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A Systematic Review of Sequencing and Combinations of Systemic Therapy in Metastatic Renal Cancer

Eur Urol. 2014;



The introduction of novel molecular-targeted agents has revolutionised the management of patients with metastatic renal cell carcinoma (mRCC). However, uncertainties remain over sequential or simultaneous combination therapies.


To systematically review relevant literature comparing the clinical effectiveness and harms of different sequencing and combinations of systemic targeted therapies for mRCC.

Evidence acquisition

Relevant databases (including Medline, Cochrane Library, trial registries, and conference proceedings) were searched (January 2000 to September 2013) including only randomised controlled trials (RCTs). Risk of bias assessment was performed. A qualitative and quantitative synthesis of the evidence was presented.

Evidence synthesis

The literature search identified 5149 articles. A total of 24 studies reporting on 9589 patients were eligible for inclusion; data from four studies were included for meta-analysis. There were generally low risks of bias across studies; however, clinical and methodological heterogeneity prevented pooling of data for most studies. Overall, the data showed several targeted therapies were associated with an improvement in progression-free survival in patients with mRCC. There were limited data from RCTs regarding the issue of sequencing; studies on combination therapies have been hampered by difficulties with tolerability and safety.


Although the role of vascular endothelial growth factor/vascular endothelial growth factor receptor targeting therapies and mammalian target of rapamycin inhibition in the management of mRCC is now established, limited reliable data are available regarding sequencing and combination therapies. Although data from retrospective cohort studies suggest a potential benefit for sequencing systemic therapies, significant uncertainties remain. Presently, mRCC systemic treatment should follow international guidelines (such as the European Society for Medical Oncology, National Comprehensive Cancer Network, and European Association of Urology) for patients fit to receive several lines of systemic therapies.

Patient summary

We thoroughly examined the literature on the benefits and harms of combining drugs for the treatment of kidney cancer that has spread and on the sequence in which the drugs should be given.

Take Home Message

Therapies targeting both vascular endothelial growth factor/vascular endothelial growth factor receptors and mammalian target of rapamycin are approved for metastatic renal cell carcinoma. Limited data from randomised controlled trials assessing sequence are available. Combination therapy studies have raised safety issues without demonstrating benefit. Patients should be treated according to guidelines and referred for clinical trials.

Keywords: Renal cell carcinoma, Tyrosine kinase inhibitor, Sequence of systemic therapies, Combination of systemic therapies.

1. Introduction

The introduction of seven new agents in the past 8 yr has transformed systemic treatment of metastatic renal cell carcinoma (mRCC), improving prognosis from a median overall survival (OS) of approximately 1 yr to >2 yr [1] : four multitargeted tyrosine kinase inhibitors (TKIs): sorafenib [2] , sunitinib, pazopanib [3] , and axitinib [4] ; the humanised antivascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab with interferon (IFN)-α2a [5] , and two mammalian target of rapamycin (mTOR) complex 1 kinase inhibitors (temsirolimus [6] and everolimus [7] ).

Only two classes of agents are used in clinical practice inhibiting either the VEGF/VEGF receptor (VEGFR) axis or mTOR. Unlike bevacizumab that can selectively inhibit VEGF (ligand of VEGFRs), the commonly used TKIs interfere with several growth factor receptors in addition to VEGFRs. Thus sunitinib and pazopanib inhibit predominantly VEGFRs and platelet-derived growth factor receptor (PDGFR), and c-Kit, whereas sunitinib may also target Flt-3. Sorafenib inhibits VEGFRs, PDGFR, c-Kit, Flt-3, and the serine-threonine kinase Raf-1. Axitinib exhibits higher affinity and higher selectivity for VEGFRs. The mTOR complex is upstream of intracellular pathways regulating key transcription factors involved in cellular survival, proliferation, metabolism, and angiogenesis, and it is critical in the pathogenesis of mRCC [8] .

Despite several years of unprecedented single-agent activity with these novel drugs, the response rate (RR), progression-free survival (PFS), and OS observed in single-agent randomised controlled clinical trials (RCTs) have finally reached a plateau. Therefore, strategies have focussed on optimal sequencing and combinations of existing agents to maximise their impact on clinical outcomes. In addition, new therapeutic targets are being actively explored.

We performed a systematic review to determine if the available data support combinations or sequencing of targeted therapies for the treatment of mRCC. The findings are discussed from a clinical perspective with a focus on the future outlook of this disease.

2. Evidence acquisition

2.1. Search strategy

The methods protocol of the European Association of Urology (EAU) renal cell carcinoma 2013 guidelines was used as a basis for the search strategy. The guidelines incorporated a systematic review designed to compare the clinical effectiveness and safety of systemic treatments for mRCC including only RCTs or quasi-RCTs (eg, alternate allocation). Eligible trials must have included one of the prespecified systemic treatment agents, such as targeted therapy, vaccines, chemotherapy, or cytokines, in one of the trial arms. A valid comparator included any of the prespecified systemic therapy agents or placebo. For the present systematic review, the original EAU search was updated (covering the period from January 1, 2000, to September 30, 2013), and eligibility was restricted to RCTs related to combining or sequencing systemic targeted therapies only. The primary outcome of interest was PFS and OS; secondary outcomes were harms of treatment. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement [9] .

The databases searched were Medline, Medline In-Process, Embase, Cochrane Controlled Trials Register (Cochrane Library, Issue 8, 2013), and the Latin American and Caribbean Center on Health Sciences Information System. The search was complemented by additional sources including systematic reviews from the Cochrane Database of Systematic Reviews (Cochrane Library, Issue 8, 2013), recent conference proceedings of the American Society of Clinical Oncology and European Society of Medical Oncology, ongoing trials from and the World Health Organisation International Clinical Trials Registry, reference lists of included studies that were hand-searched to identify additional relevant studies, and reports identified by the expert panel of coauthors.

2.2. Data collection and analysis

All abstracts and titles identified by the search were screened using a predefined study screening form. Two coauthors (F.H. and T.L.) independently performed abstract and full-text screening. Disagreement was resolved by discussion, and where no agreement could be reached, an arbiter (A.B.) was sought. In addition, studies included for qualitative analysis in the 2013 EAU guidelines were screened for inclusion in the present systematic review (ie, studies addressing sequencing or combining targeted therapies) by two coauthors (L.A. and A.B.). Some studies that did not meet the inclusion criteria for the evidence synthesis were retained for the background and discussion sections. A data extraction form was developed a priori specifically to collect information on study design, characteristics of participants, characteristics of interventions, and outcome measures. Data relating to the prespecified outcomes were extracted.

Risk of bias (RoB) assessment was performed using the standard Cochrane Collaboration RoB tool for RCTs. For data analysis, descriptive statistics were used to summarise baseline characteristics data. Quantitative synthesis (meta-analysis) was only performed for studies where there was no appreciable clinical or methodological heterogeneity. Both fixed effects and random effects models were used to derive the appropriate test statistic. For time-to-event data, hazard ratios (HRs) and 95% confidence intervals (CIs) obtained directly from studies or indirectly from presented Kaplan-Meier survival curves were used to compare results. In analysing dichotomous outcomes, relative risk with 95% CIs was used. Statistical heterogeneity between studies was assessed by visual inspection of plots of the data, the chi-square test for heterogeneity, and the I2 statistic. Analysis was performed using Cochrane RevMan v.5.2 software. Where meta-analysis was not feasible, a qualitative synthesis was provided.

3. Evidence synthesis

3.1. Narrative and quantitative synthesis

The literature search identified 5149 studies. Of these, 24 were selected for final inclusion in this review based on prespecified inclusion criteria. Only four studies were eligible for meta-analysis, due to clinical and methodological heterogeneity across most of the studies. Figure 1 provides the full details of the study inclusion and exclusion process. Of the excluded studies, 22 were retained for the discussion and future outlook sections. The RoB was generally low across most studies ( Fig. 2 ).


Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-analysis flow diagram sequence and combination of target therapy for metastatic renal cell carcinoma. LILACS = Latin American and Caribbean Center on Health Sciences Information System.


Fig. 2 Risk of bias assessment of included studies. Green: low risk of bias; yellow: unclear risk of bias; red: high risk of bias.

3.2. Systemic therapy in sequence

The first RCTs of currently approved agents were designed in the cytokine era, most often following progression after interleukin (IL)-2 or IFN administered in the first-line setting. Subsequently, the approval of VEGF/VEGFR inhibition as first-line treatment in mRCC led to the development of studies designed to assess both mTOR and VEGFR inhibition, mainly in the post-VEGF/VEGFR inhibition setting. Table 1 displays the phase 2 and 3 RCTs of different agents, assessed (1) in the cytokine-refractory setting, (2) in the second-line setting following targeted therapy, and (3) in the third-line setting following either two VEGFR inhibitors or one VEGFR TKI and everolimus.

Table 1 Retrieved phase 2 and 3 studies from systematic research in the cytokine-refractory setting, in the post–vascular endothelial growth factor inhibition setting, and in the third-line setting

Clinical trial Design n PFS, mo OS, mo
Cytokine pretreated
 Sorafenib vs placebo

 TARGET [2] and [41]
Phase 3 903 5.8 vs 2.8 17.8 vs 14.3

When censoring the crossover patients
 Pazopanib vs placebo

[3] and [42]
Phase 3 435

Prior cytokines: 46% (n = 202)
Overall population: 9.2 vs 4.2

Post cytokine: 7.4 vs 4.2
22.9 vs 20.5

Extensive crossover from placebo to pazopanib confounded final OS analysis
 Axitinib vs sorafenib

 AXIS [4] and [43]
Phase 3 723

Prior cytokines: 35% (n = 251)
Overall population: 6.7 vs 4.7

Post cytokine: 12.2 vs 6.5
Overall population: 20.1 vs 19.9
 Bevacizumab HD (10 mg/kg) vs bevacizumab LD (3 mg/kg) vs placebo [44] Randomised phase 2 116

Post IL-2: 93%
4.8 vs 3.0 vs 2.5 NS
 Lapatinib vs hormone [45] in mRCC that expresses EGFR and/or HER-2 Phase 3 416 15.3 vs 15.4 10.8 vs 9.9
VEGF inhibition refractory
 Everolimus vs placebo

 RECORD-1 [7], [12], and [24]
Phase 3 Overall population: 416

Pure second-line setting after one TKI: 21% (n = 89)

Following cytokine and one TKI: 53% (n = 219)
Overall population: 4.6 vs 1.8

Post one TKI: 5.2 vs 1.8

Post sunitinib: 4.6 vs 1.8
Overall population: 14.8 vs 14.4

Survival corrected for crossover was 1.9-fold longer with everolimus
 Axitinib vs sorafenib

 AXIS [4] and [43]
Phase 3 723

Sunitinib pretreated: 54% (n = 389)
Overall population: 8.3 vs 5.7

Postsunitinib: 4.8 vs 3.4
Overall population: 20.1 vs 19.2
 Temsirolimus vs sorafenib

Phase 3 512 4.3 vs 3.9 12.3 vs 16.6
 Sunitinib/Everolimus vs Everolimus/Sunitinib

 RECORD-3 [21]
Phase 3 471

51.6% and 53.7% of patients, respectively, received second line within the clinical trial
PFS1: 10.7 vs 7.9

Combined PFS 1 + 2: 25.8 vs 21.1
32 vs 22.4
 Sorafenib/Sunitinib vs Sunitinib/Sorafenib

 SWITCH-I [12]
Phase 3 365

57% and 42% of patients, respectively, received second line within the clinical trial

HR: 1.19; p = 0.92

Combined PFS 1 + 2: NS

HR: 1.01; p = 0.54

HR: 0.997; p = 0.49
Third line
 Everolimus vs placebo

 RECORD-1 [7], [12], and [24]
Phase 3 Pure third line after two TKIs: 26% (n = 108) 4 vs 1.8
 Dovitinib vs sorafenib

 GOLD [22]
Phase 3 570 3.7 vs 3.6 11.1 vs 11.0

Interim analysis

EGFR = epidermal growth factor receptor; HD = high dose; HER = human epidermal growth receptor; HR = hazard ratio; IL = interleukin; LD = low dose; mRCC = metastatic renal cell carcinoma; NS = not significant; OS = overall survival; PFS = progression-free survival; TKI = tyrosine kinase inhibitor.

3.3. Systemic targeted therapy in combination

IFN and IL-2 therapies were the backbone of systemic treatment in mRCC until 2005. Therefore, newly approved agents were often initially assessed in combination with or in comparison with cytokines to improve PFS and OS. After the approval of several targeted agents, combination trials of targeted drugs were designed to investigate a potential superiority of the combination versus single-agent use. Most trials investigated combinations of bevacizumab with a VEGFR TKI or mTOR inhibitor versus the approved standard of bevacizumab plus IFN. Table 2 summarises the identified RCTs based on cytokines and targeted therapy. Figure 3 presents the results of the meta-analysis comparing trials of a single targeted agent versus a combination of several targeted drugs in mRCC. Overall, four trials were identified in which HRs could be retrieved, reporting on a total of 1412 patients. This meta-analysis did not reveal any benefit from a combination therapy approach.

Table 2 Retrieved studies from systematic research of cytokine-based combination and targeted therapy–based combination

Clinical trial Design n RR, % PFS, mo
IFN based
 IFN 9 MU 3 times/wk and sorafenib

 vs IFN 3 MU 5 times/wk and sorafenib [46]
Randomised phase 2 51



 IFN and bevacizumab

 vs IFN and placebo

 AVOREN [5] and [47]
Phase 3 306



 IFN and bevacizumab [48] and [49]

 vs IFN
Phase 3 366




 vs temsirolimus alone

 vs IFN and temsirolimus

 ARCC [6]
Phase 3 207






 Sorafenib and IFN

 vs sorafenib alone [50]
Randomised phase 2 40



IL-2 based
 Sorafenib and IL-2

 vs sorafenib

 ROSORC [51]
Randomised phase 2 66



Bevacizumab based
 Bevacizumab and erlotinib

 vs bevacizumab and placebo [52]
Randomised phase 2 53



 Bevacizumab and temsirolimus

 vs sunitinib

 vs bevacizumab and IFN

 TORAVA [29]
Randomised phase 2 88






 Bevacizumab and temsirolimus

 vs bevacizumab and IFN

Phase 3 400



 Bevacizumab and everolimus

 vs bevacizumab and IFN

 RECORD-2 [27]
Randomised phase 2 182




 vs bevacizumab and temsirolimus

 vs bevacizumab and sorafenib

 vs sorafenib and temsirolimus

 BEST [53]
Randomised phase 2 89









Sorafenib based
 Sorafenib and AMG 386 (3 mg/kg)

 vs sorafenib and AMG 386 (10 mg/kg)

 vs sorafenib and placebo [54]
Randomised phase 2 51







IFN = interferon; IL = interleukin; PFS = progression-free survival; RR = response rate.


Fig. 3 Meta-analysis assessing combination targeted therapy versus single-agent targeted therapy. CI = confidence interval; IV = inverse variance; SE = standard error.

4. Discussion

4.1. Sequence

The focus of this review is on both sequence and combination, and not on the results of front-line therapy clinical trials. First-line therapy recommendations are based on prognostic groups [1] .

4.1.1. Cytokine pretreated patients

Sequencing targeted therapy as second-line treatment in cytokine pretreated patients has been assessed in randomised phase 2 (sunitinib) and large phase 3 RCTs for sorafenib, pazopanib, and axitinib. The average PFS in these reports was approximately 8 mo in cytokine-refractory patients. Several doses of temsirolimus have been evaluated in a randomised phase 2 postcytokine (91% of patients) nonplacebo controlled trial, with a median PFS of 5.6 mo. Axitinib exhibited impressive PFS in cytokine pretreated patients in a phase 2 study that was confirmed in the phase 3 AXIS RCT [4] for the postcytokine subgroup with a PFS of 12.1 mo. For tivozanib, another selective VEGFR inhibitor [10] , a median PFS of 11.7 mo was reported in a phase 2 RCT (in which 44% of patients were postcytokine). Currently, use of cytokines is usually limited to countries where TKIs are not readily available or in a highly selected first-line population. Sunitinib, or other VEGF/VEGFR inhibiting therapies, have widely become the standard of care in the first-line setting.

4.1.2. Interpretation of randomised data in the post-VEGF/VEGFR inhibition setting

Although first-line treatment options were defined by large RCTs and used prognostic models to define patient selection, studies investigating sequencing beyond the first-line setting had broad inclusion criteria and no stratification based on prognostic criteria. The data from RCTs support the use of both mTOR inhibitors and VEGFR inhibition in the VEGFR TKI–resistant setting. The AXIS trial [4] is the only RCT comparing two TKIs following first-line VEGF inhibition. Although the difference in PFS was significant in the sunitinib pretreated group in favour of axitinib versus sorafenib, the gain in PFS was short, and no difference in OS was detected in the final analysis. The INTORSECT study [11] provides a direct comparison between different classes of agents (temsirolimus, ie, an mTOR inhibitor, vs sorafenib, ie, a VEGFR TKI) following progression on sunitinib, but it failed to define an optimal sequence because there was no statistical significant difference in PFS. Median OS in the temsirolimus and sorafenib arms was 12.3 mo and 16.6 mo, respectively. The OS difference in favour of sorafenib of >4 mo was unexpected and suggests that sequenced VEGFR inhibition may benefit patients with mRCC.

Regarding sorafenib, the recent report of the randomised phase 3 SWITCH-I [12] trial investigating two sequential treatments (sorafenib/sunitinib vs sunitinib/sorafenib) concluded there was no significant difference in total PFS, OS, disease control rate, and first-line PFS between the two arms. Both drugs provided overall benefit regardless of sequence. Therefore, two issues arise from this report. First, there is no evidence of any benefit in the order of using a less potent agent prior to a more potent VEGFR TKI, or vice versa, although this does not allow further extrapolation from the currently used sunitinib/axitinib sequence. Second, it raises the question of sorafenib integration into the current landscape of second-line treatment.

Regarding mTOR inhibition following VEGFR inhibition-based therapy, data from the RECORD-1 phase 3 RCT [7] , designed to evaluate the mTOR inhibitor everolimus as second-line treatment versus placebo, have to be interpreted with caution because only 21% of the patients (53% received two previous treatments including one VEGFR inhibition plus cytokine) were purely second-line postsunitinib. Further retrospective studies did assess the use of everolimus as a pure second-line therapy [13] , and the ongoing phase 2 nonrandomised trial RECORD-4 ( NCT01491672 ) should prospectively confirm the observed PFS of 4–5 mo.

Both randomised and retrospective cohorts highlight the lack of absolute cross-resistance between VEGFR-targeted therapies [14] . However, analysis of stratification factors from different phase 3 RCTs [4], [7], and [11] [RECORD-1, AXIS, and INTORSECT] did not reveal specific factors to determine an optimal second-line sequence for individual patients. In particular, the duration of first-line therapy and its correlation to outcomes in the second-line setting has been at the centre of controversy. Al-Marrawi and colleagues [15] evaluated 464 patients receiving second-line VEGFR inhibition after first-line VEGF/VEGFR inhibition. Median duration of first-line and second-line therapies was 7.5 mo and 3.9 mo, respectively. This report did not find any correlation between first- and second-line PFS or RR. Nevertheless, in the AXIS trial, longer exposure to first-line sunitinib was associated with a longer PFS with second-line axitinib when compared with a short PFS with first-line therapy [4] . Retrospective data of primary VEGFR inhibitor-resistant patients who had a dismal OS despite second-line treatment support this observation [16] .

The use of PFS as a surrogate of OS is not only common practice in medical oncology but was previously investigated in mRCC in the TKI era [17] . Instead of PFS, RR may be an alternative surrogate of OS in RCC [18] . However, data from the phase 3 INTORSECT RCT [11] challenge surrogate end points for OS. The discrepancy between OS, despite a comparable PFS in both arms, has raised many issues including hidden bias from confounding factors.

Most of the evidence on second-line therapy is based on first-line sunitinib. Although it is conceivable that a class effect exists, results were extrapolated to all VEGFR inhibiting agents without having studied their use in sequence. This particularly applies to pazopanib, the most recently approved following the COMPARZ [19] study results.

In contrast, sequences after mTOR inhibition are poorly defined. Subsequent therapy in poor prognosis patients having received first-line temsirolimus therapy may not provide any additional benefit [6] . Very few poor prognosis patients are likely to receive second-line therapies, which are associated with a PFS of 3.1 mo and an OS of 5.3 mo using data from the retrospective analysis of the International mRCC Database Consortium (IMDC) in poor prognosis patients treated with temsirolimus (n = 40) [20] . For good and intermediate prognosis patients, the sequence of mTOR inhibition followed by VEGFR targeting agents was assessed prospectively by the RECORD-3 trial [21] . Although the assessment of combined PFS (PFS1 and PFS2) was limited by the number of patients who did not receive second-line treatment (only 45% and 42% of patients, respectively, in the everolimus/sunitinib and sunitinib/everolimus arms received second-line therapy) within the clinical trial), OS was significantly lower for the sequence of everolimus/sunitinib than for sunitinib/everolimus, especially in the first part of the study. These results therefore do not lead to any change in the current sequence proposed by oncology guidelines.

Summarising the available evidence, it can be concluded that both everolimus and axitinib are valid options after first-line VEGF/VEGFR inhibition failure. Sorafenib, in view of the recent OS results of the INTORSECT trial [11] , might be considered as an alternative option. However, current PFS of second-line treatment is limited, with a median of 4–5 mo. In clinical practice, in addition to evidence regarding second-line treatment from RCTs, other factors such as patient preferences, comorbidities, tumour burden, and symptoms need to be taken into account when making treatment decisions while bearing in mind that the cost of these treatments has resulted in heterogeneous access and reimbursement policies depending on the country.

4.1.3. Treatment beyond second line

Treatment in the third-line setting was assessed for the first time in the large dedicated GOLD RCT [22] . PFS was not statistically significantly different between a VEGFR inhibition by sorafenib and dual fibroblast growth factor receptor-VEGFR inhibition by dovitinib in patients who had already received both VEGFR inhibition and an mTOR inhibitor (3.6 vs 3.7 mo, respectively; HR: 0.86 [0.72–1.04]; p = 0.063). Interim OS analysis was also similar in the two arms (11.0 vs 11.1 mo, respectively; HR: 0.96 [0.75–1.22]). This highlights the relevance of maintaining VEGF inhibition beyond progression, as pointed out in previous preclinical models and a retrospective analysis of axitinib after two prior VEGFR TKIs resulting in a PFS of 7.1 mo [23] . Subgroup analysis [13] within the RECORD-1 [7] and [24] trial assessed everolimus as a third-line agent exhibiting a significant benefit regarding PFS versus placebo (4.0 mo PFS vs 1.8 mo; HR: 0.32; p < 0.01). However, most data are from retrospective cohort studies that explored third-line treatments. These studies provide useful information but are inherently biased. These studies suggest that <20% of patients proceed to third-line therapy [25] , and it is likely that such patients represent those with less rapid disease progression. This may explain the reported median PFS of 4 mo and a median OS of 11 mo both in clinical trials and in small cohort studies in this patient population. Although comparative retrospective assessment of the sequence VEGFR TKI/VEGFR TKI/mTORi (mTOR inhibitor) versus VEGFR TKI/mTORi/VEGFR TKI suggests superiority of TKI/TKI/mTORi [26] , no recommendations can be given at present.

4.2. Combination therapy

Simultaneous inhibition of multiple signalling pathways offers the theoretical benefit of overcoming both de novo and acquired resistance, and ideally it results in therapeutic synergy. Both RECORD-2 [27] and INTORACT [28] studies investigated first-line combination regimens that did not ultimately prove superior to single agents. The use of a combination approach in the second-line setting is also being assessed in the CALGB trial comparing everolimus plus bevacizumab versus everolimus alone. However, substantial toxicity has been a recurrent observation with combination studies including bevacizumab plus temsirolimus, both in the phase 2 TORAVA [29] and phase 3 INTORACT [28] studies, or bevacizumab plus sunitinib or any mTORi with sunitinib. Despite increased toxicity, and perhaps at least in part because of it, such combinations have not demonstrated improvements in RR or PFS ( Fig. 3 ).

4.3. Sequence of systemic therapy for non–clear cell renal cell carcinoma

Non–clear cell histologies (non-ccRCC) were usually excluded from RCTs, due to clinical heterogeneity and poor prognosis. The three RCTs [6], [11], [30], and [31] that included this population are listed in Table 3 , as well as the two dedicated ongoing RCTs that randomise VEGFR inhibition first line versus mTOR inhibition. The ARCC [6] , a phase 3 trial that randomised 626 patients with previously untreated poor prognosis mRCC, included 73 patients with non-ccRCC to receive temsirolimus versus INF-α or combination therapy. The post hoc subgroup analysis of the ARCC study [30] suggested that mTOR inhibition could be a valid option in non-ccRCC. The more recent subgroup analysis of RECORD-3 [31] does not appear to confirm the previous findings; the direct comparison of first-line PFS achieved in non-ccRCC is lower than the respective PFS in ccRCC, and everolimus does not exhibit any improvement when compared with first-line sunitinib in this small cohort of patients. These results are in line with the two dedicated papillary RCC phase 2 nonrandomised clinical trials RAPTOR [32] and SUPAP [33] achieving first-line PFS of 3.7 mo (n = 92 patients) and 5.9 mo (n = 60 patients) for everolimus and sunitinib, respectively. A recently published study investigated the non-ccRCC population within the IMDC [25] . This large report assessed first-, second-, and third-line PFS in non-ccRCC in comparison with ccRCC PFS and revealed a dismal prognosis of this population, with an OS of 12.8 mo, and it confirmed the importance of prognostic assessment using IMDC risk model criteria in this population. Median OS of the favourable, intermediate, and poor prognosis groups was 31.4, 16.1, and 5.1 mo, respectively (p < 0.0001). Due to the poor prognosis of these heterogeneous populations, there is an urgent need for better characterisation of the biology of each entity that will ultimately lead to more rational therapeutic approaches. For example, foretinib, a dual VEGFR/c-MET inhibitor, demonstrated a PFS of 9.3 mo in a phase 2 study [34] .

Table 3 Systemic treatment in non–clear cell renal cell carcinoma population

  Clinical trial Design n PFS, mo OS
First line IFN

vs temsirolimus alone

vs IFN and temsirolimus

ARCC [30]
Subgroup phase 3 73 7.0 vs 1.8

HR 0.38;

95% CI, 0.29–0.85
11.6 vs 4.3

HR: 0.49;

95% CI, 0.29–0.85
Second line Temsirolimus vs sorafenib

Subgroup phase 3 90

HR: 0.88

95% CI, 0.53–1.45;NS

HR: 1.42

95% CI, 0.86–2.35; NS
First and second line Sunitinib/Everolimus

vs Everolimus/Sunitinib

RECORD-3 [21]
Subgroup phase 3 66 5.1 vs 7.2

HR: 1.54

95% CI, 0.86–2.75; NS
ASPEN NCT01108445 Everolimus vs sunitinib Dedicated randomised phase 2 108
ESPN NCT01185366 Everolimus vs sunitinib Dedicated randomised phase 2 108

CI = confidence interval; HR = hazard ratio; NS = not specified; OS = overall survival; PFS = progression-free survival.

4.4. Overall treatment strategies

In addition to treatment sequence, there are several additional practical issues regarding the management of patients with mRCC, such as when to initiate, switch, or discontinue systemic treatment. The issue of delaying treatment is currently considered in patients with slow-growing disease and is being prospectively evaluated [35] . Several factors have an impact on the decision to switch therapies including treatment tolerance, disease-related symptoms, imaging assessment, and drug availability.

Regarding the potential interest of an early switch to prevent the occurrence of resistance to targeted therapy, no randomised data are available. Studies are ongoing and might in the future provide some information in terms of ability to delay the time to resistance. Two RCTs [10] and [36] (Supplemental Table 1) assessed the opportunity for drug discontinuation in patients achieving stable disease after a short course of systemic therapy. Other reports did not randomise the discontinuation but assessed the occurrence of rapid angiogenesis onset after discontinuation of sunitinib treatment in mRCC [37] . Whether this observation is applicable to all patients irrespective of the prior duration and response to VEGFR inhibition is unknown. Some authors consider a drug holiday as a potential option in the rare setting of complete response (CR) [38] achieved with either medical treatment alone or combined with focal treatment such as metastasectomy, or in sustained long response.

4.5. Emerging agents and their future use in sequence or combination

Ongoing clinical trials include several new agents or sequence approaches that may transform the current treatment landscape ( Table 4 ). Regarding sorafenib, in line with the recent report of SWITCH-I, SWITCH-II might further address the issue of sorafenib alternative in the current landscape of second-line therapies.

Table 4 Ongoing phase 3 clinical trials assessing sequence and/or emerging agents

Study name: identifier Treatment groups Title Population to be enrolled
SWITCH-2: NCT01613846 Pazopanib/Sorafenib vs Sorafenib/Pazopanib Phase 3 randomised sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced/metastatic renal cell carcinoma n = 544
BMS CA 209025: NCT01668784 Nivolumab vs everolimus A randomised open-label phase 3 study of nivolumab (BMS-936558) vs everolimus in subjects with advanced or metastatic clear cell renal cell carcinoma who have received prior antiangiogenic therapy n = 822
METEOR: NCT01865747 Cabozantinib vs everolimus A phase 3 randomised controlled study of cabozantinib (XL184) vs everolimus in subjects with metastatic renal cell carcinoma that have progressed after prior VEGFR tyrosine kinase inhibitor therapy n = 650

VEGFR = vascular endothelial growth factor receptor.

Besides optimising sequence strategy, the major unmet need is the development of a new class of agents or a combination that may have the potential to achieve CR and long-term response in mRCC. Novel immunotherapies such as PD-1/PD-L1 inhibition that target an inhibitory T-cell coreceptor or its ligand expressed by tumour cells raise expectations in mRCC. Supplemental Table 2 presents the current PD-1 and PD-L1 agents investigated in mRCC. Nivolumab (PD-1 Ab, BMS-936558), the PD-1 inhibitor most advanced in clinical development, was explored in a phase 3 trial in patients who progressed on prior VEFGRs inhibition therapy. Results are pending, but this type of immunotherapy has the potential of completely altering the landscape of second-line treatment. Defining which patients benefit most from PD-1/PDL-1 blockade, and where in the sequence of therapies PD-1/PDL-1 blockade is optimally used, requires additional translational research. For example, the utility of PD-L1 expression as a predictive biomarker needs to be defined, and the impact of prior therapies of PD-1/PD-L1 expression needs to be assessed. A recent report from Sharpe et al. [39] demonstrating PD-L1 downregulation by VEGFR TKIs would not favour combination therapy or VEGFR TKI prior to PD-L1 inhibition. Other translational studies of therapeutic sequences suggest a theoretical benefit for particular treatment sequences. For instance, c-MET upregulation observed in VEGFR TKI–pretreated patients could support the rationale of MET inhibition in a VEGFR TKI–refractory population, as currently assessed by the METEOR study ( Table 4 ) and observed as a promising target in the phase 2 trial assessing cabozantinib in heavily pretreated patients [40] .

5. Conclusions

Targeted therapies have revolutionised the treatment of mRCC and improved the outlook for patients. Yet recent reports have revealed a plateau in terms of PFS and OS achieved with the current generation of VEGFR TKIs and mTOR inhibitors. Despite several attempts, combination therapy of currently approved targeted drugs did not demonstrate a benefit in comparison with single-agent use mainly due to tolerability issues, let alone cost issues. Therefore, there is a need to sequence available agents properly according to the most recent RCT results and to investigate the integration of novel agents under development into the recommended algorithm to meet the challenge of extending OS in mRCC.

Author contributions: Laurence Albiges had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Albiges, Bex, Hofmann, Lam.

Acquisition of data: Albiges, Hofmann, Lam, Bex.

Analysis and interpretation of data: Albiges, Hofmann, Lam, Bex.

Drafting of the manuscript: Albiges, Bex, Porta, Sternberg, Galsky, Lam, Hofmann.

Critical revision of the manuscript for important intellectual content: Albiges, Choueiri, Escudier, Galsky, George, Hofmann, Lam, Motzer, Mulders, Porta, Powles, Sternberg, Bex.

Statistical analysis: Hofmann, Lam, Bex.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Bex.

Other (specify): None.

Financial disclosures: Laurence Albiges certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Laurence Albiges received research grants from Pfizer and Novartis, and she has participated on the advisory boards at Novartis, Pfizer, Amgen, and Sanofi. She has received honoraria from Novartis and Pfizer. Toni Choueiri received a research grant from Pfizer and has participated on the advisory boards at Pfizer, GSK, Bayer, Aveo, and Novartis. Bernard Escudier has had a consultant or advisory board role with Bayer Pharma, Pfizer, and Novartis; he has received honoraria from Bayer, Roche, Pfizer, Genentech, Novartis, Aveo, and GSK. Matthew Galsky received research funding from Novartis; he has participated on the advisory boards at Janssen, Astellas/Medivation, and Dendreon; he has equity in Dual Therapeutics LLC. Dan George has had a consultancy role with and/or received honoraria or research funding from Bayer, Novartis, and Pfizer. Fabian Hofmann has no conflicts of interest to disclose. Thomas Lam has no conflicts of interest to disclose. Robert J. Motzer has received research funding from Novartis, Pfizer, and GlaxoSmithKline, has consulted for Bayer and Pfizer, and has provided paid expert testimony for Pfizer. Peter Mulders has participated on the advisory boards at Bayer, GSK, Pfizer, and Novartis. Camillo Porta has participated on the advisor boards and/or had a speaker role at Pfizer, GSK, Bayer-Schering, Novartis, Astellas, Aveo, and Boehringer-Ingelheim; he has received research grants from Pfizer. Thomas Powles has received research funding and participated on the speakers’ bureau for Pfizer, GSK, Novartis, and Bayer. Cora N. Sternberg has received honoraria from Novartis, Pfizer, and GlaxoSmithKline. Axel Bex has participated on the advisory boards at Pfizer, Bayer, GSK, and Novartis. He is the principal investigator of the EORTC SURTIME trial, supported in part by an educational grant from Pfizer.

Funding/Support and role of the sponsor: None.

Acknowledgement statement: The authors acknowledge the contribution of the European Association of Urology Renal Cell Carcinoma Guideline panel for providing their expertise and critique of the meta-analysis. The review work was undertaken in conjunction with the panel's guideline update for 2014, and the authors also thank the panel for allowing them to cite some of the results of the guideline update.


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a Institut Gustave Roussy, Villejuif, France

b Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

c The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

d Duke University Medical Center, Durham, NC, USA

e Department of Urology, Sunderby Hospital, Sunderby, Sweden

f Academic Urology Unit, University of Aberdeen, Aberdeen, UK

g Memorial Sloan-Kettering Cancer Center, New York, NY, USA

h Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands

i Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy

j Barts Cancer Institute, London, UK

k Department of Medical Oncology, San Camillo and Forlanini Hospitals Padiglione Flajani, Rome, Italy

l Division of Surgical Oncology, Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

lowast Corresponding author. Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805, France.

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