Critical Reviews in Oncology/Hematology 90 (2014) 49–57

A critical appraisal of systemic treatment options for metastatic non-clear cell renal cell carcinoma Salima Ismail a,b,∗,1 , Malek Meskawi a,1 , Jens Hansen a,c , Marco Bianchi a,d , Zhe Tian a , Mathieu Latour e , Markus Graefen c , Francesco Montorsi d , Quoc-Dien Trinh a,f , Paul Perrotte b , Pierre I. Karakiewicz a,b , Maxine Sun a a

Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada b Department of Urology, University of Montreal Health Center, Montreal, Canada c Martini-Klinic, Prostate Cancer Center Eppendorf-Hamburg, Hamburg, Germany d Department of Urology, Urological Research Institute, Vita-Salute San Raffaele University, Milan, Italy e Department of Pathology, University of Montreal, Montreal, Canada f Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA Accepted 3 December 2013

Contents 1. 2. 3.

4.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Material and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Incidence of metastatic papillary or chromophobe RCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Literature review of the systemic treatment options for metastatic nccRCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Temsirolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Sunitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Sorafenib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. Other agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.5. Ongoing trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

50 50 50 50 51 51 52 54 54 54 54 56 56 56 57

Abstract Current guidelines provide most support for the use of temsirolimus in first line therapy for metastatic non-clear cell renal cell carcinoma (nccRCC). However, this recommendation is based on scant level 2a evidence. The objective of this review is to examine the evidence supporting first line temsirolimus use in patients with metastatic nccRCC as well as alternative first line treatment options. Six studies, that assessed the efficacy of five agents qualified for inclusion. Among recognized treatment options for metastatic nccRCC, mean weighted

∗ Corresponding author at: Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center (CHUM), 264 Boul. Rene-Levesque East, Suite 228, Montreal, QC, Canada H2X 1P1. Tel.: +1 514 890 8000x35336; fax: +1 514 227 5103. E-mail address: [email protected] (S. Ismail). 1 Equally contributed.

1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.12.003

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progression free survival values of 7.9 months for temsirolimus vs. 7.3 for sunitinib vs. 8.5 months for sorafenib vs. ≈4.1 months for erlotinib were recorded based on data from 10, 74, 33 and 51 patients respectively. In conclusion, the data supporting first line temsirolimus for metastatic nccRCC are based on a small patient sample. Sunitinib’s efficacy is similar to that of temsirolimus but is based on a bigger patient sample that originates from phase II studies. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Renal cell carcinoma; Non-clear cell; Metastatic; Papillary; Chromophobe; Systemic therapy; Targeted therapy; Temsirolimus; Sunitinib; Sorafenib

1. Introduction In 2013, approximately 65,000 patients will be diagnosed with renal cell carcinoma (RCC) in the United States [1]. Of those, up to 30% will present with metastatic disease [2–9]. In the metastatic stage, non-clear cell RCC (nccRCC) is associated with worse prognosis compared to clear cell RCC (ccRCC) [10–13]. Specifically, it has been previously established that the biological basis of the treatment of nccRCC may be different than ccRCC, where alternative pathways could be targeted according to different nccRCC subtypes [9]. According to contemporary guidelines for the treatment of metastatic ccRCC, 4 molecules are available for first-line therapy (sunitinib, pazopanib, bevacizumab with interferon, and temsirolimus in the context of poor-risk patients) while 3 molecules are available for second-line therapy (everolimus, axitinib, sorafenib after tyrosine kinase inhibitor therapy), based on randomized phase III trials [8,14–22]. Unfortunately, the treatment recommendations for metastatic nccRCC are not as clear-cut. Indeed, due to the low prevalence of nccRCC, clinical trials focusing on metastatic patients with non-clear cell histological subtype are scarce and offer limited evidence supporting the use of available agents [23]. Therefore, contemporary guidelines strongly support participation in clinical trials as the standard option for 1st line nccRCC [21,22]. Alternatively, guidelines provide most support for the use of temsirolimus in first-line therapy for metastatic nccRCC for poor prognosis patients [22]. Such recommendations were based on results originating from a randomized controlled phase III trial examining the effect of temsirolimus relative to interferon, as well as temsirolimus in combination with interferon, in patients with poor or intermediate prognosis metastatic RCC of all histological subtypes, including nccRCC [15]. Additionally, other agents are also available: sunitinib (level of evidence 2A), sorafenib (level of evidence 2A), pazopanib (level of evidence 3), erlotinib (level of evidence 3), and axitinib (level of evidence 3) [22]. However, recommendations are not as evident and differ slightly from one guideline to another. For example, the National Comprehensive Cancer Network (NCCN) 2013 suggest temsirolimus as first choice and sunitinib and sorafenib as alternatives, whilst the European Society of Medical Oncology (ESMO) guidelines suggest temsirolimus, sunitinib and sorafenib with no preferences between agents [21,22].

These above observations and guidelines indicate that other agents than temsirolimus may represent valid alternatives as first-line therapies for metastatic nccRCC. We examined the data that may refute or substantiate this hypothesis.

2. Material and methods A detailed literature review was performed using the PubMed (United States National Library of Medicine National Institutes of Health) database for articles published until October 1st 2012. Electronic articles published ahead of print were also considered. Search was conducted using the following key words: ‘renal cell carcinoma’, ‘non-clear cell’, ‘metastatic’, ‘papillary’, ‘chromophobe’, ‘systemic therapy’, ‘targeted therapy’, ‘temsirolimus’, ‘sunitinib’, ‘sorafenib’, ‘erlotinib’ and ‘pazopanib’. The search was limited to English literature, humans, and persons aged 18 years and older. Subject and outcome of interest, pertinence, quality and detail of reporting were the indicators of manuscript quality. We included studies that focused on patients with papillary and/or chromophobe RCC (pRCC and chRCC, respectively) and reported progression free survival (PFS) after targeted therapy. The search was performed by one author (S.I.) and was validated by others (P.K., M.S., M.M.). All selected studies were grouped according to histological subtype and treatment type. When more than one PFS estimate was available, mean weighted PFS values were calculated. Moreover, we examined the incidence trends of metastatic RCC (International Classification of Disease for Oncology (C67.0–C67.9)) in the Surveillance, Epidemiology and End Results (SEER) database in patients aged 18 years or older between years 1988 and 2008. Histological subtypes were grouped into four categories: clear cell, papillary, chromophobe and other. Death certificate only and/or autopsy cases were removed from our analyses.

3. Results 3.1. Incidence of metastatic papillary or chromophobe RCC Since the exact incidence of metastatic nccRCC is unknown, we relied on the SEER database to better elucidate these rates in 20,456 patients with metastatic

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Fig. 1. Incidence of metastatic RCC histological subtypes from 1988 to 2008.

RCC between years 1988 and 2008. A total of 459 (2.3%) patients with metastatic nccRCC harbored papillary (1.9%) or chromophobe (0.4%) histological subtype. These rates increased in most recent years from 0.5 to 3.3% and from 0 to 0.7% for papillary and chromophobe histological subtypes, respectively (Fig. 1). Taken together, these data corroborate the rarity of metastatic nccRCC in the United States.

3.2. Literature review of the systemic treatment options for metastatic nccRCC The literature search identified eight studies focusing on treatment of metastatic nccRCC [2,11,24–29]. Of these, five were prospective studies [2,25–28], one was a subanalysis of a prospective randomized trial [11], and two were retrospective studies [24,29]. Within those studies, five molecules were examined: temsirolimus, sunitinib, sorafenib, erlotinib and capecitabine. Of those five agents, four (temsirolimus, sunitinib, sorafenib and erlotinib) are considered as treatment options for metastatic nccRCC and those agents represent the focus of this analysis [22]. These four molecules were used within seven studies as either first or subsequent line of therapy, between years 2005 and 2011 [2,11,24–29]. Sample sizes ranged from 23 to 202 metastatic nccRCC patients. Median PFS ranged from 1.4 to 27.5 months for each study cohort (Table 1). It is noteworthy that 75 patients in the expanded access program for everolimus had metastatic nccRCC [30]. However, results for this sub-cohort were not reported, which prevented us from including the study. A similar restraint was also applicable for the expanded access program for sunitinib, where the exact number of patients who had nccRCC was not specified [31]. Such limitations resulted in the exclusion of these two studies from the current review.

3.2.1. Temsirolimus Temsirolimus is a selective inhibitor of mammalian target of rapamycin (mTOR), a critical component of intracellular signal transduction cascades that mediates cell proliferation and tumor angiogenesis [4,5,11,15]. According to guidelines, temsirolimus holds the highest evidence level supporting its use in metastatic nccRCC. Its use is supported by level 2a evidence for patients with metastatic nccRCC that are classified within the intermediate or favorable prognosis groups. Level 1 evidence support its use in poor-prognosis patients, regardless of histological subtype [22]. The pivotal temsirolimus data originates from a first-line phase III trial [15]. Of 626 patients, 209 (33%) were assigned to the temsirolimus arm for which a median PFS of 5.5 months was reported. The histological subtypes of patients with nccRCC were further examined in a sub-analysis performed by Dutcher et al. [11]. Of 40 nccRCC patients, three did not have a specific primary cell type reported, which resulted in 37 remaining patients. Of those, only three (8%) had intermediate prognosis. All others (n = 34; 92%) belonged to the poor-prognosis category. Moreover, of the 37 nccRCC patients, only 13 had primary non-clear histological subtype. Of these 13 patients, ten had exclusive papillary histology, one patient had exclusive chromophobe histology and one patient had exclusive collecting duct histological subtype. Data were unavailable for the final patient (Fig. 2). To better examine the evidence favoring temsirolimus in patients with metastatic nccRCC, Dutcher et al. re-examined the phase III temsirolimus data with focus on metastatic nccRCC patients [11]. Specifically, they examined data recorded for 25 individuals with pRCC component in whom other histological subtypes such as clear-cell may have coexisted or may even have represented the dominant histological subtype. In these 25 individuals, the mean PFS was 5.9 months. In a subgroup of 10 patients with exclusive papillary histological subtype, the mean PFS was 7.9 months.

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Table 1 Summary of previous studies on the efficacy of temsirolimus, sunitinib, sorafenib, erlotinib and capecitabine in patients with metastatic non-clear cell RCC. Authors

Temsirolimus Dutcher et al. [11] (Sub-analysis of prospective study) Sunitinib Tannir et al. [28] (Prospective study)

Lee et al. [2] (Prospective study)

Molina et al. [26] (Prospective study)

Choueiri et al. [24] (Retrospective study) Sorafenib Stadler et al. [29] (Retrospective study)

Choueiri et al. [24] (Retrospective study) Erlotinib Gordon et al. [25] (Prospective study) Capecitabine Tsimafeyeu et al. [27] (Prospective study)

Number of patients with nccRCC in each study

Median PFS (95%CI) (months)

25 papillary subtype - 10 exclusive pRCC

5.9 (3.7–9.0) 7.9 (3.8–11.1)

10

55 (of 57 nccRCC) - 27 pRCC - 5 chRCC - 7 sarcomatoid - 6 cdRCC/medullary - 8 unclassified - 4 other 31 nccRCC - 22 pRCC - 3 chRCC - 6 unclassified 23 nccRCC - 8 pRCC - 2 chRCC - 4 cdRCC - 22 medullary - 13 unclassified 20 (of 53 nccRCC) - 12 pRCC - 7 chRCC

2.7 (1.4–5.4) 1.6 (1.4–5.4) 12.7 (8.5–NA) 1.4 (1.3–NA) 3.1 (1.4–NA) 3.2 (1.4–NA) – 6.4 (4.2–8.6) –

129

202 nccRCC - 158 pRCC - 30 chRCC - 11 cdRCC - 1 TFE translocation - 1 medullary 33 (of 53 nccRCC) - 28 pRCC - 5 chRCC

5.25 (NA)

45 pRCC

51 nccRCC - 39 pRCC - 7 chRCC - 5 cdRCC

Total number of patients for each molecule

mwPFS (months)

7.9

5.3

5.5 (2.5–7.1) 5.6 (1.4–7.1) – – –

11.9 (NA) 8.8 (NA) 221

2.2

≈4.1

45

≈4.1

10.1 (8.7–11.5) – – –

51

10.1

5.1 (NA) 27.5 (NA)

chRCC: chromophobe renal cell carcinoma; cdRCC: collecting duct renal cell carcinoma; mwPFS: mean weighted progression free survival; nccRCC: non-clear cell renal cell carcinoma; PFS: progression free survival; pRCC: papillary renal cell carcinoma.

Unfortunately, data are not provided to sub-stratify these 25 patients according to prognostic category. However, based on the proportions recorded in the entire phase III temsirolimus study, only 6–8% of patients belonged to the intermediate prognosis category. Taken together, the phase III temsirolimus data provide limited evidence regarding its efficacy in metastatic nccRCC patients who did not belong to the poor-prognosis category. For those few patients who truly harbored metastatic nccRCC and belonged to poor-prognosis category, PFS from 5.9 to 7.9

months may be expected. It is noteworthy that an ongoing study, conducted by Hutson et al., suggests that temsirolimus yielded a longer PFS relative to sorafenib in a sub-cohort of patients with exclusively nccRCC. However, results remain to be published. 3.2.2. Sunitinib Sunitinib is an inhibitor of tyrosine kinases including vascular endothelial growth factor (VEGF) and plateletderived growth factor (PDGF) receptors [2,4,5,7,13,24,26].

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Fig. 2. Histological subtypes of mRCC in Hudes et al.’s [15] and Dutcher et al.’s studies [11].

The NCCN guidelines recommend sunitinib as an alternative first line treatment option for metastatic nccRCC [22]. To date, several studies examined the use of sunitinib in first line therapy. Unfortunately, the only first line phase III sunitinib study exclusively focused on patients with ccRCC [7]. Therefore, no phase III data support sunitinib use in metastatic nccRCC patients. However, four reports that qualified for inclusion in the current analysis addressed sunitinib use in patients with metastatic nccRCC [2,24,26,28]. Tannir et al. conducted a recent phase II trial that focused on sunitinib in patients with metastatic nccRCC [28]. Within their cohort, the distribution of histological subtypes of the 57 patients was 27 (47%) pRCC, 5 (9%) chRCC, 7 (12%) sarcomatoid, 6 (11%) collecting duct RCC/medullary, 8 (14%) unclassified, and 4 (7%) other. The median PFS for the entire cohort was 2.7 months. Specifically, the median PFS for the

pRCC and the chRCC subtypes were 1.6 months and 12.7 months, respectively. Another phase II study was conducted, within the Memorial Sloan-Kettering Cancer Center (MSKCC) between years 2007 and 2009, on 23 metastatic nccRCC patients predominantly exposed to first line sunitinib (83% treatment naïve vs. 17% previously treated: 9% temsirolimus, 4% interferon␣ and 4% cisplatin/gemcitabine) [26]. Of all individuals, 8 patients (35%) harbored papillary histological subtype vs. 15 patients (65%) other nccRCC subtypes (medullary (n = 5, 22%), chromophobe (n = 4, 17%), unclassified (n = 3, 13%) and collecting duct (n = 1, 4%)). Prior nephrectomy was reported in 18 patients (78%). Within the entire cohort, favorable and intermediate prognosis accounted for 52 and 44% of patients, respectively. The median PFS was 5.5 months in all patients and 5.6 months in individuals with exclusive pRCC.

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Median PFS was not reported for patients with exclusive chRCC. Lee et al. reported the results of 31 patients with metastatic nccRCC treated with sunitinib between years 2008 and 2011, within a multi-institutional phase II study in South Korea [2]. Sunitinib was administered as first line therapy in 64% of patients. Of the entire cohort, 22 patients (71%) harbored papillary histology vs. 3 (10%) chromophobe histology vs. 6 (19%) unclassified histology. Favorable and intermediate prognosis accounted for 29% and 45% of patients, respectively. Prior nephrectomy was reported in 24 patients (77%). The median PFS was 6.4 months for all individuals. Specific PFS was not reported according to histological subtype. Choueiri et al. reviewed the record of 25 patients with metastatic nccRCC, from the United States and France, treated with sunitinib between years 2002 and 2006 [24]. Although no patient had previously received a tyrosine kinase inhibitor (TKI) treatment, most had received other treatment types: 49% cytokines, 23% chemotherapy, 4% bevacizumab and 1% immunotherapy. Of patients treated with sunitinib, 13 (52%) had metastatic pRCC and 12 (48%) had metastatic chRCC. Prior nephrectomy was performed in 46 patients (87%). The MSKCC prognosis status was not reported. The overall median PFS was 8.6 months. The median PFS were 11.9 months and 8.8 months for patients with pRCC and chRCC, respectively. Taken together, the two phase II studies (Molina et al. and Lee et al.) demonstrate that the use of sunitinib in 54 predominantly untreated metastatic nccRCC patients should yield a median PFS from 5.5 to 6.4 months [2,26]. Additionally, retrospective data from 20 patients indicate even longer PFS that ranged from 8.8 to 11.9 months [24].

3.2.3. Sorafenib Sorafenib is an inhibitor of tyrosine kinases including VEGF-pathway inhibitor [2,4,8,13,24]. According to the guidelines, sorafenib has level 1 evidence for use in 2nd line after cytokine failure (phase III trial) and level 2a after TKI failure in patients with metastatic ccRCC [21,22]. However, its use in 1st line therapy may be considered in selected patients with clear cell histology. For nccRCC, sorafenib holds a category 2A recommendation for treatment naïve patients according to the NCCN and ESMO guidelines [21,22]. The latter recommendation was based on the sorafenib expanded access program that included 202 patients with metastatic nccRCC [29]. The majority of the patients enrolled in this study were treated with systemic therapy (interferonalpha (24%), interleukin-2 (17%), bevacizumab (12%), thalidomide (4%), sunitinib (2%) and other (24%)). The median PFS for patients with metastatic pRCC and chRCC was 21 weeks (5.25 months). Moreover, the above-mentioned Choueiri et al. retrospective study also recorded data from 33 patients treated with sorafenib for metastatic pRCC (n = 28, 85%) or chRCC (n = 5,

15%) [24]. The median PFS were 5.1 and 27.5 months for patients with pRCC and chRCC, respectively. 3.2.4. Other agents Erlotinib is an inhibitor of tyrosine kinase that acts on the epidermal growth factor receptor [26,32]. It may represent an option for patients with metastatic nccRCC based on level 3 evidence [22]. This recommendation was based on data reported by Gordon and colleagues [25]. Within their multicenter Eastern Cooperative Oncology Group (ECOG) trial, they examined the use of erlotinib in 45 patients with pRCC between years 2005 and 2006. The MSKCC prognosis grouping and nephrectomy status were not available. The estimated median PFS was 4.1 months. Finally, capecitabine is a fluoropyrimidine carbamate that is selectively activated to fluorouracil by a sequential triple enzyme pathway in liver and tumor cells [27,33]. Currently, it is not recognized as a treatment option for metastatic nccRCC. Tsimafeyeu et al. assessed its efficacy in a phase II multicenter uncontrolled trial in 51 patients with metastatic nccRCC in Russia [27]. The majority of patients were previously untreated (92%) and had an intermediate prognosis (86%). The median PFS value was 10.1 months. 3.2.5. Ongoing trials A lot of effort in research has been invested on the treatment of nccRCC recently. At the ESMO 2012 meeting, Escudier et al. showed a PFS of 7.3 months for patients treated with first-line everolimus for metastatic pRCC, within a phase 2 open-label trial (n = 71) [21,34]. Moreover, Ravaud and colleagues reported their results on the use of first-line sunitinib in patients with metastatic pRCC, within the SUPAP phase 2 trial [35]. 15 patients with type 1 and 46 patients with type 2 pRCC were included. The majority undergone a nephrectomy (87%) and were intermediate risk group according to the MSKCC classification (54%). The median PFS were 6.6 and 5.5 months for type 1 and 2 pRCC, respectively. Other ongoing phase II trials on the treatment of metastatic nccRCC are shown in Table 2. These studies are assessing different agents: everolimus, sunitinib, bevacizumab, capecitabine, sunitinib, bortezomib, premetrexed plus gemcitabine, RAD001 and pazopanib. These will hopefully elucidate the optimal therapy for the management of patients with metastatic nccRCC.

4. Discussion The objective of this review was to examine the evidence supporting the use of first line temsirolimus in patients with metastatic nccRCC and to compare it to alternative agents. Additionally, we assessed the incidence of metastatic nccRCC, within a population-based dataset. The paucity of data pertaining to patients with metastatic pRCC or chRCC stems from very low incidence rates. The assessment of the SEER database revealed that only 2.3%

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Table 2 Ongoing clinical trials in advanced or metastatic non-clear cell renal cell carcinoma (as per clinicaltrials.gov). Studied agent(s)

Treatment line

Phase

nccRCC histological subtype

Allocation

Identifier

Everolimus vs. sunitinib Everolimus

First Previously treated with temsirolimus First No prior VEGF pathway inhibitors nor mTOR inhibitors First Up to third, no prior multi-tyrosine kinase inhibitors Any First line

II II

Any pRCC, chRCC, medullary, unclassified Any pRCC, chRCC, cdRCC, medullary, unclassified

Randomized Non-randomized

NCT01108445 NCT01798446

Randomized Non-randomized

NCT01185366 NCT01399918

Everolimus vs. sunitinib Everolimus vs. bevacizumab

Capecitabine Sunitinib

Bortezomib Temsirolimus vs. sunitinib Pemetrexed plus gemcitabine RAD001 Sunitinib

II II

II II

Any pRCC, chRCC, cdRCC, medullary, unclassified, sarcomatoid

Non-randomized Non-randomized

NCT01182142 NCT00465179

II II

Any pRCC, chRCC, cdRCC, medullary, unclassified Any pRCC pRCC, chRCC, cdRCC

Non-randomized Randomized

NCT00276614 NCT00979966

Non-randomized Non-randomized Non-randomized

NCT00491075 NCT00688753 NCT01219751

Any pRCC, chRCC, cdRCC, unclassified pRCC, chRCC, cdRCC, oncocytic, sarcomatoid, medullary

Non-randomized Non-randomized

NCT01034878 NCT01538238

Non-randomized

NCT01767636

Non-randomized

NCT00830895

II II II

Sunitinib Pazopanib

Up to third First No prior treatment on sunitinib, sorafenib, bevacizumab First First

Pazopanib

Any

II

RAD001

No previous mTOR inhibitor

II

II II

pRCC: papillary renal cell carcinoma; chRCC: chromophobe renal cell carcinoma; cdRCC: collecting duct renal cell carcinoma; VEGF: vascular endothelial growth factor; mTOR inhibitors: mammalian target of rapamycin inhibitor.

of all patients with metastatic RCC harbor either papillary or chromophobe histological subtype. In the most recent year (2008), the combined rate of papillary and chromophobe RCC increased to 4%. This rise may be attributed to increased familiarity with histological subtypes of RCC in the pathology community. As such, given the low prevalence of nccRCC in general, there is difficulty in enrolling patients with such disease in clinical trials. Indeed, our review only identified eight studies that met the inclusion criteria [2,26,28]. Indeed, patients with metastatic nccRCC often do not meet the inclusion criteria of the majority of clinical trials [31]. The problematic of clinical trials in rare cancers may be resolved by focusing on biomarkers and novel trial designs, such as the adaptive trials, or the use of Bayesian statistics, as well as the promotion of off-label use of novel agents in rare cancers [36]. Current guidelines provide most support for the use of temsirolimus or sunitinib in first line therapy for metastatic nccRCC for poor prognosis patients. Sorafenib as well as other agents represent alternatives [22]. The recommendation favoring temsirolimus is based on efficacy and tolerability data that originate from a randomized controlled trial [15]. However, the drawbacks of these data consist of the fact that the trial focused on predominantly poor risk patients with

any histological subtype. The findings of this trial therefore apply to poor risk patients in whom temsirolimus represents the agent of choice. However, the indications for temsirolimus in metastatic nccRCC are not convincing. First, the temsirolimus efficacy for metastatic nccRCC data only applies to a small number of patients with non-clear cell histological subtype. Within the 37 patients with other than clear cell histological subtype, only 13 had exclusive nccRCC [11]. Therefore, the level 2A evidence supporting the use of temsirolimus is undermined by the excessively small number of observations with truly papillary or chromophobe histological subtypes. Second, the phase III temsirolimus study predominantly recruited poorprognosis patients for whom there is no controversy about first line therapy. Only 8% of patients with a histological subtype other than clear cell did not have poor-prognosis [11]. Since the prognosis distribution may be expected to remain the same across all metastatic RCC with other than clear cell histological subtypes, it is highly likely that as few as 8% of the 13 patients with either predominant metastatic pRCC or chRCC represented intermediate prognosis patients in whom the efficacy of temsirolimus relative to other agents warrants a close examination. Based on this estimate, fewer than 13 patients qualify for inclusion in the assessment of

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temsirolimus efficacy. This fact reduces the number of observances to a critically low level where generalizability and robustness can no longer be considered. Taken together, the above limitations of the temsirolimus phase III study question the validity of temsirolimus for first line use in patients with either favorable or intermediate prognosis and either papillary or chromophobe histology. However, the temsirolimus data truly support the use of this molecule in poor-prognosis patients regardless of histological subtype. The limitations of temsirolimus data with respect to its use in patients with other than poor-prognosis, who harbor metastatic nccRCC that primarily consists of either papillary or chromophobe histological subtype, indicate that alternative treatment options are necessary. Sunitinib qualifies for being best recognized as a valid option. The data supporting the use of sunitinib originate from three phase II studies and one review [2,24,26,28]. The combined sample size of the three phase II studies (n = 23 + 31 + 55) exceeds that of the 13 patients exposed to temsirolimus, with other than ccRCC, within the phase III study [11]. These data are further supported by 20 additional observations [24]. The median PFS with sunitinib in the phase II studies ranges from 1.6 to 12.7 months vs. 8.8–11.9 months in the review report [2,24,26,28]. These values compare favorably with the median PFS of 7.9 months for temsirolimus [11]. In consequence, sunitinib may at least be qualified as a very reasonable alternative first line treatment modality for patients with metastatic nccRCC (papillary or chromophobe). The limitations of temsirolimus data for papillary and chromophobe metastatic RCC may even justify the consideration of sunitinib as the first line agent of choice for patients with papillary or chromophobe metastatic RCC, who do not qualify for inclusion in the poor-prognosis group. The data supporting the use of first line sunitinib in patients with metastatic nccRCC (papillary or chromophobe) are convincing. Preliminary results based on abstracts presented at the ESMO 2012 demonstrate potential for sunitinib as a first-line agent in patients with nccRCC [35]. However, final results remain to be published. A retrospective review by Choueiri et al. in 33 patients supports the efficacy of sorafenib [24]. Stadler et al. expanded access program for sorafenib also shows that sorafenib appears to have antitumor activity in papillary and probably chromophobe RCC [29]. In the phase two study performed by Gordon et al., erlotinib failed to achieve a competitive PFS compared to other recognized agents (estimated PFS was 4.1 months vs. 7.3 months for sunitinib and 7.9 months for temsirolimus) [25]. In the light of these results, as well as preliminary results from abstract presentations everolimus deserves further evaluation in the treatment of metastatic nccRCC [21,34]. In summary, we have examined the data supporting the use of temsirolimus, as well as of alternative treatment modalities for patients with metastatic nccRCC, who are not in the poor-prognosis category. Our findings showed that the

robustness and the generalizability of temsirolimus efficacy data are weak at best. Conversely, the data supporting the use of sunitinib are much stronger, but do not originate from a phase III study. No other molecule qualifies for consideration, but several trials are ongoing.

Conflict of interest statement The authors declare nothing to disclose.

Acknowledgements Pierre I Karakiewicz is partially supported by the University of Montreal Health Centre Urology Specialists, Fonds de la Recherche en Santé du Québec, the University of Montreal Department of Surgery and the University of Montreal Health Centre (CHUM) Foundation.

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Biographies Salima Ismail is a PGY-4 urology resident at the University of Montreal Health Center. Malek Meskawi is a PGY-1 urology resident at University of Montreal Health Center. Pierre I. Karakiewicz is a professor of urology at University of Montreal. In addition to his clinical practice, he is the director Cancer Prognostics and Health Outcomes Unit. His fields of interest are kidney, prostate and bladder cancer. Maxine Sun is clinical researcher and co-director of Cancer Prognostics and Health Outcomes Unit of the University of Montreal Health Center.