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Clinical management of metastatic kidney


cancer: the role of new molecular drugs
Maria Giuseppa Vitale*,1 & Giacomo Carten1

Over the last few years, the most recent advances of the molecular mechanisms involved in
renal cell carcinoma have led to the use of new drugs targeting VEGF, such as bevacizumab
plus interferon, sorafenib, sunitinib, pazopanib, and axitinib, or the mTOR, such as
temsirolimus and everolimus. The purpose of this review is to analyze the results of Phase III
trial with these targeted agents, and on the management of the treatment and, in particular,
when to start and to stop therapy and the use of alternative schedule of sunitinib. Recent
developments in immunotherapy are also discussed.
First draft submitted: 13 July 2015; Accepted for publication: 14 October 2015; Published online:
30November 2015

Renal cell carcinoma (RCC) accounts for 23% of all adult malignancies. The number of patients
who present with advanced disease at diagnosis has decreased over the last years due to increased use
of imaging techniques while about a third of patients undergoing surgery develops distant metastases: the choice of the best medical treatment possible is very important. An understanding of the
pathogenesis of RCC led to the development of targeted therapy utilizing tyrosine kinase inhibitors
(TKIs), anti-VEGF antibodies and mTOR inhibitors[13] .
Seven drugs have been approved by the US FDA for the treatment of advanced RCC: sunitinib,
sorafenib, pazopanib, axitinib, temsirolimus, everolimus and bevacizumab in combination with
interferon (IFN). Actually, the role of IL-2 is very limited because of modest clinical benefit and
significant toxicity. It should be an option in first-line treatment or in subsequent therapy in patients
with good performance status and normal organ function.
The aim of this review is to focus on the first-, second- and third-line treatment, and on the
management of the treatment and, in particular, when to start and to stop therapy and the use of
alternative schedule of sunitinib.

Keywords

axitinib everolimus
immunotherapy
metastatic pazopanib
renal cancer sorafenib
sunitinib target therapy
treatment

First-line treatment
Three drugs have shown efficacy (in terms of the progression-free survival [PFS] over either IFN-
or placebo) in the first-line treatment of patients with good or intermediate prognosis: bevacizumab
(combined with IFN-), sunitinib and pazopanib[47] .
Temsirolimus has shown an improvement of overall survival (OS) compared with IFN- or
combination of temsirolimus and IFN- in the first-line treatment of patients with poor prognosis[8] . Sunitinib is also an option in these patients as demonstrated by the subgroup analysis from
the pivotal trial and expanded access programs. Sorafenib is another option (Table 1) .
UOSC Oncologia Medica, Azienda Ospedaliera di Rilievo Nazionale Antonio Cardarelli, 80131 Naples, Italy
*Author for correspondence: vitalemariag@gmail.com

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part of

ISSN 1479-6694

Review Vitale & Carten


Table 1. Phase III trials of targeted therapy in first-line treatment in metastatic renal cell carcinoma patients.
Study

Targeted
therapy

Patients (n)

ORR (%)

Median PFS
(months)

Median OS
(months)

More frequent grade 3/4 toxicities


(%)

Motzeretal.

S vs I

375 (S)
375 (I)

31(S)
6 (I)

11 (S)
5 (I)

26.4 (S)
21.8 (I)

AVOREN

I+B vs I+P

325 (I+B)
316 (I+P)

31 (I+B)
13 (I+P)

10.2 (I+B)
5.4 (I+B)

23.3 (I+B)
21.3 (I+P)

CALGB 90206

I+B vs I

363 (I+B)
369 (I)

25.5 (I+B)
13.1 (I)

8.5 (I+B)
5.2 (I)

18.3 (I+B)
17.4 (I)

ARCC

I
T
I+T

207 (I)
209 (T)
210 (I+T)

4.8 (I)
8.6 (T)
8.1 (I+T)

1.9 (I)
3.8 (T)
3.7 (I+T)

7.3 (I)
10.9 (T)
8.4 (I+T)

Sternbergetal.

Paz vs P

290 (Paz)
145 (P)

30 (Paz)
3 (P)

9.2 (Paz)
4.2 (P)

22.9 (Paz)
20.5 (P)

COMPARZ

Paz vs S

557 (Paz)
553 (S)

31 (Paz)
25 (S)

8.4 (Paz)
9.5 (S)

28.3 (Paz)
29.3 (S)

Fatigue 7 (S), 12 (I)


Neutropenia 12 (S), 7 (I)
Lymphopenia 12 (S), 22 (I)
Hyperlipasemia 16 (S), 6 (I)
Hyperuricemia 12 (S), 8 (I)
Fatigue 12 (I+B), 8 (I+P)
Asthenia 10 (I+B), 7 (I+P)
Proteinuria 7 (I+B), 0 (I+P)
Anemia 3 (I+B), 6 (I+P)
Hypertension 9 (I+B), 0 (I)
Anorexia 17 (I+B), 8 (I)
Fatigue 35 (I+B), 28 (I)
Proteinuria 13 (I+B), 0 (I)
Asthenia 26 (I), 11 (T), 38 (I+T)
Anemia 22 (I), 20 (T), 38 (I+T)
Neutropenia 7 (I), 3 (T), 15 (I+T)
Hyperglycemia 2 (I),11 (T), 6 (I+T)
Infection 4 (I), 5 (T), 11 (I+T)
Hypertension 4 (Paz)
Diarrhea 4 (Paz)
ALT elevation 30 (Paz)
AST elevation 21 (Paz)
Fatigue 11 (Paz), 18 (S)
HF syndrome 6 (Paz), 12 (S)
Thrombocytopenia 4 (Paz), 22 (S)
Neutropenia 5 (P), 20 (S)
ALT elevation 17 (Paz), 5 (S)
AST elevation 12 (Paz), 3 (S)

B:Bevacizumab; HF:Handfoot; I:IFN-; ORR:Objective response rate; OS:Overall survival; P:Placebo; Paz:Pazopanib; PFS:Progression-free survival; S:Sunitinib; T:Temsilorimus.

Sunitinib is a multikinase inhibitor targeting several receptor tyrosine kinases, including


VEGFr-2, PDGFR, FLT-3 and stem cell factor
receptor (c-KIT)[9] .
Sunitinib has shown effectiveness in a PhaseIII
trial of sunitinib (50 mg/day given orally for
4 weeks followed by 2 weeks without treatment) versus interferon (9 MIU subcutaneously
three-times a week) demonstrating a significant
advantage with sunitinib in 750 metastatic RCC
(mRCC) patients[5] . In this trial, 90% of patients
had a favorable or intermediate prognosis risk.
The primary end point was PFS and secondary
end points included patient-related outcome, OS,
response rate. The median PFS was 11 months
for sunitinib arm and 5 months for IFN- arm.
The objective response rate was 31% for sunitinib arm and 6% for IFN- arm. Patients in
the sunitinib group had a not statistically significant OS advantage compared with IFN- arm
(median OS was 26.4 months for sunitinib arm
and 21.8 months for IFN- arm; p = 0.051). The

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OS in mRCC patients in treatment with sunitinib became 26.4 months and for IFN- arm
20 months (p = 0.036), without considering 25
cases of crossover with sunitinib[10] .
Results from an EAP (expanded access trial)
demonstrated that sunitinib is also active in
patients with brain metastases, poor performance status and nonclear cell histology with a
good profile of toxicity[11] .
EAP revealed the activity and efficacy of
sutinitib in 373 patients with poor risk mRCC,
with a median PFS of 4.1 months and a median
OS of 5.3 months (in all mRCC patients the
EAP demonstrated ORR 17%, median PFS of
10.9months and median OS 18.4 months).
The main toxicities of sunitinib were hematologic, endocrine (thyroid dysfunction), gastrointestinal (stomatitis, diarrhea) and skin
(handfoot skin syndrome), asthenia/fatigue
and hypertension[10,11] .
Treatment of mRCC with sunitinib is often
associated with toxicity necessitating dose

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Clinical management of metastatic kidney cancer: the role of new molecular drugs
reduction. Maintaining adequate dosing and
drug levels are important to optimize clinical
efficacy. Standard sunitinib schedule is 4 weeks
of treatment and 2 weeks of rest (schedule 4/2).
Alternative regimens to the standard 4/2
schedule include schedule of 50 mg/day 2 weeks
on/1 week off, continuous schedule of 37.5 mg
daily and the Stop and Go strategy. Many trials
(observational and Phase II) have evaluated the
alternative schedules of sunitinib[12] .
Some randomized Phase II and retrospective
trials showed that the alternative schedule of
sunitinib (50 mg/day 2 weeks on/1 week off)
was better tolerated than standard schedule and
was similar in efficacy.
In particular, at 2014 ASCO Genitourinary
Cancer Symposium, Bracardaetal. have presented the final results of a multicenter retrospective analysis, the RAINBOW study. This trial
has demonstrated that the use of schedule 2/1 of
sunitinib shows an improved safety profile and
increased efficacy compared with schedule 4/2.
The study included three groups: group A, 208
patients with schedule 2/1 for toxicities during
initial therapy using schedule 4/2; group B, 41
patients with schedule 2/1, because of poorer
clinical conditions; group C, 27 patients with
schedule 4/2. Toxicities such as fatigue were
inferior with schedule 2/1[13] .
Patients have often different ability to metabolize the drug that is highly dependent by hepatic
cytochromes. This could explain both the different toxicity and effectiveness. Therefore, the use
of schedule should not be defined from the start
of treatment but evaluated only on the toxicity
reported with the classical schedule. The use of
schedule could reduce the emergence of resistance by maintaining the full dose and using of
the schedule.
Bevacizumab plus IFN

Bevacizumab is a humanized monoclonal antibody directed against VEGF[14,15] .


A multicenter Phase III trial (AVOREN) randomized 649 patients to receive IFN (9 MU subcutaneously three-times/week) combined with
either bevacizumab (10 mg/kg every 2 weeks)
or placebo.
Median PFS was 10.2 months in patients treated
with bevacizumab plus IFN versus 5.4months of
control arm; bevacizumab plus IFN has shown
a higher response rate in the combination arm
(31% vs 13%). Fatigue was the most common
grade 3 toxicity. A trend toward improved OS was

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also observed (IFN + bevacizumab 23.3months


vs 21.3 months IFN + placebo; p = 0.129) but was
not statistically significant[4,16] .
The efficacy and safety of Bevacizumab was
also demonstrated in a multicenter Phase III
trial, conducted in the USA and Canada by the
Cancer and Leukemia Group B[17] . Median
PFS and objective response rate were better in
patients receiving bevacizumab plus IFN (PFS:
8.5 vs 5.2 months; objective response rate: 25.5
vs 13.1%). Toxicity was most frequent in the
bevacizumab and IFN group: grade 3 hypertension (9 vs 0%), anorexia (17 vs 8%), fatigue
(35 vs 28%) and proteinuria (13 vs 0%). There
were no significant difference between the two
groups in term of OS (18.3 months in bevacizumab plus IFN arm and 17.4 in those receiving
IFN alone)[18] .
No difference in terms of OS was evident in
both studies, probably because patients receive
second-line treatments after progression (62%
of patients CALGB 90206 in the IFN- arm
and 54% of patients in the bevacizumabIFN-
arm, respectively, received anti VEGF-targeted
agents such as sunitinib and sorafenib). Despite
primary end point of these studies OS was
not reached, the bevacizumab and Interferon has
been considered a valid option of treatment on
the basis of the PFS results.
Temsilorimus

Temsirolimus is an inhibitor of mTOR (a serine


threonine kinase implicated in the processes of
transduction and regulation of protein degradation and angiogenesis) for intravenous use[19,20] .
The ARCC trial evaluated temsilorimus, IFN,
or their combination for the first-line treatment
of patients with poor-risk disease.
Two-thirds of patients had received prior
nephrectomy and 80% had clear cell histology.
Patients had a Karnofsky performance status
(KPS) <80 and three or more of the following
characteristics: the time from diagnosis to first
treatment <1 year, corrected serum calcium >10
mg/dl, LDH >1.5-times the upper limit of normal, hemoglobin <lower limit of normal, and
multiple sites of metastases. Temsirolimus was
less toxic than IFN or and combination.
The median OS was longer in the single-agent
temsirolimus arm (10.9 months for temsirolimus, 7.3 months for IFN and 8.4 months for
the combination).
Fatigue was the most common grade 34 toxicities observed in 12% of patients treated with

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temsirolimus, 27 and 30% of IFN in combination
while anemia of grade 34 toxicity was observed in
21% of patients treated with temsirolimus, 24 and
39% of IFN in combination. Response rates were
similar in all three arms. Overall, temsirolimus
significantly improved OS of poor-risk mRCC
patients with a good profile of toxicity. Therefore,
it should be considered as standard first-line
therapy for patients with poor-risk features[8] .
Pazopanib

Pazopanib has a broad spectrum of kinase inhibition including VEGFR 13, PDGFR AB
and c-Kit[21] . The safety and effectiveness of
pazopanib was evaluated in a Phase III trial in
which patients (naive and cytokine-pretreated)
with metastatic or locally advanced RCC with
no prior were randomized to oral pazopanib or
placebo (randomization 2:1 for pazopanib). The
primary end point was PFS[6] . PFS was longer
in patients who received pazopanib (median PFS
9.2 vs 4.2 months) and becomes even longer in
naive subpopulation (11.1 vs 2.8 months). The
objective response rate was 30% with pazopanib,
compared with 3% with placebo. The analysis
of QoL showed a no significant trend in favor
of pazopanib (vs placebo) of the scores of the
questionnaires (validated) [22] .
Main toxicities (any grade) were diarrhea
(52%), hypertension 940%), hair color changes,
nausea (26%) and anorexia (22%).
Hepatotoxicity with elevated levels of alanine (30%) and aspartate (21%) transaminase
was significant grade 3 toxicity. There was no
statistically significant difference in terms of
OS between pazopanib- and placebo-treated
patients (22.9 vs 20.5 months, respectively;
hazard ratio [HR]: 0.91; 95% CI: 0.711.16;
one-sided p = 0.224), probably because of crossover from placebo to pazopanib and prolonged
duration of crossover treatment[23] .
Results of a large noninferiority Phase III,
randomized trial (COMPARZ) of sunitinib
versus pazopanib showed that they have a similar profile of efficacy with a different profile of
tolerability [7,24] . A total of 1110 patients with
clear-cell, mRCC, were randomized to receive
a continuous dose of pazopanib or sunitinib in
6-week cycles. The primary end point was PFS,
and the study had as objective to demonstrate
the noninferiority of pazopanib versus sunitinib. Secondary end points were OS, safety and
quality of life. OS was similar between the two
drugs and pazopanib is noninferior to sunitinib

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in terms of PFS. Fatigue (63% sunitinib vs 55%


pazopanib), handfoot syndrome (50 vs 29%)
and thrombocytopenia (78 vs 41%) was higher
for sunitinib while hepatotoxicity was more frequent with pazopanib (60 vs 43% with sunitinib). About quality of life, pazopanib seems
to be better than sunitinib.
Health-related quality-of-life (HRQoL)
assessments were administered at baseline, on
day 28 of cycles one through nine, and on day
42 of subsequent cycles; this could explain the
obtained result because of the worst toxicity of
sunitinib on day 28 of cycle.
PISCES trial was a double-blind crossover
trial that has evaluated patient preference for
pazopanib or sunitinib and HRQoL with the two
different treatments[25] . A total of 169 patients
received pazopanib 800 mg per day for 10 weeks,
a 2-week washout, and then sunitinib 50 mg per
day (4 weeks on, 2 weeks off, 4 weeks on) for
10weeks, or the reverse sequence for the first-line
treatment. Patient preference by questionnaire
was obtained at the end of the two treatment
periods. Other objectives were reasons for preference, physician preference, safety and HRQoL.
A total of 70% of patients preferred pazopanib
over sunitinib (22%) because of less fatigue and
better overall quality of life for pazopanib, with
less diarrhea for sunitinib. Pazopanib (61%)
was also preferred by physicians over sunitinib
(22%). Pazopanib was superior to sunitinib in
terms of HRQoL.
The study showed a clear preference in favor of
pazopanib, however the patient preference questionnaire had not received external validation,
and over 30% of the randomized patients could
not be evaluated for the primary end point of
the study. The parameters of QoL were generally favorable to pazopanib, but improvements
of pazopanib over sunitinib have always been less
than the minimum difference of clinical interest
(MID).
Second-line treatment
After first-line treatment with VEGF-targeted
therapy both axitinib and everolimus are valid
treatment options[26,27] . They have shown significantly improved PFS over placebo (everolimus) or
sorafenib (axitinib), but not OS. Sorafenib can be
used as another option of treatment (Table2)[28] .
Everolimus

Everolimus is a derivative of rapamycin that


acts as an inhibitor of mTOR. Everolimus was

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Table 2. Phase III trials of targeted therapy in second-line treatment in metastatic renal cell carcinoma patients.
Trial

Targeted therapy Patients (n)

ORR (%)

Median PFS
(months)

Median OS
(months)

More frequent grade 3/4 toxicities


(%)

RECORD-1

E vs P

227 (E)
139 (P)

1.8 (E)
0 (P)

4.9 (E)
2 (P)

14.8 (E)
14.4 (P)

AXIS

A vs S

361 (A)
362 (S)

19 (A)
9 (S)

6.7 (A)
4.7 (S)

20.1 (A)
19.2 (S)

TARGET

S vs P

451 (S)
452 (P)

10 (S)
2 (P)

5.5 (S)
2.8 (P)

17.8 (S)
15.2 (P)

INTORSECT

T vs S

259 (T)
253 (S)

8 (T)
8 (S)

4.28 (T)
3.91 (S)

12.27 (T)
16.64 (S)

Stomatitis 5 (E)
Infections 10 (E)
Fatigue 5 (E)
Dyspnea (E)
Lymphocytes decreased 18 (E)
Glucose increased 16 (E)
Diarrhea 11 (A), 7 (S)
Hypertension 16 (A), 11 (S)
Fatigue 11 (A), 5 (S)
HF syndrome 5 (A), 16 (S)
Hypophosphatemia 2 (A), 16 (S)
Lipase elevation 5 (A), 15 (S)
Hypertension 4 (S)
Decreased hemoglobin 3 (S)
Fatigue 5 (S)
Dyspnea 4 (S)
HF skin reaction (S)
HF syndrome 0 (T) 15 (S)
Fatigue 6 (T) 7 (S)
Anemia 9 (T) 3 (S)
Hypophosphatemia 5 (T) 7 (S)
Hyperglycemia 8 (T) 2 (S)
Diarrhea 2 (T) 6 (S)

A:Axitinib; E:Everolimus; HF:Hand-foot; ORR:Objective response rate; OS:Overall survival; P:Placebo; PFS:Progression-free survival; S:Sorafenb; T:Temsilorimus.

evaluated in a Phase III, international, multicenter randomized, double-blind, placebocontrolled study in patients with mRCC whose
disease had progressed despite prior treatment
with VEGFR-TKI. PFS was the primary end
point. Secondary end points included safety,
objective tumor response rate, OS, diseaserelated symptoms and QoL. Median PFS was
1.9 months in patients receiving placebo and
4.9 months in patients treated with everolimus. Patients randomized to placebo were
allowed to cross over to everolimus treatment
after disease progression. No statistically significant treatment-related difference in OS was
revealed, although there was a trend in favor
of everolimus. Median OS was 14.8 months
for everolimus and a trend in OS favoring
everolimus was observed (HR: 0.87, 95% CI:
0.651.15). Crossover to everolimus after disease progression confounded the OS analysis. QoL was better for patients treated with
everolimus [29] .
The REACT study has provided everolimus
in patients with mRCC after failure with VEGF
inhibitor. Everolimus was well tolerated and stable disease was the best tumor response in the
majority of patients (51.6%)[30] .

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In the prospective, noninterventional


CHANGE study between August 2009 and
January 2012, patients with mRCC (median
age: 68 years; 75% male; median KPS, 80%;
88% clear cell histology) received everolimus
10mg/d until disease progression or unacceptable toxicity after treatment with VEGF inhibitor
or cytokines. Study end points were the treatment duration, time to progression (TTP), PFS,
KPS and safety.
At the start of first-line therapy, MSKCC
risk status was favorable in 35%, intermediate in 56% and poor in 9%. Median treatment duration was 6.6 months, median TTP
7.4months, PFS 7 months. In the safety population (n = 318), median time to 10% deterioration in KPS was 8.4 months (95% CI:
6.110.1 months); the most common adverse
effects (AEs; any grade) were dyspnea (17%),
anemia (14%) and fatigue (12%). Treatment
adherence was high. The CHANGE study demonstrates favorable effectiveness and tolerability
for everolimus[31] .
The effectiveness and safety of everolimus in
the second-line treatment after failure of VEGF
receptor-targeted TKI, was evaluated in an
observational, retrospective study conducted in

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2 years (20112013) at ten oncological centers
in the Campania region of Italy. Study objectives were PFS, response rate and safety. PFS was
8months, 19% of patients had a partial response
and 62% a stable disease. No grade 4 toxicity
was reported[32] .
The Phase II RECORD-1 trial evaluated the
role of first-line mTOR inhibitor in mRCC.
Primary end point was to assess noninferiority of first line with everolimus compared with
first line with sunitinib in terms of PFS. After
progression to first-line treatment, patients were
crossed to alternative treatment. This trial has
showed that the best sequence is the use of
sunitinib in first line and everolimus in second
line: median PFS after first line with sunitinib
and everolimus was 10.71 and 7.85 months,
respectively; median PFS for the sequence
sunitinib-everolimus was 25.79 months and
21.13 months for the reverse sequence. Median
OS was 22.41months for the sequence everolimus-sunitinib and 32.03 months for the reverse
sequence[33] .
Axitinib

Axitinib is a potent and selective inhibitor of the


tyrosine kinase that acts on receptors of VEGFR1, VEGFR-2 and VEGFR-3[34] .
The Phase III randomized, prospective, openlabel AXIS trial compared axitinib (5mg twice
daily) with sorafenib (400 mg twice daily) in
patients after failure with cytokines (35% of
enrolled patients), sunitinib (54%), bevacizumab (8%) or temsirolimus (3%). The primary end point of the study was PFS; secondary
end points included OS, the objective response
rate, duration of response and QoL and safety.
The median PFS was 6.7 months for axitinib
arm and 4.7 months for sorafenib arm (HR:
0.665, 95% CI: 0.5440.812). The median
survival was 20.1 months for axitinib and
19.2months for sorafenib (HR: 0.969; 95%CI:
0.8001.174). In patients pretreated with
cytokines, the median PFS was 12.1 months for
axitinib versus 6.5 months for sorafenib (HR:
0:46; 95% CI: 0.320.68). Axitinib also caused
a relative reduction in risk of death (HR: 0.81;
95% CI: 0.561.19)[26,35] .
The most frequent adverse events during
treatment with axitinib were diarrhea (51.3 vs
50.4% for axitinib to sorafenib), hypertension
(39.3 vs 29.0%), fatigue (34.8 vs 26.2%), nausea (28.7 vs 18.3%), decreased appetite (28.4
vs 24.8%), dysphonia (28.1 vs 11.8%) and

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palmar-plantar (27.3 vs 51.0%). The parameters of QoL were similar between the two
arms [36] . Axitinib dose increases to 7 mg and
then to 10 mg, twice daily, were allowed for
those patients without hypertension or adverse
reactions above grade 2. Diastolic blood pressure of 90 mm Hg or higher appears to be a predictive biomarker of axitinib efficacy in patients
with RCC[37] .
Sorafenib

Sorafenib is a small molecule inhibing the RTKs


VEGFR2, VEGFR3, Flt-3, c-KIT and PDGFR
and the nonreceptor serine threonine kinases
BRAF and CRAF[38] . The BRAF and CRAF
kinases are involved in survival and proliferation
of tumor cells[39,40] .
In the Phase III TARGET trial 905 patients,
after failure with cytokine-based treatment,
were randomized to receive either sorafenib
400 mg orally twice daily or placebo. PFS was
5.5months for sorafenib arm versus 2.8months
for placebo arm (p < 0.000001). No significant difference in terms of OS was revealed
(17.8months for sorafenib vs 15.2 months for
placebo) because of the crossover of placebo
group to sorafenib[41] .
There are no randomized studies on the use
of sorafenib (as experimental treatment) after
VEGF inhibitor progression. There are two
studies in which sorafenib was the control arm:
Axis (axitinib vs sorafenib)[26] and Intorsect
(temsilorimus vs sorafenib) trials[27] .
The median PFS was 4.43.9 months, and
the median OS was 16.516.6 months in Axis
and Intorsect trials, respectively. About the
adverse reactions, diarrhea grade 34 were
found in 7.65.6% of cases, fatigue grade 34
in the 3.97.1%, handfoot syndrome reaction grade 34 in 17.215.1%, hypertension in
grade 34 12.1%, in Axis and Intorsect trials,
respectively.
Third-line treatment
The pivotal trial of everolimus has demonstrated
the effectiveness of using this drug even in thirdline treatment of mRCC. Another treatment
option is represented by sorafenib as demonstrated by GOLD trial, a multicenter Phase III
of sorafenib versus dovitinib. In GOLD trial,
patients in progression after a first-line treatment
with VEGF-inhibitor and a second-line treatment with mTOR inhibitor were randomized to
receive dovitinib (500 mg orally according to a

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Clinical management of metastatic kidney cancer: the role of new molecular drugs
5 days on and 2 days off schedule) or sorafenib
(400 mg orally twice daily). Primary end point
was PFS. A total of 284 patients received dovitinib while 286 patients sorafenib. Median PFS
was 3.7 months for dovitinib and 3.6 months for
sorafenib. Common grade 3 or 4 toxicities were
hypertriglyceridemia (38 [14%]), fatigue (28
[10%]), hypertension (22 [8%]) and diarrhea
(20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnea (21
[7%]) and palmarplantar erythrodysesthesia
(18 [6%]) in the sorafenib group. Dovitinib
showed to be no better than sorafenib in third
line of treatment of RCC[42] .
Algorithm of therapy of mRCC is showed in
Table 3.

When to start?
The biology of mRCC includes a subpopulation of patients with indolent disease and can
sometimes allow the possibility to delay the
start of treatment. Because of the toxicity and
noncurative nature of current systemic therapy,
initial surveillance may be an option in selected
patients. The TARGET trial (sorafenib vs placebo), RECORD-1 trial (everolimus vs placebo)
and the Phase III trial of pazopanib versus placebo show that there is no statistically significant
difference in terms of OS between the two arms
of these studies.
A prospective Phase II observation conducted
in patients with mRCC prior to initial systemic
treatment has demonstrated that a subset of
patients can be safely observed for a period of
time before starting systemic therapy.
Radiographic assessment was performed at
baseline, every 3 months for year 1, every 4
months for year 2, then every 6 months. The
primary objective was to characterize time to
initiation of systemic treatment. Secondary
end points included assessment of depression/
anxiety using standardized questionnaires
(FKSI-DRS and HADS) and peripheral blood
immune repertoire (TH1/TH2, MDSC, Tregs).
A total of 52 patients were accrued; median
age 67years (range: 4788); 75% male; 94%;
Eastern Cooperative Oncology Group performance status: 0; 96% clear cell; 8% prior
metastasectomy and Heng risk group favorable/
intermediate 26%/74%. Baseline tumor burden
(per RECIST 1.0) was 3.2 cm (0.819.6 cm).
Median time on observation until systemic
therapy was started was 14.1months (95%
CI: 10.619.3), with estimated 12-month and

future science group

Review

24-month rates of continued surveillance of


58 and 33%, respectively. Median change in
tumor burden on study was 0.8 cm (06.5 cm);
relative change +34% (0311%) and median
growth rate 0.14 cm/month (01.75). In total,
31 patients have come off observation (61% for
PD), and 25 patients have received systemic
therapy. Patients with baseline tumor burden
1.5 cm versus >1.5 cm had a median observation period of 31.6 months versus 13.8months
(p=0.06). Anxiety/depression were not prevalent at baseline, and scores did not worsen
over time. There were no significant changes
in immunologic parameters[43] . Therefore, in
patients with mRCC with small metastasis,
asymptomatic, for example, lung metastasis,
initial surveillance could be an option.
When to stop?
Prolonged treatment in mRCC patients may
cause significant AEs that sometimes requires
a treatment break. A treatment break is feasible
in selected patients. Mittal et co-workers have
analyzed retrospectively mRCC patients on targeted therapy who discontinued treatment for
3months for reasons other than progressive
disease. Pts could receive treatment breaks with
multiple lines of therapy (defined sequentially
as treatment A, B, C, among others). A number
of patients continue on treatment/observation,
hence durations were estimated using the
KaplanMeier method. One hundred and
twelve patients were observed: 75% male;
median age at diagnosis 56; 95% clear cell.
A total of 19% of patients had received prior
systemic therapy. In total, 48% patients were
favorable, 48% intermediate and 4% poor risk
by Heng criteria. Overall, patients received a
median of two treatments. Treatment A primarily included sunitinib (55%), sorafenib (13%),
or bevacizumab in combination with temsirolimus (10%)/IFN (9%). Common reasons
Table 3. Algorithm of therapy of metastatic renal cell carcinoma.
Line of therapy

Therapy

Other options

First-line therapy
Good or intermediate-risk group

Sunitinib
Pazopanib
Bevacizumab + IFN-
Temsirolimus
Sunitinib
Everolimus
Axitinib
Axitinib
Pazopanib

Observation
High-dose IL2
Sorafenib
Clinical trial

Sorafenib

First-line therapy
Poor-risk group
After tyrosine kinase inhibitor therapy
After cytokine therapy

www.futuremedicine.com

Sorafenib
Sunitinib

10.2217/fon.15.283

Review Vitale & Carten


for breaks in treatment A were toxicity/AEs
(57%) and physician choice (26%). A total of
40 (36%) patients remain on treatment break
from the first treatment (A). A total of 25 (22%)
patients have undergone two treatment breaks.
A total of 68 (61%) patients restarted treatment
(B); 33 (49%) of these were rechallenged with
previously used therapy and 35 (51%) received
alternative TKIs. Overall, 30 patients have
died; median survival is 71.7months (range:
1.393+months). Achievement of CR prior
to the initial treatment break (n = 15) was
associated with a longer surveillance period
(p=0.0004)[44] . This strategy may be associated with acceptable overall disease control and
reduced toxicity.
The Phase II/III STAR trial is comparing two
ways of taking sunitinib or pazopanib continuously with having planned treatment breaks in
patients with locally advanced and/or metastatic
advanced kidney cancer. This trial is ongoing
and its primary outcomes are 2-year OS and
averaged QoL-adjusted years (QALYs).
Other targets
Cabozantinib is an oral, small-molecule kinase
inhibitor that targets the MET receptor and
VEGFR-2 and other potentially relevant receptor tyrosine kinases including RET, KIT, AXL
and FLT3. METEOR trial, a randomized,
open-label, Phase III trial evaluated the efficacy of cabozantinib at a dose of 60 mg daily,
as compared with everolimus at a dose of 10 mg
daily, in 658 patients with RCC after VEGFRtargeted therapy. PFS was longer with cabozantinib than with everolimus: 7.4 months with
cabozantinib and 3.8 months with everolimus.
The objective response rate was 21% with cabozantinib and 5% with everolimus. A planned
interim analysis showed that OS was longer
with cabozantinib than with everolimus but
did not reach the statistical significance[45] .
The role of immunotherapy
Although the treatment with VEGF and mTOR
inhibitor have demonstrated PFS benefit, most
patients with mRCC inevitably relapsed due
to acquired resistance[46] and, therefore, there
is the notable need for treatment options with
mechanisms of action that could potentially
result in improved efficacy and a survival advantage. Multiple resistance mechanisms, such
as dysfunction of immune checkpoints help
tumors to evade specific immune responses.

10.2217/fon.15.283

Future Oncol. (Epub ahead of print)

Cancer cells have a protein called PD-L1 on


their surface that helps them evade the immune
system. Novel antibodies directed against
immune checkpoint regulators that block the
PD-L1 protein, or the corresponding PD-1 protein on immune cells called T cells, can help
the immune system recognize the cancer cells
and attack them.
Nivolumab, a fully human IgG4 PD-1
immune checkpoint inhibitor antibody, demonstrated antitumor activity with a manageable
safety profile in a randomized, dose-ranging
Phase II trial[47] .
Choueiri demonstrated that the clinical
response to treatment with nivolumab was
evident not only in mRCC patients with have
an expression pretreatment of PD-L1 but also
patients PD-L1-negative obtained responses to
treatment with nivolumab[48] . The rational
combination of the two drugs (ipilimumab and
nivolumab) is based on their inhibitory activity
on the immune system (CTLA-4 and PD-1),
to obtain efficacy of the antitumor activity of
the immune system greater than what can be
obtained by the inhibition of one of the two
checkpoints. In a Phase I study of nivolumab in
combination with ipilimumab in mRCC, the
combination of the two drugs showed acceptable safety and encouraging antitumor activity (favorable/intermediate MSKCC score;
KPS 80%; untreated or any number of prior
therapies)[49] .
A Phase III, randomized, open-label study of
nivolumab combined with ipilimumab versus
sunitinib monotherapy in subjects with previously untreated, advanced or mRCC (CA209214 trial) is on going. The purpose of this study
is to compare the PFS and the OS of nivolumab
combined with ipilimumab to sunitinib monotherapy in patients with previously untreated
renal cell cancer[50] .
Another target under investigation is atezolizumab (anti-PD-L1 antibody) in combination
with bevacizumab versus sunitinib in a randomized, open-label study in patients with inoperable, locally advanced, or mRCC in first-line
treatment[51] .
A randomized, open-label, Phase III study
compared nivolumab with everolimus in 821
patients with renal-cell carcinoma who had
received previous treatment with one or two
regimens of antiangiogenic therapy. The primary end point was OS. The secondary end
points included the objective response rate

future science group

Clinical management of metastatic kidney cancer: the role of new molecular drugs
and safety. The median OS was 25.0 months
with nivolumab and 19.6 months with everolimus. The objective response rate was greater
with nivolumab than with everolimus (25 vs
5%). The median PFS was 4.6 months with
nivolumab and 4.4 months with everolimus.
Grade 3 or 4 treatment-related AEs occurred
in 19% of the patients receiving nivolumab and
in 37% of the patients receiving everolimus;
the most common event with nivolumab was
fatigue (in 2% of the patients), and the most
common event with everolimus was anemia (in
8%)[52] .
With the advent of immunotherapy drugs, the
treatment algorithm for kidney cancer should be
enriched. Soon the oncologists will be able to use
immunotherapy drugs in both first-line and subsequent-line treatment. In the near-term future,
we will have the possibility of use nivolumab
or cabozantinib after progression with first-line
treatment.
Conclusion
The development of many drugs for the treatment of RCC has certainly changed the prognosis of this disease. About the first-line treatment
with sunitinib, the choice of an ideal schedule
for single individual patient may guide the
decision-making process. The use of a schedule
should be also evaluated with the other VEGF
and m-TOR inhibitor to optimize efficacy with
reduction of toxicity. It is not yet defined what is
the correct sequence of treatment (TKImTOR
vs TKITKI) and, therefore, further studies are
needed to better understand this choice. It is
important to define the role of immunotherapy
in the treatment of mRCC with the hope to
get good results from Phase III clinical trials
on going.

Review

Future perspective
The VEGF inhibitors and mTOR inhibitors
have dramatically improved the treatment
options and outcome for patients with advanced
RCC. Novel treatment approaches are still necessary because of the appearance of resistance.
Areas of promising investigation are the identification of the development of novel immunotherapies, particularly those involving checkpoint
inhibitors used alone or in combination with
VEGF inhibitor. We speculate that, in the next
5 years, immunotherapeutic agents will be more
and new targets will be explored.
Specific targets or agents of interest include
angiopoietins such as trebaninib, a protein that
prevents the interaction of ligands, Ang1 and
Ang2, with the Tie2 receptor involved in vascular growth, remodeling, and stabilization;
dalantercept, a protein that inhibits angiogenesis by blocking the interation of BMP9 and
BMP10, proteins in the TGF- superfamily
with ALK1 on proliferating endothelial cells
and the development of mature, functional vasculature, and HDM2 for acquired resistance to
VEGF pathway inhibition.
Together, these developments could lead to a
new era of rational and more effective therapy
for patients with advanced RCC.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a financial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.

Executive summary

S even drugs have been approved for the treatment of renal cell carcinoma: sunitinib, sorafenib, pazopanib, axitinib,
temsirolimus, everolimus and bevacizumab + interferon.

I t is important the correct management of treatment: the use of schedule of sunitinib (2:1) should not be defined from
the start of treatment but evaluated only on the toxicity reported with the classical schedule (4:2).

fter first-line treatment with VEGF-targeted therapy both axitinib and everolimus are valid treatment options.
A
Sorafenib can be used as another option of treatment.

I n patients with metastatic renal cell carcinoma with small metastasis, asymptomatic, for example, lung metastasis,
initial surveillance could be an option. On the other hand, a treatment break is feasible in selected patients.

I n a near future, a new immunotherapic agent (nivolumab) and a dual inhibitor (MET and VEGFR-2) cabozantinib will
change the algorithm of treatment of metastic renal cell cancer.

future science group

www.futuremedicine.com

10.2217/fon.15.283

Review Vitale & Carten


patients with metastatic renal cell carcinoma.
J. Clin. Oncol.27(22), 35843590 (2009).

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