Renal cell carcinoma (RCC) encompasses many distinct histological subtypes [1▪]; nonclear-cell RCC (non-ccRCC) accounts for 25% of RCC and includes papillary RCC (pRCC) (15%), chromophobe RCC (chRCC) (5%), and rare entities such as collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), translocation RCC (tRCC), and unclassified RCC. Unlike the ccRCC, where the initiating oncogenic event has been clearly established, in non-ccRCC tumors, little is known about the oncogenic substratum of these distinct entities.
From a therapeutic perspective, non-ccRCC has commonly been treated with an agent developed for ccRCC. However, the vast majority of the pivotal trials that led to the approval of the seven targeted agents in metastatic RCC have excluded patients with non-ccRCC.
Several phase II trials have investigated the role of targeted therapies in non-ccRCC [2–7,8▪,9,10▪▪], and these are summarized in Table 1. Most of these studies were single-arm, nonrandomized studies, which provided progression-free survival (PFS) results lower than in ccRCC, in the range of 2.7–6.4 months for both vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) inhibitors. Additional information came from expanded access program for sunitinib, sorafenib, and everolimus [11–13]. A few randomized phase III trials have included non-ccRCC in the past. Among these, the pivotal phase III of temsirolimus vs. interferon (IFN)-α included 73 patients with non-ccRCC, and subsequent subgroup analysis of this study suggested that temsirolimus could be considered as a valid option for patients with non-ccRCC [14,15]. More recently, the INTORSECT trial included 90 patients with non-ccRCC and demonstrated that temsirolimus did not improve PFS when compared to sorafenib after treatment with sunitinib . Overall, enrollment into specifically designed clinical trials is recommended by European Society for Medical Oncology , European Association of Urology , and National Comprehensive Cancer Network guidelines .
Over the past 2 years, the first prospective trials enrolling non-ccRCC population, either as part of a larger RCC trial or in a dedicated study, have been reported, and they provide specific results for sunitinib and everolimus in first-line setting [10▪▪,20▪▪]. Additional results from single-arm, phase II trials have explored more specifically the population of pRCC [8▪,9]. In parallel, large molecular programs aimed at identifying relevant targets in these distinct entities.
The purpose of this review is to provide an up-to-date overview of targeted agents’ results in advanced non-ccRCC that defined the current strategies in non-ccRCC and the anticipated future strategies in this population.
CURRENT STRATEGIES IN NONCLEAR-CELL metastatic renal cell carcinoma (mRCC)
The lack of specific targeted therapy in metastatic non-ccRCC arises from several obstacles. The first one is the rarity and heterogeneity of the non-ccRCC entities, which account for less than 25% of advanced RCC. The second reason is the challenge in terms of diagnosis for pathologists, to classify these tumors accurately. The International Society of Urological Pathology Vancouver classification [1▪] represents the modified version of the 2004 WHO classification [21,22] and describes the distinct entities in terms of histological characteristics, underlying the biology, and clinical presentation and outcome.
Nonclear-cell renal cell carcinoma entities
Molecular characterization of non-ccRCC has evolved with new histological entities recently defined [23▪]. The most common forms are pRCC, chRCC, tRCC, CDC, and RMC.
Papillary RCC is the second most common subtype of renal malignancies after clear-cell histologies (10–15% of RCC) characterized by papillary or tubulo-papillary morphological structure. pRCC is commonly dichotomized into types I and II subtypes . In type I, the germline mutation of the proto-concogene MET on chromosome 7 is characteristic of hereditary disease, but has also been reported in up to 13 and 21% of sporadic type I pRCC [25,26▪]. In type II, the analysis of the hereditary leiomyomatosis and RCC (HLRCC)  syndrome, which associates a risk for cutaneous, uterine leiomyomas and solitary pRCC type II, has identified the mutations of the fumarate hydratase gene and underlined the key role of cell metabolism in some type II pRCCs.
Chromophobe RCC represents 5% of the RCC cases. From a morphologic perspective, these tumors usually present large tumor cells, with voluminous pale cytoplasm, eosinophilic granules, and a specific nuclear morphology with perinuclear halos and binucleation. Hereditary forms of chRCC have been reported in patients with Birt–Hogg–Dubé (BHD) syndrome  – an autosomal dominant hereditary cancer syndrome associated with bilateral, multifocal chRCC due to mutations in the folliculin (FLCN) gene .
Translocation RCC tumors may present areas of both clear-cell and papillary or nested architecture with voluminous eosinophilic cells. Diagnosis of this subtype is done by immunohistochemical staining with transcription factor E3 (TFE3) antibody and fluorescence in-situ hybridization analysis. These tumors develop from the dysregulation of transcription factors from the microphthalmia-associated transcription factor (MiTF) family and gene fusions of TFE3 (Xp11.2) and rarely transcription factor EB (TFEB) (6p21.1), with several partner genes forming TFE3 gene fusions .
Collecting duct carcinoma and RMC are two rare non-ccRCC entities with eosinophilic cells difficult to diagnose one from another. RMC tumors are poorly differentiated, with inflammatory infiltrative cells having sheet-like or reticular pattern. RMC often occurs in young adults or children with sickle cell disease and is characterized by a very poor clinical outcome .
Sarcomatoid differentiation does not represent a specific histological entity. Sarcomatoid feature can arise from any histological subtypes and is associated with a worse prognosis [32,33,34▪]. The percentage of sarcomatoid differentiation appears as an independent prognostic feature .
Prognosis of metastatic nonclear-cell renal cell carcinoma in the era of targeted therapy
A large retrospective analysis conducted in the International Metastatic RCC Database Consortium (IMDC) has investigated the prognosis of non-ccRCC [36▪▪]. This analysis provides key messages. Taken altogether, the prognosis of non-ccRCC is worse than the prognosis of ccRCC. Among the 252 patients included in this analysis, median overall survival (OS) was 12.8 months [95% confidence interval (CI) 11.0–16.1] vs. 22.3 months (95% CI 20.7–23.5) in the ccRCC population (n = 1963) (adjusted hazard ratio 1.41, 95% CI 1.19–1.67, P value < 0.0001).
A large meta-analysis of published clinical trials including 49 studies in 7771 patients also confirmed the dismal outcome of non-ccRCC compared to ccRCC [37▪▪]. The analysis compared 1244 patients (16.0%) with non-ccRCC vs. 6300 (83.1%) with ccRCC. In studies directly comparing non-ccRCC and ccRCC, there were significantly lower response rates for non-ccRCC [odds ratio (OR) for response 0.52, 95% CI 0.40–0.68, P < 0.001]. Targeted therapy use in non-ccRCC achieved a median PFS and OS of 7.4 and 13.4 months vs. 10.5 and 15.7 months, respectively, in ccRCC (P value for difference <0.001 for both PFS and OS).
In addition, the IMDC study confirmed that non-ccRCC is a heterogeneous group in terms of prognosis in the metastatic setting in the era of targeted therapy. As an example, metastatic pRCC presented a median OS of 14.0 months (95% CI 10.9–17.1), whereas chRCC presented a median OS of 27.1 months (95% CI 12.6–75.3). Interestingly, the study identified that the application of the IMDC risk criteria in the non-ccRCC population segregated three risk groups with favorable, intermediate, and poor risk profiles in prognostication of median OS of 31.4, 16.1, and 5.1 months in good, intermediate, and poor prognosis risk groups, respectively (P < 0.0001) [36▪▪]. Finally, the dataset provided real-world results of the use of targeted therapy in non-ccRCC, with median time to failure (TTF) of 4.2 months (95% CI 3.7–5.2) vs. 7.8 months (95% CI 7.2–8.1), adjusted hazard ratio 1.54 (95% CI 1.33–1.79), adjusted P value less than 0.0001 in first line, and 2.8 months (95% CI 2.3–3.7) in second line.
Recent advances in clinical trials in nonclear-cell renal cell carcinoma
Over the past years, several trials, including randomized phase II trials, have provided important information for non-ccRCC.
Randomized clinical trials enrolling nonclear-cell renal cell carcinoma
In 2014, two randomized trials had provided valuable information on the sequence of VEGFR and mTOR inhibition use in non-ccRCC. Initially the report of the RECORD-3 clinical trial has provided the first report of a head-to-head comparison of everolimus vs. sunitinib in RCC [20▪▪]. In a subgroup analysis of 66 patients who had non-ccRCC, everolimus did not yield better results than sunitinib as a first-line therapy, with median PFS of 5.1 and 7.2 months, respectively (hazard ratio 1.54, 95% CI 0.86–2.75).
Subsequently, the ESPN trial provided the similar comparison in a randomized phase II trial in the specific population of non-ccRCC [10▪▪]. Interim analysis of 68 patients (27 pRCC, 12 chRCC, 10 unclassified RCC, seven tRCC, and 12 clear cell with sarcomatoid features) prompted early trial closure; at final analysis, median overall survival was 16.2 and 14.9 months with sunitinib and everolimus, respectively (P = 0.18). Although several limitations, including the small sample size and the heterogeneity of the population included, need to be taken into consideration, this study concluded that everolimus was not superior to sunitinib and that both agents demonstrated modest efficacy. A second trial with similar design will provide another comparison between everolimus and sunitinib in the first-line setting for metastatic non-ccRCC – the ASPEN trial (NCT01108445). It is anticipated that this will also highlight the need for better therapies in non-ccRCC and the requirement to explore non-ccRCC on a subentity basis.
Recent advances in systemic therapy for papillary renal cell carcinoma
One of the limitations of the previously mentioned clinical trials is the pooled analysis of distinct entities. Several phase II trials have focused on specific subtypes, such as pRCC, for which a growing body of literature is now available. The SUPAP trial investigated the role of first-line sunitinib in pRCC and reported a median OS of 17.8 months (95% CI 5.7–26.0) and 12.4 months (95% CI 8.2–16) in papillary type I and II RCC, respectively [8▪]. With a similar design, the RAPTOR trial investigated the role of everolimus in first line and reported a median OS of 21.0 months (95% CI 11.1–28.0) with, respectively, 28 and 21 months OS in type I and type II pRCC .
Interesting results in metastatic pRCC were reported with the use of a dual VEGFR2–cMET inhibitor, foretinib, which reported a median PFS of 9.3 months in a population of previously treated metastatic pRCC . Interestingly, the presence of a germline MET mutation was highly predictive of response. Several MET inhibitors are now actively being investigated in pRCC (NCT01524926, NCT02127710, and NCT02019693); these trials have been developed with translational program and will further dissect the exact role of MET mutations and/or other alterations in pRCC.
Recent advances in systemic therapy for chromophobe renal cell carcinoma
A recent retrospective dataset focused on the outcome of metastatic chRCC patients treated with sunitinib . In 33 patients treated with sunitinib as a first-line therapy, median PFS and OS were 10 and 26 months, respectively, and 75% of the patients achieved a clinical benefit (partial response + stable disease). In addition, the treatment outcome was not significantly different between chRCC and ccRCC patients, who were individually matched by the IMDC risk group and other prognosis factors.
Recent advances in systemic therapy for collecting duct carcinoma
On the rationale that CDC tumors respond to platinum-based chemotherapy , a small series of five CDC patients treated with a triple-drug combination of gemcitabine and platinum salt with bevacizumab, followed by bevacizumab maintenance therapy, was performed . The combination reported a median PFS of 15.1 months (95% CI 5.6–20.4) and a median OS of 27.8 months (95% CI 12.4 to unreached). A prospective single-arm, phase II trial is ongoing to assess this triple-drug regimen (NCT02363751).
Recent advances in systemic therapy for renal cell carcinoma with sarcomatoid features
One of the main challenge for physicians involved in metastatic RCC care is the management of patients presenting with sarcomatoid histologies. In patients with sarcomatoid features, the use of chemotherapy has been previously investigated [41,42] and followed by some attempt to combine with sunitinib . Recently, McKay et al.[44▪] reported a single-arm, phase II study of the combination of gemcitabine and sunitinib in patients with sarcomatoid and/or poor-risk RCC. In the sarcomatoid population of this trial (n = 39), median TTP was 5 months (95% CI 3–9), median OS was 10 months (95% CI 6–23), and overall response rate was 26% (10/39). Interestingly, analysis of the percentage of sarcomatoid features suggested that patients with more than 10% of sarcomatoid component in their tumors were more likely to achieve stable disease or an objective response than those with less than 10% of the sarcomatoid component [44▪].
FUTURE STRATEGIES IN NONCLEAR-CELL mRCC
Future strategies in non-ccRCC currently rely on the ability to better dissect the specific biology of each histological subtypes and the potential role of the new immune checkpoint blockade agents in non-ccRCC.
Molecular characterization for target identification in nonclear-cell renal cell carcinoma
Multiplatform molecular characterization of non-ccRCC is a rapidly evolving field, involving distinct complementary techniques among genome sequencing, exome sequencing, transcriptome, and copy number analysis. The ultimate goal of these large molecular surveys is to identify the relevant biological pathway and subsequently develop the targeted therapy in these rare subtypes. To date, no new compound has been approved for non-ccRCC on the basis of these ongoing efforts. Moreover, the first consortium results suggest that each histopathological entity may encompass distinct subgroups.
Papillary renal cell carcinoma
Recent molecular series suggest that pRCC is a highly heterogeneous disease and that type II pRCC encompass distinct entities . Kovac et al.[46▪] analyzed 31 pRCCs, using genomes or exomes sequencing, and identified BAP1, SETD2, ARID2, and Nrf2 pathway genes (KEAP1, NHE2L2, and CUL3) as probable drivers. Only approximately 10% of the tumors harbor detectable pathogenic changes in any one driver gene and these appear to be present within cancer subclones, unlike the large copy number gains of chromosomes 7, 12, 16, and 17 that seemed to be early, monoclonal changes in pRCC evolution [46▪]. Durinck et al.[47▪] reported on 65 pRCC and identified 10 significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD, and CPQ. MET mutations occurred in 15% (10/65) of the pRCC samples and included previously unreported recurrent activating mutations [47▪]. Distinct alterations in the MET gene, apart from the mutation, have been identified, including gene fusion  and copy number changes [26▪]. Additional insights will be provided by The Cancer Genome Atlas (TCGA) working group on pRCC.
Chromophobe renal cell carcinoma
Among the 66 chRCCs, the Cancer Genome Atlas working group on chRCC reported that mitochondrial DNA seems essential in chRCC biology. ChRCC presents recurrent breakpoints in telomerase reverse transcriptase (TERT) promoter region, leading to TERT up-regulation. A low mutation rate was found targetable genes commonly screened in precision medicine panels (TP53 mutated in 32% and mTOR pathway genes mutated in 23%) [49▪▪]. Among the 49 chRCCs, Durinck et al.[47▪] reported that TP53, phosphatase and tensin homolog, and other genes involved in metabolism, such as pyruvate dehydrogenase beta, were significantly mutated, suggesting that in some cases, chRCC biology may potentially allow the tumor to favor glycolysis over oxidative phosphorylation for energy production.
Translocation renal cell carcinoma
Translocation RCC usually encompasses tumors harboring a translocation, involving either Xp11.2 (TFE3) or 6p21 (TFEB) genes. Recent studies suggest that new MiTF gene fusions should be considered within this entity [47▪,50], and that these tumors express the antiapoptotic protein BIRC7, suggesting that therapy with an apoptosis-sensitizing BIRC7 inhibitor may be of interest in this rare setting [47▪].
Sarcomatoid renal cell carcinoma
Comparative RNA-seq of adjacent sarcomatoid and clear cell histology of RCC indicates a proliferative phenotype and increased aurora kinase A-dependent activation of mTOR signaling in sarcomatoid RCC, which could be targeted by available agents . However, retrospective analysis of patients with sarcomatoid features treated with mTOR inhibitors did not display major clinical signal to date; these findings require additional investigation [34▪].
Immune checkpoint antibodies and nonclear-cell renal cell carcinoma
No efficacy data of the new checkpoint inhibitors are available in non-ccRCC. However, the expression level of Programmed death-ligand 1 (PD-L1) in various non-ccRCC subtypes was recently reported by Choueiri et al.[52▪]. Among the 101 patients, 11 (10.9%) were considered PD-L1-positive in tumor cells: 2/36 (5.6%) of chRCC, 5/50 (10%) of pRCC, 3/10 (30%) of tRCC, and 1/5 (20%) of CDC. PD-L1-positivity in tumor cells was significantly associated with higher stage (P = 0.01) and grade (P = 0.03), as well as shorter OS (P < 0.001) in this non-ccRCC population. This finding suggests that non-ccRCC should not be excluded from the current trials, and specific trials should be conducted to assess the role of immune checkpoint antibodies in non-ccRCC.
Given the limited benefits reported with both mTOR inhibition and VEGF blockade in non-ccRCC, patients should be offered clinical trials with new investigational agents. Current research efforts have the potential to identify molecular targets that are relevant to each of the diverse subtypes of non-ccRCC and need to be confirmed in the metastatic setting. The role of multidisciplinary approach between pathologist, urologist, and oncologist within cooperative groups and international collaboration is crucial in such a rare and heterogeneous disease.
Financial support and sponsorship
Conflicts of interest
L.A. disclosed: consulting or advisory role to Pfizer, Novartis, Sanofi, Amgen; Laurence Albiges received research funding from Pfizer and Novartis and a grant from Fondation de France.
B.E. disclosed: consulting or advisory role to Bayer, Pfizer, Novartis, Honoraria: Bayer AG, Roche, Pfizer, Genentech, Novartis, AVEO, Pharmaceuticals, GlaxoSmithKline.
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