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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
part of
ISSN 1479-6694
Targeted
therapy
Patients (n)
ORR (%)
Median PFS
(months)
Median OS
(months)
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)
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.
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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
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
Review
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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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Clinical management of metastatic kidney cancer: the role of new molecular drugs
Review
Table 2. Phase III trials of targeted therapy in second-line treatment in metastatic renal cell carcinoma patients.
Trial
ORR (%)
Median PFS
(months)
Median OS
(months)
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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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
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
Review
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
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Sorafenib
Sunitinib
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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.
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References
Papers of special note have been highlighted as:
of interest; of considerable interest
1
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Clinical management of metastatic kidney cancer: the role of new molecular drugs
30 Grnwald V, Karakiewicz PI, Bavbek SE etal.
Review
https://clinicaltrials.gov
51 Clinical trials database: NCT02420821.
https://clinicaltrials.gov
52 Motzer RJ, Escudier B, McDermott DF etal.
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