importance of signaling cascades related to angiogenesis is notable among these achievements. Pazopanib is a novel small molecule tyrosine kinase inhibitor that targets VEGFR-1, -2, and -3; PDGFR-α, PDGFR-β; and c-kit tyrosine kinases. This agent exhibits a distinct pharmacokinetic profile as well as toxicity profile compared to other agents in the class of VEGF signaling pathway inhibitors. This review will discuss the scientific rationale for the development of pazopanib, as well as preclinical and clinical trials that led to approval of pazopanib for patients with advanced renal cell carcinoma. The most recent information, including data from 2010 national meeting of the American Society of Clinical Oncology, and the design of ongoing Phase III trials, will be discussed. Finally, an algorithm utilizing Level I evidence for the treatment of patients with this disease will be proposed.

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Clinical Medicine Insights: Oncology
R e v I e w
Clinical Medicine Insights: Oncology 2010:4
95
pazopanib for the Treatment of patients with Advanced
Renal cell carcinoma
Joshua M. Lang and Michael R. Harrison
Carbone Cancer Center, University of wisconsin, 7020 wisconsin Institutes for Medical Research, Madison, wI
53705-2225, USA. Corresponding author email: mrharris@medicine.wisc.edu; jmlang@medicine.wisc.edu
Abstract: Dramatic advances in the care of patients with advanced renal cell carcinoma have occurred over the last ten years, including
insights into the molecular pathogenesis of this disease, that have now been translated into paradigm-changing therapeutic strategies.
Elucidating the importance of signaling cascades related to angiogenesis is notable among these achievements. Pazopanib is a novel
small molecule tyrosine kinase inhibitor that targets VEGFR-1, -2, and -3; PDGFR-α, PDGFR-β; and c-kit tyrosine kinases. This agent
exhibits a distinct pharmacokinetic profile as well as toxicity profile compared to other agents in the class of VEGF signaling pathway
inhibitors. This review will discuss the scientific rationale for the development of pazopanib, as well as preclinical and clinical trials that
led to approval of pazopanib for patients with advanced renal cell carcinoma. The most recent information, including data from 2010
national meeting of the American Society of Clinical Oncology, and the design of ongoing Phase III trials, will be discussed. Finally, an
algorithm utilizing Level I evidence for the treatment of patients with this disease will be proposed.
Keywords: pazopanib, renal cell carcinoma, VEGF, VEGFR TKI, tyrosine kinase inhibitor, GW786034

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Clinical Medicine Insights: Oncology 2010:4
Introduction
Renal cell carcinoma
Renal cell carcinoma (RCC) was the ninth most
common cancer diagnosed in the United States dur-
ing 2009, with nearly 58,000 new diagnoses and
almost 13,000 deaths.1 Sporadic RCC has numerous
histologic subtypes that occur with varying incidences,
including clear cell carcinoma (75%), papillary (12%,
chromophobe (4%), oncocytoma (4%), collecting
duct (,1%) and unclassified (3%–5%).2,3 The his-
tologic classifications of clear cell and predominant
clear cell carcinoma are the most commonly identified
subtypes and thus the best studied to date. The main-
stay of treatment is radical nephrectomy for localized
disease, and until recently, the treatment options for
patients with either unresectable or metastatic renal
cell carcinoma were limited.
Prior to the advent of targeted therapy, the prog-
nosis of patients with metastatic renal cell carcinoma
was very poor, with a median survival of one year
and a five-year survival of 0%–20%.4 Historically,
treatment of metastatic renal cell carcinoma involved
immunotherapeutic agents such as interferon (IFN-α)
or interleukin-2 (IL-2).5 IFN-α has been shown to pro-
vide a benefit in terms of overall survival compared
to inactive therapy but with an average response rate
between 10%–15% and few durable responses. High-
dose IL-2 (infusion therapy requiring hospitalization)
has a higher overall and complete response (CR) rate
compared with low-dose cytokines (subcutaneous,
outpatient), with the real benefit realized in the small
percentage (5% to 7%) of patients who experience a
durable CR.6 The patient most likely to obtain a dura-
ble CR with high-dose IL-2 includes the young, previ-
ously untreated patient with clear-cell histology RCC,
ECOG performance status 0, and limited volume
metastatic disease to lung. The morbidity and lack of
applicability of high dose IL-2 to the broad RCC pop-
ulation has dampened enthusiasm for this approach,
although it remains a valid treatment option in a very
limited subset of patients.
The von Hippel Lindau gene in RCC
Of critical importance in the pathogenesis of clear cell
RCC is the von Hippel-Lindau (VHL) tumor suppres-
sor gene,7 the understanding of which has revolution-
ized RCC treatment. The VHL gene encodes the VHL
protein, which is composed of an E3 ubiquitin ligase
involved in the degradation of the transcription factor
hypoxia-inducible factor (HIF). In RCC, one allele of
the VHL gene is inactivated through a deletion event
that can be observed in .90% of sporadic clear cell
RCC.8 The remaining VHL allele is also commonly
affected, with inactivation in up to 50% of clear
cell RCC through gene mutation and an additional
5%–10% via altered methylation patterns.9,10 This
biallelic gene inactivation leads to intracellular accu-
mulation of the HIF transcription factor. Dimerization
of the HIF isoforms, HIF-α and HIF-β, leads to upreg-
ulation of hypoxia-inducible genes such as VEGF,
platelet-derived growth factor (PDGF), transforming
growth factor (TGF) and others.5 This overabundance
of HIF thus results in a cascade of overexpression of
multiple growth factors that are normally reserved for
cellular responses to hypoxia.
The veGF signaling pathway and vHL
Extensive work has further clarified the VEGF axis
as it relates to tumorogenesis in clear cell RCC.11
Increased levels of circulating angiogenesis factors
like basic fibroblast growth factor (bFGF), VEGF,
and angiogenin can be found in the serum of renal
cancer patients, consistent with the hypervascular
nature of these tumors.4,12–14 The VEGF ligand family
includes four protein isoforms, VEGF-A, -B, -C, -D,
that differentially interact with cell surface receptors
to initiate a cascade of downstream signaling events.15
The number of receptors able to bind VEGF isoforms
as well as the complexity of the interactions between
various signaling cascades in angiogenic pathways
has both complicated drug development in this field
and simultaneously provided new targets for thera-
peutic agents.
VEGF receptors are members of a family of
transmembrane tyrosine kinase receptors that medi-
ate signal transduction from extracellular signal-
ing ligands, like VEGF, to intracellular signaling
cascades. Members of this receptor family include
VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and
VEGFR-3 (Flt-4). Similar to Kit and platelet-
derived growth factor (PDGF) receptors, VEGF
receptors are activated upon ligand-mediated recep-
tor dimerization.16 VEGF-A binds to VEGFR-1
and -2, while VEGF-C and -D bind to VEGFR-2
and -3. Each receptor subtype interacts with differ-
ent signaling molecules at the plasma membrane to

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Clinical Medicine Insights: Oncology 2010:4
97
activate different cellular processes. For example,
activation of VEGFR-2 by VEGF-A leads to activa-
tion of Raf and the mitogen-activated protein kinase
(MAPK) pathway via phospholipase C-γ (PLC-γ) in
the endothelial cell. Activation of these intracellu-
lar signaling cascades promote tumor angiogenesis
via multiple mechanisms that include endothelial
cell survival, proliferation, and migration.16 These
molecular findings are consistent with historical
descriptions of increased vascularity of renal cell
tumors and correlate with elevated VEGF protein in
tumor and serum samples.
Therapy targeting the veGF ligand
The first VEGF targeted therapy to receive FDA
approval in solid tumors was bevacizumab. This well-
studied agent is a monoclonal antibody that binds
VEGF-A and has been shown to improve overall sur-
vival in multiple solid tumors when combined with
chemotherapy. It has also demonstrated single-agent
activity in a randomized Phase II trial in renal cell
carcinoma.17 More recently, the FDA has approved
bevacizumab in combination with IFN-α for the treat-
ment of metastatic renal cell carcinoma on the basis
of improvements in progression free survival (PFS)
compared to IFN-α alone in the AVOREN (median
PFS 10.2 versus 5.4 months, HR = 0.63, P , 0.0001)
and CALBG 90206 (median PFS 8.5 months versus
5.2 months, HR = 0.71 P , 0.0001) trials.18,19 While nei-
ther trial met the primary endpoint of overall survival,
both showed nonsignificant trends toward increased
median survival in the bevacizumab-containing
arms. The dramatic improvements in PFS resulted in
FDA approval in this setting. Of note, with multiple
therapies now approved and widely available, many
patients received second and even third line therapies
(including additional VEGF signaling pathway tar-
geted agents). These findings have contributed to the
significant debate in the field regarding the impact of
post protocol therapies on overall survival data.
Therapy targeting the veGF receptor
The VEGF Receptor Tyrosine Kinase Inhibitor
(VEGFR TKI) family of drugs continues to grow
and includes agents such as Sorafenib, Sunitinib,
Axitinib and Pazopanib. This class is broadly defined
as small molecule inhibitors of the VEGF signaling
cascade that exert their mechanism via blockade of
one or more VEGFR tyrosine kinases. These four
drugs all exhibit the ability to inhibit VEGF receptor
1, 2 and 3, PDGFR and c-kit. They differ in other off
target effects including Raf kinase (sorafenib), RET
(sorafenib and sunitinib), and FLT3 (sunitinib). They
further differ in pharmacokinetic properties such as
kinase IC50, terminal half life, and Cmax.20–23 As clini-
cal trials with these varied agents reach maturity, we
are beginning to discriminate differences in both effi-
cacy and toxicity profiles among these agents. The
first of the VEGFR TKIs to receive FDA approval
was sorafenib, based on the randomized, placebo
controlled Phase III trial by Escudier et al showing an
improved PFS of 5.5 months in the sorafenib group
versus 2.8 months in the placebo group in a cytokine-
refractory population (hazard ratio, 0.44; 95% confi-
dence interval [CI], 0.35 to 0.55; P , 0.01).24 Sunitinib
was later approved for treatment of mRCC based on
the randomized Phase III trial showing improved
PFS of 11 months for sunitinib compared with
5 months for IFN-α in a treatment-naïve population
(P , 0.001).25,26 Recent Phase II and Phase III trials
with other agents in the VEGFR TKI family of drugs
have recently been reported for treatment of mRCC.
This article will review the clinical trials conducted
with the VEGFR TKI pazopanib to date (as summa-
rized in Table 1) and discuss the evidence-based role
of pazopanib for the treatment of advanced renal cell
carcinoma with predominant clear cell histology.
Mechanism of Action,
pharmacokinetic, and Metabolism
Profile of Pazopanib
Pazopanib (GW786034, Votrient®; GlaxoSmithKline)
is a potent and selective, orally available, small mol-
ecule inhibitor of VEGFR-1, -2, and -3; PDGFR-α,
PDGFR-β; and c-kit tyrosine kinases.27,28 The agent
selectively inhibits proliferation of endothelial cells
stimulated with VEGF but not with basic fibroblast
growth factor. In preclinical angiogenesis models,
pazopanib inhibited VEGF-dependent angiogenesis
in a dose-dependent manner, and in xenograft tumor
models twice-daily administration of pazopanib sig-
nificantly inhibited tumor growth in mice implanted
with various human tumor cells.29 Pharmacoki-
netic and pharmacodynamic studies showed that a
pazopanib concentration of $40 µmol/L inhibited
VEGFR-2 in mice. These data differed from the IC50 of

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98
Clinical Medicine Insights: Oncology 2010:4
0.02 µmol/L based on VEGF-stimulated proliferation
in cell culture models and was attributed to in vivo
protein binding of pazopanib.29 A target steady-state
concentration of $40 µmol/L was thus selected for
the Phase I trial and achieved in patients receiving
either 800 mg daily or 300 mg BID.23
Pazopanib is absorbed orally with median time
to peak plasma concentrations of 2 to 4 hours and a
mean half-life of 30.9 hours after administration of
an 800 mg dose.23 Daily dosing at 800 mg resulted
a in mean AUC of 1,037 hr µg/mL and Cmax of
58.1 µg/mL with no consistent increase in AUC or
Cmax at pazopanib doses above 800 mg.23 Adminis-
tration of a single pazopanib 400 mg crushed tablet
increased Cmax approximately 2 fold and decreased tmax
by approximately 2 hours compared to administration
of the whole tablet, indicating increased bioavailabil-
ity and rate of oral absorption after administration
of a crushed tablet. Systemic exposure to pazopanib
was increased with a high-fat or low-fat meal result-
ing in an approximately 2-fold increase in AUC and
Cmax leading to the recommendation that pazopanib
be administered at least 1 hour before or 2 hours after
a meal.30 Further pharmacokinetic data from patients
with normal hepatic function (n = 12) and moderate
(n = 7) hepatic impairment indicate that pazopanib
clearance was decreased by 50% in those with mod-
erate hepatic impairment.31 The pazopanib dose in
patients with moderate hepatic impairment is recom-
mended at 200 mg once daily.30
In vitro studies demonstrated that pazopanib is
metabolized by CYP3A4 with a minor contribution
from CYP1A2 and CYP2C8. Co-administration of
oral pazopanib with CYP3A4 inhibitors has resulted
in increased plasma pazopanib concentrations. For
example, administration of 1,500 mg lapatinib, a sub-
strate and weak inhibitor of CYP3A4, with 800 mg
pazopanib resulted in an approximately 50% to 60%
increase in mean pazopanib AUC(0–24) and Cmax com-
pared to administration of 800 mg pazopanib alone.32
Clinical pharmacology studies using pazopanib
800 mg once daily have demonstrated that pazopanib
does not have a clinically relevant effect on the phar-
macokinetics of caffeine (CYP1A2 probe substrate),30
warfarin (CYP2C9 probe substrate), or omepra-
zole (CYP2C19 probe substrate). Co-administra-
tion of pazopanib 800 mg once daily and paclitaxel
80 mg/m2 (CYP3A4 and CYP2C8 substrate) once
weekly resulted in a mean increase of 26% and 31%
in paclitaxel AUC and Cmax, respectively.33
Clinical Safety and Efficacy
Pazopanib Phase I experience
A company-sponsored phase I study of orally
administered pazopanib enrolled 63 patients with
a variety of solid tumor types (dose escalation,
n = 43; dose expansion, n = 20).23 Doses admin-
istered ranged from 50 mg three times per week to
2000 mg once daily to 400 mg twice daily. Tumor
shrinkage was observed in two of twelve renal cell
carcinoma patients, with confirmed partial responses.
Of the remaining ten renal cell carcinoma patients,
stable disease was observed in four patients and pro-
gressive disease in four patients. Two other renal
Table 1. Clinical trials of pazopanib in patients with renal cell carcinoma.
study Dosesettingno. of pts
with mRcc
MsKcc risk
category37,38
(F/I/p/U§)
prior
nephrectomy
clear cell
Phase I23
A. 50 mg and 100 mg
three times weekly
B. 50 to 2,000 mg
once daily
C. 300 mg and 400 mg
twice daily.
800 mg once daily
versus placebo
800 mg once daily
versus placebo
Dose
escalation
12/63 NR NR NR
Phase II34
First-line,
cytokine-naïve
First-line, pre- or
post- cytokine
22543/41/2/14% 91% Yes†
Phase III36
290*39/55/3/3%*89%*Yes†
notes: *Pazopanib arm only; †Clear cell or predominantly clear cell histology required.
Abbreviations: §F/I/P/U, favorable, intermediate, poor, or unknown risk status; NR, not reported.

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cell carcinoma patients were withdrawn from the
study due to toxicity before the first disease assess-
ment. Tumor shrinkage was also seen in patients with
Hurthel cell and neuroendocrine tumors, as well as
chondrosarcoma. In all, 17 patients, including those
with RCC, Hurthel cell, carcinoid, GIST, neuroendo-
crine, sarcoma, melanoma, and lung cancer tumors,
remained on study for 6 months or longer. Pazopanib
was generally well tolerated up to 2,000 mg. How-
ever, the pharmacokinetic analysis demonstrated that
a plateau in steady state exposure was observed from
800 mg to 2000 mg doses. On the basis of this find-
ing, a traditional maximum tolerated dose was not
established and the recommended phase II dose was
set at 800 mg, administered one hour before or two
hours after a meal.23
The most common adverse events (AEs) seen in
this phase I trial regardless of causality were all grade
1 or 2.23 Forty eight (76%) patients experienced drug-
related AEs with the most frequently reported of all
grades including hypertension (33%), diarrhea (33%),
hair depigmentation (32%), and nausea (32%). One of
three patients treated with 2000 mg daily of pazopanib
developed dose-limiting toxicity of grade 3 fatigue.
Hair depigmentation (indicative of c-kit and, poten-
tially, VEGFR modulation) was seen in 12 patients,
all of whom were treated at doses $ 800 mg. One of
three patients dosed at 2000 mg once daily experi-
enced grade 3 fatigue that resolved upon dose reduc-
tion to 800 mg. As seen with many VEGF signaling
pathway inhibitors, grade 1–3 hypertension that could
be controlled with antihypertensive medication was
observed in the phase I study. In addition, there were
single events of gastrointestinal bleeding, pulmonary
thrombosis, and deep vein thrombosis. Pazopanib did
not affect QTc in this phase I trial, nor was hand foot
syndrome observed.23,24
Pazopanib Phase II results in metastatic
renal cell carcinoma
Upon designation of the recommended phase II dose of
pazopanib, a randomized, discontinuation phase 2 trial
was designed for patients with metastatic or locally
recurrent RCC.34 Study patients were required to have
predominantly clear cell histology with measurable
disease who had received either no systemic therapy
or 1 prior systemic therapy, that may have included
bevacizumab. Pazopanib was administered at 800 mg
PO daily until progression of disease. The primary
end point was progressive disease rate at 16 weeks
post randomization. Two hundred twenty-five patients
with metastatic RCC were treated (69% were previ-
ously untreated and 84% had favorable or intermedi-
ate risk). Interestingly, after a planned interim analysis
showing indication of activity, the study was changed
to an open-label trial design. At that time, the primary
endpoint was changed to overall response rate accord-
ing to RECIST guidelines. Accrual was completed
by this interim analysis and the amendment allowed
patients with stable disease who had been random-
ized to placebo to restart the study drug (n = 28). The
PFS attributable to pazopanib was estimated using
Kalbfleish-Prentice estimation to account for these
patients. The independently reviewed overall response
rate was 34.7% (95% CI, 28% to 41%), and the median
PFS was 51.7 weeks. The PFS in the randomized com-
parison (n = 55) was 11.9 months for pazopanib versus
6.2 months for placebo (P = 0.0128).
Further analysis of this study was recently reported
at the 2010 American Society of Clinical Oncology
meeting. Suttle et al performed a retrospective analy-
sis of the pharmacokinetics of pazopanib as related to
patient outcome.35 Of the 225 patients enrolled on the
trial, Cmin data was available for 205 patients at four
weeks and 185 patients at 12 weeks. When separated
into quartiles and stratified by PFS, it was observed
that patients with a week 4 Cmin . 20.6 µg/mL had
a median PFS of 49.4 weeks versus 20.3 weeks for
patients unable to achieve this plasma level of drug.
In addition, response rate was improved in this group
(45% versus 18%), as was mean percent tumor
shrinkage (37.8% vs. 8.8%). Importantly, nearly 70%
of patients assessed at this time point (143/205) were
able to reach or exceed this drug level. No data related
to toxicity stratified by plasma level was available.
While still a retrospective analysis, these data support
both the initial dosage chosen for this drug as well as
a potential role for maintaining dose intensity during
treatment whenever possible.
Pazopanib Phase III results
in metastatic renal cell carcinoma
The results of a single phase III trial with pazopanib
in metastatic renal cell carcinoma were recently

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published by Sternberg et al.36 This trial was a
randomized, double blind, placebo controlled trial
in patients with clear cell, or predominantly clear
cell, histology who either received no prior therapy
or who had progressed on one prior cytokine-based
systemic therapy. Patients were randomized in a 2:1
fashion to receive pazopanib at 800 mg once daily
or placebo. Randomization was stratified according
to performance status, prior nephrectomy, and treat-
ment history. Patients who progressed on the placebo
arm were allowed to enroll on an open label study of
pazopanib, with seventy patients (48%) choosing this
option. The primary endpoint of this trial was pro-
gression free survival with secondary endpoints of
overall survival, confirmed objective response rate,
duration of response, and safety.
Between April 2006 and April 2007, 435 patients
were enrolled from 80 centers worldwide, with 290
randomized to pazopanib and 145 to placebo. The
experimental and control arms were well balanced
with regards to MSKCC risk category (94% vs. 92%
with favorable/intermediate group, respectively)
and prior nephrectomy (89% vs. 88%, respectively).
The study was originally designed to include only
cytokine-pretreated patients, but was rapidly amended
to include treatment-naïve patients as well. Therefore,
of the patients enrolled, 233 (54%) were treatment-
naïve and 202 (46%) had been previously treated
with IFN-α or IL-2. The experimental and control
arms were well balanced in this regard, with the per-
centage of treatment naïve patients at 53% vs. 54%,
respectively.
Pazopanib was found to significantly improve
PFS compared to placebo (median 9.2 months vs.
4.2 months; HR, 0.46; 95% CI, 0.34 to 0.62; P , 0.0001)
in the overall study population. The improvement in
PFS was more pronounced in the treatment naïve
subpopulation (median 11.1 vs. 2.8 months; HR,
0.40; 95% CI, 0.27 to 0.60; P , 0.0001), though the
pretreated subpopulation also showed a significant
improvement (median 7.4 vs. 4.2 months, HR, 0.54;
95% CI, 0.35 to 0.84; P , 0.001) as well. The objec-
tive response rate in this study was 30% (95% CI,
25.1 to 35.6), with a median duration of response of
58.7 weeks. At the time of reporting, the percentage
of patients on study greater than 12 months reached
32% in the pazopanib arm and 15% in the placebo
arm. Interim overall survival results did not meet
significance and final results will be reported when
data mature. Importantly, predefined subgroup analy-
ses of PFS supported the pazopanib arm in all catego-
ries (MSKCC risk category, treatment history, gender,
age, performance status).
Further trials with pazopanib include: 1) the exten-
sion trial of patients enrolled to the placebo arm in
the Phase III trial (discussed above); 2) an ongoing
phase III open-label trial, COMPARZ (Pazopanib
Versus Sunitinib in the Treatment of Subjects With
Locally Advanced and/or Metastatic Renal Cell Car-
cinoma); and the PISCES (Patient Preference Study
of Pazopanib Versus Sunitinib in Advanced or Meta-
static Kidney Cancer) trial. The COMPARZ trial is
designed to test pazopanib versus sunitinib (Sutent®,
Pfizer) in locally advanced and/or metastatic RCC
patients who have had no prior treatment. Approxi-
mately 876 patients with treatment naïve metastatic
clear cell RCC will be included. The PISCES trial
will address patient preferences between pazopanib
and sunitinib. This trial is a randomized, double-
blind, crossover study of pazopanib versus sunitinib
in patients with metastatic RCC who have received no
prior systemic therapy. Approximately 160 patients
are planned.37
Adverse events with pazopanib
Pazopanib exhibits a similar toxicity profile to other
agents in the VEGFR TKI class of agents as summa-
rized in Table 2. Although comparisons across trials
do not allow definitive conclusions, there appears to
be a lower incidence of hand foot syndrome, diarrhea,
asthenia and myelosuppression in the Phase III trial
with pazopanib compared to the Phase III trials of
sunitinib and sorafenib. There was a 40% incidence
of hypertension in the phase III trial with pazopanib
which appears to be somewhat higher compared to
other VEGFR TKIs. Of note, the incidence of Grade 3
hypertension was less than 1% and 4% of patients on
the Phase II and Phase III trials, respectively. Arte-
rial thrombotic events occurred in 3% of pazopanib-
treated patients, of which 2% were myocardial
infarction/ischemia and 1% due to cerebrovascular
accident/TIA. The incidence of hemorrhagic events
(all grades) in the pazopanib arm was 13% compared
with 5% in the placebo arm. Laboratory abnormali-
ties observed included predominantly grade 1/2 elec-
trolyte abnormalities, including hypo-phosphatemia,

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101
Table 2. Adverse events reported in Phase III trials with veGFR TKIs.
Adverse eventspazopanib (%)36
All
sunitinib (%)25
All
sorafenib (%)24
All G3–4 G3–4G3–4
AST elevation
ALT elevation
Hyperglycemia
Hypertension
Neutropenia
Thrombocytopenia
Bleeding
Rash
Fatigue/asthenia
Diarrhea
Stomatitis
Hand-foot syndrome
Hypothyroidism
Heart failure
Renal impairment
53
53
41
40
34
32
13
–
19
11
,0
,0
–
–
–
9
12
1
4
2
1
NR
–
3
4
,1
,1
–
–
–
52
46
–
24
72
65
12
19
51
53
25
20
6
10
66
2
2
–
8
11
8
1
2
7
5
1
5
1
2
1
–
–
–
–
17
–
–
15
40
37
43
NR
30
–
3
–
4
–
–
3
1
5
2
1
6
–
3
–
-calcemia, -natremia, and -magnesemia. In combina-
tion with clinical findings of prolonged QT intervals
and torsades de pointes, this led to the recommenda-
tion that electrocardiograms and electrolytes be mon-
itored in patients considered at risk.30
Death resulting from AEs was reported in 4% of
patients in the pazopanib arm and 3% of patients in
the placebo arm. Four patients (1%) in the pazopanib
arm had fatal AEs that were assessed by the investiga-
tor as attributable to study treatment: ischemic stroke,
abnormal hepatic function and rectal hemorrhage,
peritonitis/bowel perforation, and abnormal hepatic
function (one patient each). Importantly, of the two
patients who died of peritonitis/bowel perforation in
the phase II and phase III trials, one had RCC metas-
tasis present at the site of perforation and the other
had a history of diverticulitis.
A major difference with pazopanib and other
VEGFR TKIs includes an apparent higher probabil-
ity of severe hepatotoxicity and hyperbilirubinemia
with pazopanib. Elevations in the liver enzyme ALT
occurred in 65% of patients, of which 12% experi-
enced Grade 3–4 toxicity. ALT elevation recovered
to #grade 1 after dose modification, interruption
or cessation of drug in 87% of patients while the
remaining 13% did not have adequate follow up
data for reporting. One patient died of abnormal
hepatic function that was attributed to study drug was
later found to have extensive hepatic infiltration of
tumor. These findings led to a black box warning for
pazopanib stating “Increases in serum transaminase
levels and bilirubin were observed. Severe and fatal
hepatotoxicity has occurred. Measure liver chemis-
tries before the initiation of treatment and regularly
during treatment”. A genetic analysis performed by
Xu et al attempted to identify genetic markers that
may predict risk of ALT and/or bilirubin elevation in
patients treated with pazopanib.38 Serum samples from
225 patients from the Phase II trial and 290 patients
from the Phase III trial were analyzed for numerous
genetic polymorphisms. Interestingly, the UGT1A1
TA repeat polymorphism was strongly associated with
maximum on-treatment bilirubin concentration and
bilirubin increase from baseline. None of the other
markers tested was related to elevation of ALT. While
screening for the UGT1A1 TA repeat polymorphism
was not recommended, it is important to consider that
isolated elevations of total bilirubin may not indicate
pazopanib-induced hepatotoxicity.
patient preference
Overall patient preference amongst the evidence-
based first-line treatments for favorable or intermedi-
ate risk metastatic renal cell carcinoma is unknown.
These questions have been examined in retrospective
studies, but may be subject to bias. Discussion of
both side effects and the convenience of oral therapy,
among other factors, will be critical in the decision-
making process for patients with mRCC. Although
the lack of head-to-head comparison studies limits

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Lang and Harrison
102
Clinical Medicine Insights: Oncology 2010:4
definitive conclusions, we believe pazopanib may
exhibit several key differences versus previously
approved VEGFR TKIs. Reviewing the toxicity pro-
files of VEGFR TKIs in renal cell carcinoma would
suggest that the lower incidence of fatigue, diar-
rhea and hand-foot syndrome might favor pazopanib
(Table 2). However, patients with poorly controlled/
difficult to treat hypertension or baseline liver dys-
function may well have greater difficulty with
pazopanib. These questions regarding patient prefer-
ences and differential toxicity profiles will hopefully
be answered more definitively in the prospective
PISCES study discussed above.
pazopanib: place in Therapy
Treatment naïve patients
With the dramatic advances in treatment of mRCC, a
question that would have been unheard of ten years
ago now comes to the forefront: What is the best first
line systemic therapy for mRCC? We support an evi-
dence-based approach to upfront therapy based on the
inclusion criteria in phase III trials and other patient
characteristics. Important factors include MSKCC
risk group,39,40 number and type of prior therapies,
histologic subtype, and patient-specific factors.
The strongest evidence for pazopanib is in the first
line setting for patients with favorable/intermediate
risk, predominantly clear cell renal carcinoma (see
Figure 1). Other appropriate agents for treatment-
naïve patients falling into an intermediate or favor-
able risk group include sunitinib, or bevacizumab
plus interferon-α.2,5,39,41 For poor risk or non clear
cell histology patients, there is Level 1 evidence for a
survival advantage of temsirolimus, an intravenously
administered inhibitor of the mammalian target of
rapamycin (mTOR) pathway, when compared with
interferon-α alone in the first line setting.42 Patients’
co-morbidities which could be exacerbated by agent-
specific toxicities should be considered before ini-
tiating treatment. Other factors that may play a role
include convenience of oral agents as well as prescrip-
tion drug coverage status (ie, out-of-pocket cost).
Treatment options in the second line setting, after
progression on a first line VEGF signaling pathway
MSKCC risk status39,40
1. Time from initial RCC diagnosis to start of therapy less than 1 year.
2. High lactate dehydrogenase; >1.5x ULN
3. Low serum hemoglobin
4. High corrected serum calcium; >10
5. Number of metastatic sites ≥2
Favorable:
Intermediate:
Poor:
0 Risk factors
1 or 2 Risk factors
≥3 Risk factors
Advanced renal
carcinoma:
Favorable or intermediate
MSKCC risk, clear cell
component*
Pazopanib
Sunitinib
P
R
O
G
R
E
S
S
I
O
N
Everolimus
Clinical trial
High dose IL2
(selected group)
Bevacizumab/
interferon
First line
Second line
Dosing of agents
1.
2.
Pazopanib 800 mg PO Daily for 4 weeks36
Sunitinib 50 mg PO Daily for 4 weeks on
followed by 2 weeks off25
Bevacizumab 10 mg/kg D1 and D5;
Interferon 9 MU SQ 3 times/week18,19
High Dose IL2 600,000 or 720,000 IU/kg IV
q8 hours for up to 14 consecutive doses over
5 days6
Everolimus 10 mg PO Daily for 4 weeks41
3.
4.
5.
Figure 1. evidence-based treatment algorithm for treatment-naïve metastatic renal cell carcinoma (category 1).
note: *Temsirolimus is FDA approved for the first line treatment of poor risk or non clear cell histology metastatic renal cell carcinoma (category 1).42

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Pazopanib in advanced renal cell carcinoma
Clinical Medicine Insights: Oncology 2010:4
103
agent, are even less clear. Inhibitors of the mammalian
target of rapamycin (mTOR) pathway, including
everolimus, have been reported to show efficacy
in the second line setting.41 The strongest evidence
supports everolimus after progression on TKIs. The
role of VEGFR TKI therapies as second line treat-
ment options are currently being evaluated in clinical
trials, with the only published data in smaller phase II
trials testing sorafenib either before or after treatment
with sunitinib. However, the critical questions are:
By what mechanisms does angiogenesis inhibition
fail and what rationale would support their continued
use? Reports of increasing serum VEGF levels during
treatment with VEGFR TKIs would support continued
use of these agents with alternative dosing strategies.43
This hypothesis is supported by a Phase II trial with
escalated dose sorafenib showing a responses in 42%
of patients who had progressed on standard dose.44
Other Phase II trials have shown response rates with
sunitinib in bevacizumab refractory disease12 and axi-
tinib in sorafenib refractory disease.22 Whether these
results are related to more potent VEGF inhibition or
inhibition of additional targets is unclear. However,
these results do suggest that VEGF signaling path-
way inhibitors could play an important role as second
line therapies and beyond. A phase III trial comparing
sorafenib and sunitinib sequencing (NCT00732914)
is designed to address a related VEGFR TKI sequenc-
ing question. Whether the results of this trial will be
applicable to other VEGFR TKIs such as pazopanib
and axitinib is unclear.
Cytokine-refractory patients
With the approval of six targeted therapy regimens
for advanced renal cell carcinoma, the population of
cytokine-refractory patients is dramatically shrinking.
Therefore, the question of how to use these novel agents
in cytokine-refractory disease is currently less pressing.
However, randomized controlled studies of pazopanib36
and sorafenib24 provide category 1 (ie, Phase III RCT
data) evidence supporting their use in this population
(See Figure 2). As the use of VEGFR signaling path-
way inhibitors for first line treatment is now standard of
care, we expect to see fewer and fewer cytokine-refrac-
tory patients in clinical practice in the upcoming years.
conclusion
Pazopanib is a novel VEGFR TKI that has now dem-
onstrated efficacy in a randomized Phase III trial in
metastatic renal cell carcinoma in both the front line
and cytokine-refractory settings. The unique toxicity
profile of this agent, as well as the convenience of an
oral therapy, makes it an attractive option in treatment
of mRCC. Further trials defining the comparative
efficacy, toxicity, and patient preference of pazopanib
versus other VEGFR TKIs are currently underway.
Further research to test the efficacy of this agent in
the setting of patients who have failed prior VEGF
blockade (bevacizumab, sunitinib, etc.) is needed.
Acknowledgements
The authors would like to thank Dr. Douglas McNeel
for his thoughtful critique of this manuscript. This work
Advanced renal
carcinoma:
Favorable or intermediate
MSKCC risk, clear cell
component
Pazopanib
Sorafenib
P
R
O
G
R
E
S
S
I
O
N
Everolimus
Clinical trial
First line
Second line
Dosing of agents
1.
2.
3.
Pazopanib 800 mg PO Daily for 4 weeks36
Sorafenib 400 mg PO BID for 6 weeks24
Everolimus 10 mg PO Daily for 4 weeks41
Figure 2. evidence-based treatment algorithm for cytokine refractory metastatic renal cell carcinoma (category 1).

Page 10

Lang and Harrison
104
Clinical Medicine Insights: Oncology 2010:4
was supported by NIH Grants T32 CA009614 and
K12 CA087718.
Disclosures
This manuscript has been read and approved by all
authors. This paper is unique and not under consid-
eration by any other publication and has not been
published elsewhere. The authors and peer reviewers
report no conflicts of interest. The authors confirm
that they have permission to reproduce any copy-
righted material.
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