Current Treatment Considerations in Metastatic Renal Cell Carcinoma
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- Haddad, H. & Rini, B.I. Curr. Treat. Options in Oncol. (2012) 13: 212. doi:10.1007/s11864-012-0182-8
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In general, debulking neprhectomy is still considered for metastatic RCC patients with primary tumor in place, assuming good performance status. Initial systemic therapy should consider high-dose IL-2 for the highly select patient. One reason for initial consideration of this therapy is the less certain risk/benefit profile if employed after targeted therapy. Notably, due to its potential toxicity and emergence of new effective and more tolerable drugs, IL-2 has become a less favorable and subsequently a less utilized therapeutic tool in the current era. Otherwise, VEGF-targeted therapy is the treatment of choice, preferably on a clinical trial. Off trial, sunitinib has long been favored but pazopanib is gaining more use for tolerance pending the comparative trial. Continued VEGF targeting is favored by these authors given the underlying biology of RCC and the prospective clinical data, noting no direct comparison of mTOR and VEGF agents has yet occurred. Maintaining patient dose is critical and requires optimal supportive care and appreciation/early intervention for toxicity. Predictive biomarkers are desperately needed, and enrollment on clinical trials remains a priority to optimize patient outcome.
KeywordsRenal cell carcinomaTargeted therapySunitinibPazopanibSorafenibBevacizumabTemsirolimusEverolimus
As the list of effective therapies for advanced renal cell carcinoma (RCC) continues to grow with new agents on the verge of approval, so do the questions about the comparative efficacy and safety profiles of these agents and the optimal use of each agent. Interleukin-2 reserves its role and potential ability to produce a durable complete response in a highly selected group of patients. Targeted therapy has assumed the main role in the treatment of metastatic RCC. The choice of which drug to use takes into account factors like familiarity, safety in the comorbidity context of each patient, ease of administration (PO vs. IV) and cost issues. Given the extensive clinical experience with sunitinib and its superior PFS and ORR compared with other agents across the trials and its ease of administration, it tends to be the default first line treatment option in the United States regardless of the histology type or risk group. Ongoing clinical trials are investigating specific sequences, comparative efficacy and exploring predictive biomarkers. This review summarizes the major clinical data for systemic therapy in metastatic RCC.
Incidence and molecular biology of RCC
Targeted therapy in renal cell carcinoma
Phase III trials of currently approved targeted therapies for RCC
Number of patients
Common grade 3 or higher AE
400 mg bid
10 vs. 2
5.5 vs. 2.8 P < 0.01
17.8 vs. 15.2, p = 0.15*
Fatigue, HFS, dyspnea, anemia, HTN
50 mg qd,4 week on, 2 week off
IFN 9MU 3×/week
39 vs. 8
11 vs. 5 P < 0.001
26.4 vs. 21.8, p= 0.051**
Fatigue, diarrhea, vomiting, HTN, HFS, neutropenia, thrombocytopenia
800 mg qd
Cytokine refractory or Treatment naive
30 vs. 3
9.2 vs. 4.2, p < 0.0001
22.9 vs. 20.5, p = 0.22
AST, ALT elevation, hypophosphatemia and HTN.
Bevacizumab + IFN 
10 mg/kg q2wk plus IFN 9MU 3×/week
IFN 9MU 3×/week
31 vs. 12
10.2 vs. 5.4 p < 0.0001
23.3 vs. 21.3, p = 0.336
Fatigue, asthenia, HTN, proteinuria, neutropenia
Bevacizumab + IFN 
10 mg/kg q2wk plus IFN 9MU 3×/week
IFN 9MU 3×/week
25.5 vs. 13.1
8.5 vs. 5.2 p < 0.0001
18.3 vs. 17.4, p = 0.097
Fatigue, anorexia, HTN, proteinuria
25 mg qwk alone or 15mg qwk plus IFN 6MU 3X/week
IFN 3MU 3×/week with an increase to 18MU 3×/week
8.6 vs. 4.8 vs. 8.1 a
3.8 vs. 1.9 vs. 3.7, p < 0.0001 b
10.9 vs. 7.3 vs. 8.4, p = 0.008 b
Anemia, asthenia, rash, hyperglycemia
10 mg qd
1.8 vs. 0
4.9 vs. 1.9 p < 0.001
14.8 vs. 14.4,p = 0.162
Lymphopenia, hyperglycemia, anemia, infections
Sorafenib is a RAF kinase and VEGFR inhibitor that inhibits tumor growth by either directly (through inhibition of Raf and Kit signaling) thereby inhibiting tumor cell proliferation or more likely through inhibition of tumor angiogenesis. On December 20, 2005, the FDA granted approval for sorafenib for the treatment of patients with advanced renal cell carcinoma. This approval was based on a phase III study, a randomized, double-blind, placebo-controlled trial . The study randomized 903 patients with advanced clear cell RCC that was resistant to prior therapy (largely cytokines) to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. The study excluded patients in the poor risk group per MSKCC model . Consequently, crossover was permitted from placebo to sorafenib upon disease progression in the placebo group. The median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio 0.44; 95% confidence interval [CI], 0.35 to 0.55; P < 0.01). The final overall survival-which was reported later- was 17.8 months for the sorafenib group and 15.2 months for the placebo group (p = 0.146). The above mentioned crossover was the likely explanation of lack of overall survival advantage of sorafenib. When post-cross-over placebo survival data were analyzed, the difference became significant (17.8 v 14.3 months, respectively; P = .029) [5••]. This phenomenon (PFS advantage without OS advantage) has been replicated in most other phase III targeted therapy studies noted below. The general consensus is that subsequent active therapy makes demonstration of an OS advantage within any one trial difficult if not impossible at present, although clearly metastatic RCC patients are living much longer compared to the cytokine era. The predominant grade 3–4 adverse events with sorafenib in the phase III trial included fatigue (5%), anemia (3%), hand and foot skin reaction (6%), dyspnea (7%) and hypertension (4%). Fatigue, skin rash, diarrhea and nausea were the most common adverse reactions of all grades.
In a subsequent phase II study, sorafenib was evaluated in comparison with interferon-alpha as a first line treatment for metastatic RCC . The study concluded that sorafenib resulted in similar PFS as IFN-α in patients with untreated RCC (5.7 vs. 5.6 months) but greater rates of tumor size reduction and better quality of life. These phase II data have relegated sorafenib to largely a drug used in the refractory setting given the more robust front-line data for other targeted agents. Some studies have explored the role of dose-escalation of sorafenib. Although supported by initial reports of activity [6, 7], more recent data does not indicate tolerability or increased efficacy from this approach . Further, efforts to predict sorafenib activity have not resulted in any clinically reliable biomarkers to allow for identification of susceptible patients [5••]. Sorafenib remains a reasonably well-tolerated oral agent most often used in refractory RCC but without a significant role in the front line setting. Based on these data, sorafenib is recommended by the NCCN panel mainly as a subsequent therapy for patients with metastatic clear cell RCC following other tyrosine kinase inhibitor (category 2A) and following cytokine therapy (category 1) .
Sunitinib is an inhibitor of multiple protein tyrosine kinases, including VEGF-R, PDGF-R, FMS-like tyrosine kinase 3 (FLT3), stem cell factor receptor c-KIT, colony stimulating factor CSF-1R and neurotrophic factor receptor RET. Preclinical data suggest that sunitinib antitumor activity results from both inhibition of angiogenesis and direct antiproliferative effects . On January 26, 2006, the FDA granted approval for sunitinib for the treatment of advanced renal cell carcinoma. The efficacy of this agent as first-line treatment for metastatic RCC was demonstrated through a phase III clinical trial  in which 750 treatment-naïve patients with metastatic RCC (more than 92% of patients belonged to the good or intermediate risk groups per MSKCC model)  with a clear-cell histology were randomized to receive interferon alpha (at a dose of 9 MU given subcutaneously three times weekly) or sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) based on prior phase I and II trials [12, 13]. Median PFS (the study primary endpoint) was 11 months for the sunitinib arm vs. 5 months for the interferon arm. Sunitinib was associated with a higher objective response rate compared to interferon alpha (31% vs. 9%). Updated results revealed an overall survival of 26.4 months with sunitinib vs. 21.8 months with interferon (p= .051) [14••]. Severe (grade 3–4) adverse events related to sunitinib included fatigue (7%), diarrhea (5%), vomiting (4%), hypertension (8%), hand and foot syndrome (5%), neutropenia (12%) and thrombocytopenia (8%). An expanded access trial published subsequently, evaluated broader and larger (n = 4,564) population of advanced RCC patients that included patients with brain metastases, ECOG of 2 or higher and non-clear cell histology tumors. This study demonstrated that sunitinib has an acceptable safety profile and has potential efficacy in these subgroups of patients that are generally excluded from clinical trials [15•].
The approved dosing schedule (50 mg once daily, 4 weeks on/2 weeks off) was compared to a continuous lower dose schedule (37.5 mg continuously daily) in a phase II study, namely, the EFFECT trial . The study showed that the standard schedule was associated with superior time to progression but similar OS and AE profile compared to the continuous schedule suggesting that the standard dosing scheduled should be the primarily adopted schedule in prescribing sunitinib. Based on the available data, the NCCN panel recommends sunitinib as first line therapy for metastatic RCC with category 1 designation for clear cell and category 2A for non clear cell histology. In the United States, sunitinib represents the most commonly-used initial agent, based on strong clinical data, oral administration and familiarity as one of the earliest targeted therapies approved.
Another area of significant interest and effort has been with investigation of predictive biomarkers with sunitinib. An observational prospective study [17•] identified certain single nucleotide polymorphisms (SNPs) in VEGFR3 and CYP3A5*1 genes as predictive markers of reduced PFS with sunitinib and increased risk of dose reductions due to toxicity, respectively. Another study demonstrated that a number of genetic markers involved in the pharmacokinetic and pharmacodynamic pathways of sunitinib predispose for development of certain toxicities including thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome as well as any high grade adverse events [18•]. In a retrospective analysis, patients with sunitinib–induced hypertension had a significantly better clinical outcome compared to those without treatment related hypertension (objective response rate: 54.8% vs. 8.7%; median PFS: 12.5 months vs. 2.5 months; and OS: 30.9 months vs. 7.2 months, P < .001 for all) . All of the above clinical and biochemical markers can only partially predict the variability in the response and the tolerability of sunitinib but validation of these markers awaits further prospective and controlled studies.
Pazopanib is an oral angiogenesis inhibitor that targets VEGF-R PDGF-R-α, and c-KIT. It is the third tyrosine kinase inhibitor and the sixth targeted therapy that has received US FDA approval for the treatment of advanced or metastatic RCC (October, 2009). The phase III randomized double-blind clinical trial that lead to this approval included 435 patients with metastatic RCC of clear cell or predominantly clear cell histology, including treatment naïve or cytokine pretreated patients [20••]. The majority (93–94%) of patients were in the good or intermediate MSKCC risk groups. Patients were randomized 2:1 to receive 800 mg pazopanib once daily or placebo. Median progression-free survival was significantly prolonged with pazopanib compared with placebo in the overall study population (median PFS, 9.2 vs. 4.2 months; HR, 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS, 11.1 vs. 2.8 months; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 vs. 4.2 months; P < .001). The final OS analysis data from this study showed no significant OS advantage of pazopanib compared to placebo (22.9 versus 20.5 months, respectively p = .224). The early, high rate and prolonged duration of crossover from placebo to pazopanib was the factor that likely confounded the OS analysis [21•]. Based on these data, pazopanib is recommended in the NCCN guidelines as category 1 as first line therapy or second line therapy after cytokine therapy failure and category 3 following other tyrosine kinase inhibitors. This drug has gained common use in more refractory patients and is being used in earlier lines of therapy pending full COMPARZ trial results [24•].
Common adverse events related to pazopanib in this phase III trial included (any grade): diarrhea (52%), hypertension (40%), hair color changes (38%), fatigue (19%), nausea (26%), anorexia (22%), vomiting (21%), abdominal pain (11%), headache (10%), neutropenia (34%) and thrombocytopenia (32%). Notable grade 3 and 4 toxicities included liver enzyme elevation (ALT in 12%, AST in 7%), hypophosphatemia (4%) and hypertension (4%). Arterial thrombotic events occurred in 3% of pazopanib-treated patients (myocardial infarction/ischemia [2%], cerebrovascular accident [<1%], and transient ischemic attack [<1%]) compared with none in the placebo arm. ALT elevations recovered to grade 1 or normalized after dose modification, interruption, or discontinuation. Death attributed to treatment related liver toxicity was reported in one patient (0.25%). Therefore, concerning the management of pazopanib related hepatotoxicity, if transaminase levels are <8 × ULN, treatment continuation is allowed with once weekly LFT monitoring until resolved to grade 1. If transaminase rises to >8 × ULN, interruption of pazopanib is recommended until it resolves to grade 1 with consideration of the risk-benefit of re-challenge, but if the decision is taken to re-start pazopanib, then it should be re-introduced at a reduced dose and LFTs should be monitored weekly for 8 weeks. If transaminases rise to >3 × ULN after re-introduction, then pazopanib, must be discontinued.
Two trials studying pazopanib in various sequencing orders with other targeted therapies are still underway [22, 23]. An important trial completed but yet to be reported in COMPARZ, a randomized trial of pazopanib versus sunitinib in previously untreated metastatic RCC [24•]. This trial is a non-inferiority trial with a PFS primary endpoint. These data are eagerly awaited to provide further insight into the relative risks and benefits of agents with a similar biochemical profile.
Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes circulating VEGF and prevents the stimulation of its receptor (VEGFR-2) on endothelial cells. The FDA approved bevacizumab in combination with interferon-alpha for the treatment of advanced RCC in July, 2009. The trial that lead to this approval, the AVOREN trial, was a multicenter international phase III randomized double blinded trial in which 649 patients with previously untreated, predominantly clear cell, metastatic renal cell carcinoma were randomized to receive interferon alpha 9MU SC three times a week and bevacizumab 10 mg/kg every 2 weeks or placebo and interferon alpha. . The study included patients from all three prognostic risk groups, but with less than 10% of patients from the poor risk category per MSKCC model. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alpha group than it was in the control group (10.2 months vs. 5.4 months), p< .0001. Increases in progression-free survival were seen with bevacizumab plus interferon alpha irrespective of risk group. A final analysis of overall survival published subsequently showed a trend toward improved OS in the combination therapy arm that did not reach statistical significance 23.3 months in the bevacizumab plus IFN arm compared with 21.3 months in the control arm (unstratified HR = 0.91; 95% CI, 0.76 to 1.10; P = .3360). These results were confounded by the fact that more than half of patients in either study arms received post protocol systemic therapies including a TKI [26••]. Fatigue (bevacizumab plus IFN, 13%; IFN plus placebo, 8%) and asthenia (bevacizumab plus IFN, 11%; IFN plus placebo, 7%), were the most commonly reported grade ≥3 AEs, irrespective of treatment arm; proteinuria (8%) and hypertension (6%) were the most common grade 3 or 4 AEs associated with bevacizumab treatment. Less common Grade 3 and 4 adverse events included gastrointestinal perforations (1%) and thrombo-embolic events (3%). A similar trial was conducted in the United States by the CALGB . In this randomized multicenter unblinded phase III trial, 732 patients with previously untreated, metastatic clear-cell RCC were randomly assigned to receive bevacizumab plus IFN or IFN monotherapy. The median PFS was 8.5 months in patients receiving bevacizumab plus IFN versus 5.2 months in patients receiving IFN monotherapy (P < .0001). The updated survival data from this trial showed non-significant difference in OS between the two study arms (18.3 months for bevacizumab plus IFN-alpha vs. 17.4 months for IFN-alpha monotherapy, P = .097) [28••].
Clinical trials evaluating various combinations of targeted therapies
Patel et al. 
RCC, 2 or less prior therapies
Temsirolimus plus sunitinib
Patnaik et al. 
Solid tumors, lymphoma
Temsirolimus plus sorafenib
No responses in RCC
Sosman et al. 
RCC, first or second line after cytokine therapy
Bevacizumab plus sorafenib
MTDb 5 mg q2wk/200 mg QD
ORR 46% median TTP 11.2 month
Feldman et al. 
Bevacizumab plus sunitinib
Cen et al. 
Everolimus plus sorafenib
MTD 10 mg qd/400 mg bid
ORR 27%, PFS 5.5 month, OS 7.9 month
Kroog et al. 
Everolimus plus Sunitinib
MTD 20 mg/week/37.5 mg qd
ORR 31 %
Temsirolimus plus bevacizumab
Sunitinib, bevacizumab plus IFN (2 control arms)#
Temsirolimus plus bevacizumab not well tolerated
No additive efficacy
NPR-48a: 43.2%, 47.6% and 65.9%
Hainsworth et al. 
First or second line after TKI
Everolimus 10 mg QD plus bevacizumab 10 mg q2wk
PFS 9.1 month as first line and 7.1 month as second line d
BeST/ECOG E2804 
Bevacizumab/temsirolimus vs. bevacizumab/sorafenib vs. sorafenib/temsirolimus
Bevacizumab plus sunitinib
Bevacizumab 10 mg/kg q2wk plus everolimus 10 mg qd
Bevacizumab plus interferon
Bevacizumab plus temsirolimus
Bevacizumab plus interferon
CALGB 90802 
At least one prior TKI
Everolimus plus bevacizumab
Everolimus plus placebo
Temsirolimus is a prodrug that gets converted in vivo to rapamycin which inhibits mTOR, thereby down regulating the translation of specific mRNAs required for cell cycle progression from G1 to S phase. It was the first mTOR inhibitor to be approved for treatment of RCC (May, 2007). The safety and efficacy of multiple dose levels of temsirolimus were evaluated in a phase II trial .The results of this trial lead to the ARCC trial  which was a randomized phase III trial of treatment naïve metastatic RCC patients with at least three of the six predictors of short survival (a serum lactate dehydrogenase level of more than 1.5 times the upper limit of the normal range, a hemoglobin level below the lower limit of the normal range; a corrected serum calcium level of more than 10 mg/dL, a time from initial diagnosis of renal-cell carcinoma to randomization of less than 1 year, a Karnofsky performance score of 60 or 70, or metastases in multiple organs). Seventy six percent were in the high risk group and the rest were in the intermediate risk per MSKCC model . Twenty percent of the patients were of non clear cell histology. A total of 626 patients were randomized to receive temsirolimus 25 mg iv per week versus interferon monotherapy versus the combination of temsirolimus 15 mg IV per week plus interferon. The median PFS in the interferon, temsirolimus, and combination-therapy groups were 1.9, 3.8, and 3.7 months, respectively. Patients treated with temsirolimus alone had a longer overall survival than those on interferon monotherapy and those on combination therapy (10.9 vs. 7.3 vs. 8.4 months respectively). The lack of survival benefit in the combination arm over interferon is believed to be largely due to the increased frequency of grade 3 or 4 adverse events in this group which resulted in increased morbidity as well as treatment delays and reductions.
Common adverse events (all grades) included asthenia (51%, 11% grade 3 or 4), rash (47%, 4% grade 3 or 4), anemia (45%, 20% grade 3 or 4), nausea (37%), anorexia (32%), dyspnea (28%, 9% grade 3 or 4), hyperlipidemia (27%) and hyperglycemia (26%) reflecting inhibition of mTOR-regulated glucose and lipid metabolism. Incidence of temsirolimus-related pneumonitis, not specifically addressed in this study, was evaluated in a retrospective radiographic review and found in 29% of patients on temserolimus arm of whom 31% were symptomatic . Based on this study a subset analysis was performed to determine the effect of temsirolimus vs. IFN on OS and PFS in pts with clear cell or other RCC histologies (82.3% vs. 17.7% respectively). The study concluded that temsirolimus benefited patients regardless of tumor histology with OS of 10.7 vs.11.6 months and PFS of 3.8 vs. 4 months in clear and non clear cell respectively . Despite these observations from this subset analysis indicating that temsirolimus has potential activity in non clear cell as well as poor risk RCC patients, prospective data are still lacking on which drug or group of drugs has superior efficacy in these subsets of patients. Based on these data the NCCN guidelines included Temsirolimus as category 1 recommendation for poor prognosis patients with metastatic RCC including clear cell and non clear cell cancers and category 2B in patients from other risk groups.
Everolimus, a derivative of rapamycin, is an orally administered inhibitor of mTOR. It was approved by the FDA in March, 30, 2009 as a subsequent therapy for patients with metastatic RCC whose disease progressed on tyrosine kinase inhibitors. The trial that lead to this approval is the RECORD1 trial, an international multicenter double blinded randomized phase III trial that included patients with advanced clear cell RCC from all three prognostic risk groups per MSKCC model. Four hundred and sixteen patients were randomized to receive either everolimus 10 mg PO once daily or placebo . All patients had already failed either sunitinib or sorafenib or both, as well as other prior systemic therapy was allowed (approximately 21% of patients were second-line). The median PFS for the everolimus arm was 4.9 months versus 1.9 months for the placebo arm (P < .001). A final analysis of that trial published later showed that everolimus did not result in improved OS (14.8 versus 14.4 months, p = 0.162) [36••]. Stomatitis (44%), infections (37%), asthenia (32%), fatigue (31%), diarrhea (30%), cough (30%) and rash (29%) were the most commonly reported adverse events. Grade 3 or 4 treatment related abnormalities included lymphopenia (16%); hyperglycemia (15%); anemia (12%), infections (7%), dyspnea (6%), hypophosphatemia (6%); hypercholesterolemia (4%) and stomatitis (4%). Pneumonitis was detected in 14% of patients in the everolimus group and 4% were of grade 3 severity. A number of ongoing studies are currently evaluating the role of everolimus in combination with other targeted therapies (Table 2) and as part of sequential therapy for RCC (see sequential therapy). Everolimus has assumed a role in the treatment of refractory RCC pending further data.
Which drug for initial therapy?
There are as yet no data comparing two active targeted therapies in the front-line setting. As such, treatment decisions in this setting are empiric, based on interpretation of the strength of clinical data, toxicity profile of drug and potential interaction with patient comorbidities, route of administration, costs and physician experience. The COMPARZ trial of pazopanib versus sunitinib has completed accrual with results expected sometime in 2012 [24•]. This trial will provide insight into the relative risks and benefits and will inform the front-line therapy decision. Given the number of agents, trials comparing all agents are not possible, so this likely will remain an open question moving forward.
A frequently raised, yet remaining to be answered, question, is in what sequence should current therapy be used. Does a particular drug have more efficacy when used in the front line setting than when used after failing other therapies or vice versa? And another related question, is there any cross resistance between these therapies that might preclude using a specific combination of these drugs in sequence? A number of trials and retrospective analyses, some of them still in progress, have tried to address this issue. The major phase III trials that lead to the approval of these targeted therapies demonstrated the efficacy of temsirolimus, sunitinib, pazopanib and bevacizumab in the first line setting, sorafenib and pazopanib after failing cytokine therapy and everolimus after failing TKI. Temsirolimus, everolimus, sunitinib and bevacizumab have shown efficacy as subsequent therapies after cytokine therapy failure in a number of phase II studies [13, 30, 31, 37]. Sunitinib demonstrated significant antitumor activity in bevacizumab-refractory mRCC patients in a phase II study . Two retrospective analyses suggested the lack of cross resistance between sorafenib and sunitinib, and support the sequential use of sorafenib and sunitinib in either order in RCC [39, 40]. Efficacy of temsirolimus in sequential use after failing TKI treatment was demonstrated in a retrospective study by Weikert et al. . The START trial is an ongoing phase II study that compares 6 different 2-drug “sequences” of everolimus, bevacizumab, or pazopanib . A number of ongoing phase II trials are evaluating the utility of everolimus/sunitinib sequence , temsirolimus vs. sorafenib after failing sunitinib  and bevacizumab plus temsirolimus following tyrosine kinase Inhibitor therapy . Thus, there is relative but not absolute resistance to sequential therapy. That is, the activity of each approach generally goes down with successive lines of therapy, but clear clinical activity remains, accounting for the improved overall survival of advanced RCC patients. Ongoing prospective investigation is needed to further define this field. More importantly, however, is the discovery of predictive biomarkers to predict individual patient benefit from a given therapy.
Concurrent targeting of multiple signaling pathways has been theorized to be a potential tool to maximize the clinical benefit derived from targeted therapies by combining two or more agents that inhibit different pathways. A number of studies have tried to explore the additive/synergistic effect as well as the safety profile resulting from combining targeted therapies (Table 2). Noteworthy is that bevacizumab was the drug in many of the combination regimens in these trials. Most of these studies were either prematurely terminated due to unacceptable toxicity profile or were completed but concluded that there was no significant gain from combining targeted therapies. One of the combinations that showed promise in terms of safety and efficacy was everolimus plus bevacizumab (PFS initially reported at 12 and 11 months in treatment naïve and TKI refractory patients respectively)  which provided the rationale for larger phase II and phase III studies evaluating this combination [55, 57]. However, the updated data from this study revealed PFS 9.1 and 7.1 months in the first and second line setting respectively which compares to PFS 10.2 months achieved with bevacizumab plus interferon in the AVOREN trial and implies a weaker rationale for conducting the above mentioned trials . In short, it does not seem that combinations of existing targeted therapy will be a major advance above and beyond sequential monotherapy. Newer agents in development, e.g. novel immunotherapy, other anti-angiogenic agents, may prove to be more suitable partners for the existing agents to improve outcome.
The first observation of clinical activity of IL-2 in renal cell cancer was reported in 1985 by Rosenberg et al. . The FDA approved high-dose IL-2 for the treatment of patients with metastatic RCC in 1992 based on a phase II data from 255 patients treated with high dose intravenous IL-2, that was updated later and showed overall objective response rate of 15% with 7% complete response rate and 8% partial response rate [60, 61]. Although no new data has emerged to guide patient selection, IL-2 is currently a treatment option for patients with clear cell RCC, good performance status, no significant co morbidities, and normal cardiac and renal function to be given in a center with appropriate expertise. In a refractory setting, the administration of IL-2 after failing anti-VEGF therapies was associated with a significant rate of toxicities and lack of efficacy .High-dose IL-2 remains a viable treatment consideration for highly select clear cell RCC patients, and likely should be given as initial therapy if considered.
Another type of cytokine therapy, Interferon alfa, is associated with median overall survival time of 13 months, improvement in median overall survival of 3.8 months and median time to progression of 4.7 months. Despite its lacking of the ability to produce durable complete remissions as opposed to IL-2 therapy, its more favorable safety profile and proven superiority in improving survival compared to a variety of controls it became a standard of care for advanced RCC in the pre targeted therapy era and gained a role as a comparative treatment arm in the trials evaluating new drugs in the targeted therapy era [63, 64]. Though not as severe as IL-2, IFN-α is also associated with significant profile of adverse events including flu-like symptoms (92%), fatigue (88%), headache (44%), diarrhea (37%), and rash (18%). It is currently approved in combination with bavacizumab with a category 1 designation as first line therapy for advanced RCC based on the AVOREN trial . More sophisticated immunotherapy has recently emerged with ongoing clinical trials (see below).
Emerging agents in development
A number of promising compounds are currently under development. These agents fall into four categories by mechanism of action: angiogenesis inhibitors (axitinib, tivozanib, dovitinib, AZD2171, IMC-1121B, AVE0005, AMG386), signal transduction inhibitors (perifosine, RX-0201, ispinesib, panobinostat, vorinostat, entinostat, GSK1363089, AMG102), immune checkpoint inhibitors (MDX-1105/1106) and cancer vaccines (IMA901) . Both axitinib and tivozanib have shown efficacy in completed trials while dovitinib (TKI258) as well as IMA901 are still being evaluated in phase III studies that are currently recruiting participants [66, 67].
Axitinib is a selective potent oral inhibitor of VEGFR1, 2 and 3, which is distinguished by greater potency against VEGFR compared to the approved VEGFR inhibitors. It showed efficacy in phase II studies in both sorafenib-refractory and cytokine-refractory metastatic clear cell RCC [68, 69]. The AXIS trial was a randomized, open-label, phase III trial that compared the efficacy and safety of axitinib versus sorafenib as second-line therapy for clear cell mRCC who failed prior therapy with VEGF, mTOR inhibitors or cytokine-based therapy [70••]. Axitinib demonstrated a significantly longer PFS and higher objective response rate compared to sorafenib (6.7 mo vs. 4.7 mo and 19.4% vs. 9.4% respectively) with an acceptable safety with common AEs including hypertension (40%), fatigue (39%), dysphonia (31%), hypothyroidism (19%) and hand-foot syndrome (27%). A phase III study evaluating the safety and efficacy of first line axitinib with and without dose titration is finished and awaiting final data .
Tivozanib is a highly potent and selective oral inhibitor of VEGFR1, 2 and 3. The safety and efficacy of this agent was evaluated in a phase II study that included treatment naïve and immunotherapy or chemotherapy (but not targeted therapy) pre treated RCC patients (including clear and non clear cell) and randomized them to receive either tivozanib or placebo . Tivozanib was associated with ORR of 30% and PFS of 11.7 months. Common adverse events of all grades included hypertension (50%), diarrhea (12%) and asthenia (10%). Nine percent discontinued the trial due to AEs. TIVO-1 is a global phase III study comparing tivozanib to sorafenib in the same setting as the phase II study. The study completed accrual and results are awaited .
Dovitinib is an oral inhibitor of VEGFR and fibroblast growth factor receptors (FGFR). It has shown tolerability and favorable antitumor activity in a phase I/II study [74, 75]. Nausea, diarrhea, vomiting, and asthenia were the most common adverse events. The median PFS was 6.1 months. Based on these preliminary data, a phase III study is currently evaluating the efficacy of dovitinib compared to sorafenib as third-line treatment for patients with metastatic RCC whose disease has progressed after both VEGF-targeted and mTOR inhibitor therapy .
IMA901, a multi-peptide-based vaccine consisting of 9 different HLA class I-binding tumor-associated peptides (TUMAPs) and 1 HLA class II-binding TUMAP, represents a new approach to cancer immunotherapy. This vaccine utilizes two immunimodulators to enhance the immunogeneity of the TUMAPs, GM-CSF and low dose cyclophosphamide. After the safety and tolerability of this agent in combination with GM-CSF was evaluated in a phase I study, namely the IMA901-101, its clinical activity in TKI- or cytokine-refractory patients was evaluated in a phase II study with or without low dose cyclophosphamide . Compared to pre-defined no-effect levels derived from historical controls, IMA901 resulted in a higher 6 months disease control rates (DCR). OS results of cytokine pre-treated patients in this study compare favorably to historical data for sorafenib and sunitinib in similar patient populations with a trend for improved OS in patients pretreated with cyclophosphamide. A currently-recruiting phase III study is trying to investigate whether IMA901 can prolong overall survival in patients with advanced RCC when added to standard first-line therapy with sunitinib compared to sunitinib monotherapy .
BMS-936558 is a fully human monoclonal antibody that targets the programmed death-1 (PD-1), a member of the CD28 family of T-cell costimulatory receptors. Activated PD-1 delivers a negative signal that downregulate T-cell activation. By blocking PD-1, MDX-1106 results in activation of T cells and an immunoresponse against cancer cells. In a phase I study, this agent showed antitumor activity in patients with RCC, melanoma and NSCLC, with ORR of 33% and PFS of 8 months in RCC patients and limited toxicity profile . It is currently being evaluated in the second line setting in a randomized, double-blinded, 3-arm dose-ranging Phase 2 study with other RCC trials planned .
AMG 386 is an investigational peptide-Fc fusion protein that inhibits angeogenesis by blocking the interactions between angiopoietins -1 and -2 (Ang1 and Ang2) and their receptor Tie2. Phase I data studying this agent in combination with sunitinib or sorafenib did not show increased toxicity . In a phase II trial the combination of sorafenib plus AMG 386 in the first line setting was tolerable and was resulted in increased ORR but did not improve PFS compared to sorafenib plus placebo . An ongoing phase II trial is currently evaluating AMG 386 in combination with sunitinib in treatment naïve or cytokine pretreated patients .
There are several agents targeting either VEGF/R or mTOR which have shown clinical effect in metastatic RCC and are now in common use, each with somewhat differing actions and toxicities. Ongoing trials are required to define the optimal initial therapy and sequence, as no convincing data exists to date. Immunotherapy with high dose IL-2 remains a viable option, but only for a highly select subset of patients. Novel immunotherapy is entering clinical testing in RCC with promise to further improve outcomes and be applicable to a broader population of patients. Combination therapy to date has proven toxic and not more effective than sequential monotherapy. Substantive efforts at predictive biomarker development including clinical markers such as hypertension and molecular makers including SNPs are underway and are the key to fully optimize the current generation of targeted therapy in RCC.
BI Rini: Consultancy for Pfizer, AVEO, GlaxoSmithKline and Bayer/Onyx, has grants/grants pending with Pfizer and GlaxoSmithKline, and has had travel/accommodations expenses covered or reimbursed by Pfizer, AVEO, and GlaxoSmithKline; H Haddad: none.