Journal of Kidney Cancer and VHL 2014; 1(6): 63-73. Doi: http://dx.doi.org/10.15586/jkcvhl.2014.14
Review
Article
Targeted Therapy for Metastatic Renal Carcinoma: an Update
1Department of Urology, Denver Health Medical Center, Denver, Colorado, USA; 2Department of Pathology and Department of Bioengineering, University of Colorado Denver, Aurora, Colorado, USA; 3University of Colorado Cancer Center Denver, University of Colorado Denver, Denver, Colorado, USA
Abstract
Conventional
chemotherapy is associated with poor outcomes in metastatic renal cell
carcinoma (RCC). Advances in the understanding of tumor molecular biology and
the implementation of new drugs that target these molecular pathways have
increased the arsenal against advanced RCC and improved outcomes in these
patients. Herein, we briefly describe the latest data on targeted therapies
used in the treatment of advanced renal cell carcinoma. Search strategy was
performed according to PRISMA guidelines. Abstracts of relevant studies
published in PubMed between 2000 and 2014 were analyzed by two authors.
Abstracts were selected if they were published in English, data reported was of
phase II or III clinical trials, and outcomes followed FDA approval. If consensus between the two authors was
achieved, they were included in the review. Key words used were “target
therapy” and “metastatic renal cell carcinoma”. The results of the studies
analyzed in this review support the benefits of targeted therapy in metastatic
RCC. These include improved progression-free survival, overall survival, and
quality of life as well as reduced toxicities compared to immunotherapy. The
improvement in outcomes in metastatic RCC makes these drugs a preferred option
as a primary treatment for these patients. Copyright: The Authors.
Received: 16 October 2014; Accepted after revision: 20 October 2014; Published: 21 October 2014.
Author
for correspondence: Professor
Fernando J. Kim, MD, FACS, Department
of Urology, Denver Health Medical Center, Denver, Colorado, USA. E-mail: [email protected]
How
to cite: da
Silva RD, Gustafson, D, Nogueira, L, Werahera PN, Molina WR, Kim, FJ. Targeted
therapy for metastatic renal carcinoma: an update. Journal of Kidney Cancer and
VHL 2014; 1(6): 63-73. DOI: http://dx.doi.org/10.15586/jkcvhl.2014.14
Introduction
Figure 1. Targeted therapies for metastatic renal cell carcinoma and their mode of action.
A better understanding of the molecular signaling that governs tumor growth and progression has
led to the development of molecular therapies targeting the vascular
endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR)
pathways, resulting in significant improvement in overall survival and quality
of life(3). The objective of this systematic review is to briefly describe the
latest data regarding targeted therapies used in the treatment of advanced
renal cell carcinoma.
Methods
Search
Strategy and Study Selection
Search strategy and study selection were performed according to the
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)
guidelines. Abstracts of relevant
studies and clinical trials from PUBMED/MEDLINE (2000 to 2014) were analyzed by
two authors and were included if both agreed with the selection. A third author
was consulted when the two authors disagreed. After abstract selection, all
manuscripts were revised and were only included if it met the selection
criteria and if consensus was achieved by the authors.
The key words used were “target therapy” and “metastatic renal cell
carcinoma”. The terms identified
included names of following therapies: Sunitinib,
Sorafenib, Pazopanib, Axitinib, Cediranib, Everolimus, Temsirolimus, Bevacizumab, and Erlotinib.
Study inclusion criteria included contemporary articles published in
English after 2000 that reported data of phase II and III Clinical Trials and
outcomes followed FDA approval. A total of 40 studies were eligible for review.
Data
Extraction and Analysis
Variables collected from eligible studies were: study name, period of
the study, molecular targets of the drug, FDA approval status, indication of
treatment, recommended dosage of the drug, and safety and efficacy of the drug. Efficacy was evaluated by the Overall
survival (OS), progression free survival (PFS), and time to progression (TTP)
as defined by the FDA Center for Drug Evaluation and Research. Safety was evaluated by the severity of
adverse events defined by the Common Toxicity Criteria (CTC).
Evidence
synthesis
VEGF Targeted
Therapies
Angiogenesis is critical for tumor growth and progression, especially in solid tumors with vast vascularization such as RCC. Vascular endothelial growth factor and its receptor (VEGF/VEGFR) mediate VEGFR regulation of vessel permeability, endothelial cell activation, survival, proliferation, invasion, and migration. VEGFR and PDGFR pathways exhibit tyrosine kinase activity and activate downstream signaling pathways as the Raf/MEK/ERK (8). During angiogenesis, Raf is key in regulating endothelial cell survival by controlling apoptosis pathways (9). Several drugs have been developed to target this pathway and control tumor angiogenesis. A list of novel therapeutics targeting the angiogenesis/VEGF pathway is summarized in Table 1.
Table 1. VEGF inhibitors: dose, molecular target and PFS outcome.
Therapy |
Dose |
Target |
Line of Therapy |
Study |
PFS (months) |
Ref |
Sorafenib |
Oral;
400mg BID |
Raf-1
serine/threonine kinase, B-Raf, VEGFR-2, PDGFR. C_KIT |
Second
Linecyto |
Sorafenib
v. Placebo |
5.5
v. 2.8* |
(10) |
Sunitinib |
Oral;
50mg
qd |
VEGFR1-3,
c-KIT, FLT3 PDGFR |
First
Line |
Sunitinib
v. IFN |
11
v. 5* |
(11) |
Pazopanib |
Oral;
800mg qd |
VEGFR1-3;
RET, c-kit |
First
Line |
Pazopanib
v. Sunitinib |
8.4
v. 9.5 |
(15) |
First
Line |
Pazopanib
v Placebo |
11.1
v. 2.8* |
(14) |
|||
Second
Line |
Pazopanib
v Placebo |
7.4
v. 4.2* |
(17) |
|||
Axitinib |
Oral;
5mg
tid |
VEGFR1 |
First
Line |
Axitinib
v. Sorafenib |
10.1
v. 6.5* |
(19) |
Second
Linecyto, vegf, mtor |
Axitinib
v. Sorafenib |
6.7
v. 4.7* |
(18) |
|||
Cediranibi |
Oral; 45mg
tid |
VEGF1-3 |
First
Line |
Cediranib
v. Placebo |
12.1
v. 2.8* |
(22) |
Bevacizumab-IFN |
IV; 10mg/Kg 2/2weeks |
VEGF |
First
Line |
Bevacizumab-IFN
v IFN |
8.5
v. 5.2* |
(26) |
Bevacizumab-IFN
v IFN |
10.2
v. 5.4* |
(25) |
||||
Bevacizumab-Erlotinibi |
Oral; 150mg
qd |
EGFR
tyrosine kinase |
First
Line |
Bevacizumab-Erlontinib
v Bevacizumab |
9.9
v. 8.5 |
(28) |
Sorafenib
Sorafenib is an oral multi-tyrosine kinase inhibitor with activity
against Raf-1 serine/threonine kinase, B-Raf, vascular endothelial grow factor
receptor 2 (VGEFR-2), PDGFR, and c-kit. A phase III trial (TARGET trial) showed
a significantly longer PFS with sorafenib compared to placebo (5.5 vs. 2.8
months; p < 0.001). Moreover, partial responses were significantly higher
(10%) in those patients treated with sorafenib compared to 2% of those treated
with placebo (P<0.001). Cross over was performed in patients of the placebo
group which presented a reduced risk of death. 16 months after crossover, the
overall survival in the sorafenib treated cohort was 17.8 months compared to
15.2 months for the patients initially treated with placebo (p < 0.146). The
estimated overall survival for the placebo-treated patients was 14.3 months.
Sorafenib is considered a second line therapy and the suggested dose is
800 mg a day. Adverse effects were skin rash, hand-foot skin reaction, and
fatigue. Discontinuation of the treatment was required in 9% of patients, and
no deaths were reported due to toxicity of the treatment (10). Sorafenib was the
first anti-angiogenic multi-tyrosine kinase inhibitor for mRCC approved by the
FDA (2005).
Sunitinib
Sunitinib is also an inhibitor of VEGFR1-3, c-kit, FLT-3 and PDGFR.
Sunitinib has direct antitumor and anti-angiogenic activity (10, 11). This drug
was approved by the FDA in 2006 and is now considered a first-line therapy for
mRCC. It is orally administered with the
recommended daily dose of 50 mg/day by a schedule 4/2.
In a phase III trial comparing sunitinib to interferon, the sunitinib
arm showed doubled progression-free survival (PFS), improving PFS from 5 months
with interferon to 11 with sunitinib as monotherapy. The objective response
rates were 47% and 12% for sunitinib and interferon-α, respectively (P
<0.001) and the median overall survival was 26.4 months for sunitinib and
21.8 months for interferon-α (P = 0.051) (12). Moreover, access expanded globally,
and another phase III trial was designed to provide sunitinib on relatively
unselected or trial-ineligible patients with brain metastases and poor ECOG
performance status. Treatment with sunitinib demonstrated a PFS of 10.9 months
and median overall survival of 18.4 months with similar overall survival in
patients with and without prior cytokine therapy.
Sunitinib did not present high severity adverse events, but
hypertension, fatigue, diarrhea, and hand-foot syndrome were described during
treatment with this drug. Sunitinib was compared with IFN-α regarding
quality-adjusted time without symptoms of disease progression or toxicity of
treatment (Q-TWiST score). Sunitinib resulted in better clinical efficacy and
quality-of-life outcomes compared with IFN-α for mRCC patients (13).
Pazopanib
Pazopanib is a second generation, orally administered multi-target
tyrosine kinase receptor inhibitor that blocks
VEGFR1-3, RET, and c-kit receptors (11-13). A randomized phase III trial comparing
pazopanib with placebo showed a significant improvement in PFS and
tumor response in treatment-naive metastatic RCC patients (54%) and previously
cytokine-treated patients (46%). Compared to placebo, the overall PFS was 9.2
months for the pazopanib group vs 4.2 months for placebo patients (HR: 0.46;
95% CI: 0.34-0.62; p<0.0001). In the treatment-naive subpopulation, PFS was
11.1 months vs 2.8 months (HR: 0.40; 95% CI: 0.27-0.60; p<0.0001) for
pazopanib and placebo, respectively. In patients pretreated with cytokine, PFS
was 7.4 months vs 4.2 months (HR: 0.54; 95% CI: 0.35-0.84; p<0.001) for
pazopanib and placebo, respectively (14).
Another non-inferiority randomized phase III trial compared pazopanib
with sunitinib. PFS and OS of pazopanib
were not inferior to sunitinib, and quality of life with pazopanib was
statistically better than sunitinib in those patients (15). Pazopanib
demonstrated acceptable safety and tolerability even though it has been
associated with liver toxicity. Common adverse events reported with pazopanib
were hair color changes, nausea, anorexia, and vomiting while Grade 3-4
toxicity effects were hypertension, diarrhea, and liver toxicity (14). Pazopanib was
approved by the FDA in 2009. It is considered as a first-line treatment and an
option as a second-line treatment in previously cytokine-treated patients (16, 17). Pazopanib is
usually administered orally at 800 mg daily.
Axitinib
Axitinib is another second-generation inhibitor of VEGFR-1 which also
has minimal effect on other targets. Axitinib is a second-line therapy option
in cytokine-refractory metastatic RCC. A Phase III clinical trial (18) that
compared axitinib and sorafenib in 723 patients who were previously treated
unsuccessfully with cytokine or VEGF inhibitors showed a median PFS of 6.7
months for the axitinib group and 4.7 months for the sorafenib group
(p<0.0001). The OS was 29.9 months with a TTP of 15.7 months.
The overall response rate was 22.6%, and the median duration of response
was 17.5 months. The adverse events of axitinib included diarrhea,
hypertension, fatigue, dysphonia, and hand-foot syndrome (19). Grade 3 to 4
adverse events included hand-foot syndrome, fatigue, hypertension, dyspnea,
diarrhea, dehydration, and hypotension. Axitinib was approved by the FDA in
2012. Its potency is 50 to 450 times greater than the first-generation VEGFR
inhibitors (20, 21). The recommended
dose of axitinib is 5.0 mg twice a day (18).
Cediranib
Cediranib is an ATP-competitive inhibitor of receptor tyrosine kinases
(RTKs) related to VEGF1-3 (11). A phase II trial compared the efficacy of cediranib with placebo in
patients with metastatic or recurrent clear cell RCC who had not previously
received a VEGF signaling inhibitor. Partial responses were achieved in 34%
patients, and 47% experienced a stable disease. PFS significantly improved when
compared to placebo with median 12.1 versus 2.8 months (p = 0.017) (22). In addition, more
than 50% of patients who achieved a partial response with cediranib experienced
responses lasting more than a year.
The most common adverse effects in patients were diarrhea, fatigue,
hypertension, and dysphonia (23). The recommend dose is 45 mg/day. Cediranib is still an investigational
drug under the FDA.
Bevacizumab
Bevacizumab is a humanized recombinant IgG monoclonal antibody that
binds to VEGF-A, increasing vascular permeability and reducing proliferation
and migration of endothelial cells.
The AVOREN (phase III) double-blind trial randomized 649 naive patients
to receive bevacizumab (10 mg/kg every 2 weeks) plus IFN-α (9 MUI) or placebo
and IFN-α. The median overall response (OR) and stable disease in the
bevacizumab plus IFN-α versus placebo plus IFN-α arms were 31 and 46% versus 13
and 50%, respectively. PFS was significantly longer in the bevacizumab and
IFN-α (10.2 versus 5.4 months; p<0.0001), but only in good-risk and
intermediate-risk patients. In poor-risk patients, bevacizumab did not present
any benefits (24). After
progression, crossover was performed and the median OS was 23.3 months for
bevacizumab-IFN-α vs 21.3 months for IFN-α alone (p=0.336) (25). Fatigue, asthenia, and proteinuria were the most common grade 3
toxicities (11, 26). FDA approved bevacizumab in 2009 at 10 mg/kg IV every 2 weeks in
combination with IFN-α.
Another phase III (CALGB 90206)(26) randomized trial enrolled 732 previously untreated metastatic RCC
patients for bevacizumab (10 mg/kg each 2 weeks) plus IFN-α (9 million U/3
times weekly) versus IFN-α monotherapy. PFS was 8.5 months for the combination
compared to 5.2 months for INF-α alone. After crossover, median OS was 18.3 for
the combination compared to 17.4 for IFN-α alone. OR with bevacizumab plus
IFN-α was higher compared to IFN monotherapy (25.5 vs 13.1% p< 0.0001). The
combination therapy was associated with higher grade 3 to 4 hypertension (HTN),
anorexia, fatigue, and proteinuria.
Erlotinib
Erlotinib inhibits the tyrosine kinase domain of epidermal growth factor
receptor (EGFR), leading to the inhibition of EGFR auto-phosphorylation and
downstream signaling (27). Erlotinib demonstrated encouraging activity in renal cell carcinoma
when associated with bevacizumab in a phase II trial (28). 63 patients with metastatic clear-cell RCC were treated with
bevacizumab at 10 mg/kg every 2 weeks and erlotinib at 150 mg/daily. Objective
responses were achieved in 25% of the patients, disease was stable in 61% after
8 weeks, and survival at 18 months was 60%.
Another randomized double-blind phase II trial compared the combination
of erlotinib and bevacizumab with bevacizumab alone. Combined therapy did not
provide additional benefits when compared to bevacizumab alone (29).
The combination of erlotinib with sirolimus in metastatic RCC did not
show benefits when compared to a single agent in a phase II trial (30). 25 patients
previously treated with sunitinib and/or sorafenib were evaluated and included.
Partial responses or complete responses were observed; however, stable
disease was noted in 21.8% of patients in 46 months. The progression-free
survival and overall survival were 12 and 40 weeks respectively. Currently,
Erlotinib is not approved by the FDA for the treatment of metastatic RCC.
Mammalian
Target of Rapamycin (mTOR) Inhibitors
Another signaling pathway that is critical for cellular growth, proliferation, and angiogenesis is a mammalian target of rapamycin (mTOR) pathway (31). This pathway is more significantly mutated in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features (32, 33). A list of novel therapeutics targeting the mTOR pathway is summarized in Table 2.
Table 2. m-TOR inhibitors: dose, molecular
target and PFS outcome.
Therapy |
Dose |
Target |
Line of Therapy |
Study |
PFS (months) |
Ref |
Temsirolimus |
IV; 25mg weekly |
mTOR; HIF1-2; VEGF |
First Line |
Temsirolimus v IFN |
10.9 v. 7.3* |
(38) |
Second Linevegf |
Temsirolimus v Sorafenib |
4.3 v. 3.9 |
(45) |
|||
Everolimus |
Oral; 10mg Qd |
mTOR; HIF1;VEGF |
Second/Third Linevegf |
Everolimus v. Placebo |
4.9 v. 1.9* |
(36) |
Everolimus is an mTOR inhibitor used in the treatment of VEGF-
refractory disease. A phase II trial was conducted using everolimus at a daily
dose of 10mg for a 28-day cycle in 41 patients with metastatic RCC who were
previously treated with one therapy at most.
Median progression-free survival of 11.2 months and median overall
survival of 22.1 months was reported (34). Partial responses were observed in 5 patients, stable disease lasting
3 months was reported in 27 patients, and stable disease lasting 6 months was
reported in 21 patients.
Another phase II trial in metastatic RCC patients who hadn’t received
previous treatment or who had failed RCC treatment on sunitinib and/or
sorafenib demonstrated anti-tumoral activity with the combination of everolimus
and bevacizumab. Bevacizumab was given at 10 mg/kg intravenously every 2 weeks
and everolimus at 10 mg per day, orally. The median progression-free survival
in previously untreated patients was 9.1 months and 7.1 months in previously
treated patients (35).
A placebo-controlled phase III trial was designed with everolimus as a
second-line therapy for advanced clear cell carcinoma refractory to sunitinib,
sorafenib, or both agents. 410 patients were randomized to receive everolimus
or placebo. Patients were stratified according MSKCC (Memorial Sloan-Kettering
Cancer Center) prognostics score and whether they had previously received one
or two VEGF receptor tyrosine kinase inhibitors. PFS was significantly
prolonged for everolimus by 4.9 months when compared to 1.87 months with
placebo (36) .
Common adverse effects reported were stomatitis, rash, diarrhea, and
non-infectious pneumonitis. Everolimus was approved by the FDA in 2009 as an
option for advanced RCC patients who had failed treatment with VEGF therapy.
The usual dose is 10 mg once daily (37).
Temsirolimus
Temsirolimus is a specific inhibitor of mTOR and inhibits tumor
angiogenesis by reducing synthesis of VEGF. Temsirolimus and IFN-α were used in
a phase I/II Trial (38) for advanced RCC.
71 RCC patients were eligible and the recommended doses for temsirolimus was 15
mg and IFN-α was 6 million units. Among patients who received the recommended
dose, 8% achieved partial response, 36% had a stable disease for 24 weeks, and
the median overall progression-free survival was 9.1 months.
A phase III trial with 626 advanced and poor prognosis patients
established that temsirolimus in combination with interferon did not improve
survival (39). Overall survival
medians in the interferon, temsirolimus, and combination groups were 7.3, 10.9,
and 8.4 months, respectively. Monotherapy with temsirolimus showed longer
overall survival and progression-free survival (P<0.001) than patients who
received interferon alone (P<0.001). The median OS of temsirolimus and IFN-α
as monotherapies were 10.9 and 7.3 months respectively. The median PFS time for
the temsirolimus was 5.5 months compared with 3.1 months on IFN-α (p = 0.001).
Common adverse events were rash, peripheral edema, hyperglycemia, and
hyperlipidemia in the temsirolimus group whereas asthenia was more significant
in the interferon group. Grade 3 or 4 toxicity occurred in almost 90% of patients
in the combination therapy. Temsirolimus was approved by the FDA in 2007 for
advanced/metastatic RCC patients with three or more poor prognostic features.
The standard dose is 25 mg IV/weekly.
Non-clear
cell histology
Presently, there is a lack of phase III trials on systemic treatment of
patients with non-clear cell RCC. Small studies for papillary type 1 and 2 were
performed with sunitinib and everolimus, but none of them were prospectively
randomized (40, 41). A phase II trial
in patients with papillary RCC treated with foretinib (multikinase inhibitor)
showed a median PFS of 9.3 months and 13% response rate. The presence of germ
line MET mutation was a strong predictor of a response (42). There is a lack
of data to support systemic therapy in patients with collecting-duct subtype.
These tumors have been included in prospective trials but with smaller numbers
of patients, invalidating any type of analysis (43).
Cytoreductive
Nephrectomy in target therapy era
Cytoreductive nephrectomy has been shown to extend overall patient
survival in the multimodal treatment of metastatic RCC comparing immunotherapy alone or combined with
cytoreductive nephrectomy (44). In this target therapy era, it’s likely to remain part of the
treatment and is recommended when possible. Complete removal of metastasis
contributes to improved clinical prognosis and should be considered when
feasible (2).
Conclusion
A
better understanding of the tumor biology and the development and
approval of multiple targeted agents for treatment of advanced RCC
enables
improved survival in patients with metastatic RCC. The standard of care
in
metastatic RCC is use of drugs that target VEGF and mTOR pathways. The
third
generation of tyrosine kinase inhibitors appears to have similar or
superior
efficacy as well as lower toxicity than existing agents. Compared to
previous systemic therapies, these drugs showed evident
clinical benefits. They increase progression-free overall survival and
improve
the quality of life, but complete responses have been rarely noted.
Some questions have yet to be answered and demand more debate. The most
efficacious sequence of therapies and time to start a second-line agent
(before
or not progression of the disease) should be addressed in further
studies.
Conflict of Interest: None
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