Abstract: The non–clear cell renal cell carcinomas (nccRCCs) are a diverse group of rare-variant renal carcinomas. Each subtype harbors a distinct cell of origin and exhibits a distinct clinical behavior and response to therapy. The advent of next-generation sequencing has drastically advanced our understanding of key genetic and epigenetic drivers in these tumors, although mechanistic studies are needed to elucidate pathogenesis. The only 2 randomized clinical trials in nccRCC included patients with diverse histologic subtypes. Both of these trials compared everolimus with sunitinib and provided evidence suggesting that frontline sunitinib is superior to everolimus in terms of progression-free survival. Renal medullary and collecting duct carcinomas do not respond to targeted agents, supporting the use of platinum-based chemotherapy as frontline therapy. Clinical evidence is currently emerging on the efficacy of c-MET inhibitors in patients with papillary type 1 RCC harboring germline c-MET mutations. Data on the activity of immune checkpoint inhibitors in this setting are lacking; however, several trials are ongoing in this space. The management of patients with nccRCC likely will improve in the future with histology-driven trials, which may pave the way for personalized therapies based on the molecular characterization of these orphan kidney cancer subtypes. Efforts must also be made to establish in vitro and animal models for testing hypotheses generated through extensive genomic analysis. Ultimately, collaborative national and international studies are urgently needed to improve therapeutic strategies in patients with metastatic disease.
In the European Union, there were approximately 59,000 new cases of kidney cancer and 26,000 disease-specific deaths in 2012.1 The incidence is similar in the United States, with approximately 63,000 new cases reported in 2016.2 Among patients with malignant tumors of the kidney, non–clear cell renal cell carcinomas (nccRCCs) account for approximately 25% of cases. Approximately 30,000 patients per year are candidates for systemic therapy in the European Union alone, of whom an estimated 7000 have tumors with non–clear cell histology.2 nccRCCs arising from different cells of the nephron exhibit diverse histologies associated with distinct clinical behaviors. In the 2016 World Health Organization (WHO) classification of kidney tumors, 13 subtypes of nccRCC are identified: multilocular cystic renal neoplasm of low malignant potential, papillary RCC, hereditary leiomyomatosis and RCC syndrome–associated RCC, chromophobe RCC, collecting duct carcinoma, renal medullary carcinoma, MiT family translocation RCC, succinate dehydrogenase–deficient renal carcinoma, mucinous tubular and spindle cell carcinoma, tubulocystic RCC, acquired cystic disease–associated RCC, clear cell papillary RCC, and unclassified RCC.3
Unfortunately, despite their unique biological behaviors, all these subtypes are lumped together as nccRCC when they are compared with clear cell renal cell carcinoma (ccRCC) in clinical trials. Indeed, only a handful of clinical trials reported to date have investigated the efficacy of chemotherapy or targeted agents in a specific histologic subtype of nccRCC. This type of research is currently evolving with the implementation of next-generation sequencing, which has allowed exploration of the genetic landscape of some of the subtypes—although much is not understood about their intra- and inter-heterogeneity. The first part of this review focuses on the cells of origin of these kidney tumors and discusses new insights based on next-generation sequencing and the identification of key alterations. The second part discusses available clinical trial data and provides a perspective on novel trials and the management of nccRCC.
Ontogenesis of Non–Clear Cell Renal Cell Carcinoma
At least 10 distinct cell types make up the proximal and distal parts of the nephron; thus, the various subtypes in the diverse group of RCCs exhibit different histologic features and biology.4 Recently, using DNA methylation profiling, we (Drs Malouf and Tannir) reported that oncocytoma and chromophobe tumors cluster together, suggestive of a cell of origin within distal cells of the nephron.5 Our data are consistent with the chromophobe data from The Cancer Genome Atlas (TCGA), which also investigated the ontogenesis of these tumors.6 In addition, using DNA methylation signatures, we found that translocation RCCs and mucinous and spindle cell carcinomas cluster together with clear cell and papillary RCCs, consistent with a cell of origin within the proximal tubule.5 Using transcriptome analysis, we recently demonstrated that collecting duct carcinomas may arise from the distal convoluted tubule of the kidney.7 In renal medullary carcinoma, immunohistochemical staining indicates that this rare and aggressive tumor may arise from the distal part of the nephron, likely within the collecting duct. Interestingly, all types of RCC may be associated with sarcomatoid dedifferentiation, suggesting that sarcomatoid features are a marker of high-grade and aggressive RCC rather than a distinct histopathologic subtype.8 Given all these data, future efforts to understand RCC ontogenesis should focus on the microdissection of kidney cells and an integrative analysis of their transcriptome and epigenetic features.
Molecular Biology of Non–Clear Cell Renal Cell Carcinoma
As previously discussed, each subtype of nccRCC is characterized by a unique signature and often harbors genetic aberrations distinct from those of clear cell RCC, which typically harbors VHL aberrations.9 This review focuses on the most frequent nccRCC subtypes, which were recently characterized through TCGA.
Papillary Renal Cell Carcinoma
Papillary RCCs are a heterogeneous group of tumors that pathologists usually divide into papillary type 1 and papillary type 2 subtypes.10 The biology and natural history of these groups are completely different. Papillary type 1 tumors usually have an indolent course, whereas papillary type 2 tumors are more aggressive. Historically, germline mutation of the c-MET gene leading to its constitutive activation has been described in families with hereditary papillary RCC.11 Even when they are sporadic, 10% to 21% of papillary type 1 tumors harbor somatic c-MET mutations.11-13 Likewise, papillary type 2 disease is usually described in patients with hereditary leiomyomatosis and RCC, which confers a predisposition to an aggressive form of type 2 papillary RCC caused by germline mutation of the gene encoding fumarate hydratase (FH), an enzyme in the tricarboxylic acid cycle.14 With the advent of next-generation sequencing, TCGA undertook major efforts that characterized 161 cases of papillary RCC: 75 papillary type 1, 60 papillary type 2, and 26 unclassified papillary tumors.15 The study identified previously described somatic mutations of c-MET in papillary type 1 tumors in 17% of cases. In addition, the study revealed several novel findings, particularly in the classification of papillary type 2 tumors, which were divided into 3 distinct subgroups on the basis of molecular differences associated with patient outcome.15 In particular, type 2 tumors were characterized by CDKN2A silencing, mutations in chromatin-modifying genes (SETD2, BAP1, or PBRM1 mutations are associated with a high rate of TFE3 or TFEB fusion), or a CpG island methylator phenotype (CIMP; characterized by poor survival and mutation of the FH gene).15 Interestingly, beyond MET and FH mutations, somatic mutations were also identified in the Hippo and NRF2 pathways as well as in chromatin modifiers, including members of switch/sucrose nonfermentable (SWI/SNF) complex.15 The relevance of these mutations is still unclear.
Chromophobe Renal Cell Carcinoma
Chromophobe RCCs account for fewer than 5% of kidney tumors and usually exhibit indolent behavior. Only 1.3% of patients have distant metastases at diagnosis.16 Chromophobe RCC is associated with germline mutation of the folliculin gene (FLCN) in Birt-Hogg-Dubé syndrome17 and with germline mutation of PTEN in Cowden syndrome.18 Until recently, the genomic basis of chromophobe RCC occurring sporadically was unknown. TCGA consortium recently reported on an integrative analysis of 66 cases of chromophobe RCC; it identified a profound change affecting mitochondrial function as a hallmark of the disease biology, which was characterized as relying on oxidative phosphorylation.6 The most frequent somatic mutations in chromophobe RCC were related to TP53 and PTEN genes and affected 32% and 9% of the tumors, respectively. Mutations in the mammalian target of rapamycin (mTOR) gene occurred in 23% of chromophobe RCCs; however, the significance of these mutations regarding response to therapy is unknown. Finally, both mutations in the telomerase reverse transcriptase promoter (TERT) gene and genomic rearrangements within the TERT promoter region were observed.5 However, the driving events in aggressive vs indolent cases remain undetermined and deserve further study.
MITF Translocation Renal Cell Carcinoma
Translocation RCC is a rare subtype of RCC that was introduced in 2004 as a genetically distinct entity in the WHO classification of kidney tumors. It accounts for one-third of pediatric RCC cases and almost 15% of RCC cases in patients younger than 45 years.19 The most frequent translocations involve the TFE3 (Xp11.2) and TFEB (6p21.1) genes, discovered almost 2 decades ago.20 Recent analysis of TCGA cohorts with clear cell and papillary type 2 RCC identified misclassified translocation RCC in 1.5% and 12% of cases, respectively.21,22 In addition, comprehensive analysis of several nccRCC subtypes identified MITF (3p13) translocation in a subgroup of papillary RCCs, expanding the spectrum of the disease.23 Of note, TFE3, TFEB, and MITF can fuse with different partners, although the role of those partners in carcinogenesis remains unknown. Recently, virtual karyotyping revealed a range of phenotypes in translocation RCC, including some cases harboring clear cell RCC or papillary RCC patterns and pediatric cases harboring a normal karyotype.24 Of note, aggressive translocation RCC in adults was characterized by gain of 17q, and this was induced through multiple mechanisms.24 Translocation RCC displays a unique gene expression signature in comparison with other RCC subtypes. In addition to the driving translocation, a high rate of mutations in chromatin-modifying genes was identified in translocation RCC, but these did not overlap with the mutations commonly seen in ccRCC, such as those of VHL, PBRM1, and BAP1.21
Collecting Duct Carcinoma
Collecting duct carcinoma, also known as Bellini duct carcinoma, is a rare subtype of kidney tumor that is thought to arise from the distal part of the nephron within the collecting duct. The diagnosis of collecting duct carcinoma is challenging because the differential diagnosis includes renal medullary carcinoma and upper-tract urothelial carcinoma. Recent transcriptomic analysis of collecting duct carcinoma identified a unique gene expression signature of this subtype among other kidney carcinomas, and this was consistent with a putative cell of origin within the distal convoluted tubule.7 Furthermore, transcriptomic signature identified metabolic shift with impairment of oxidoreductase activity and the tricarboxylic acid cycle, as well as an immunogenic response consistent with tumor-infiltrating lymphocytes.7 In addition, SLC7A11, a cisplatin resistance–associated gene, was identified as being overexpressed in 80% of collecting duct carcinoma tumors.25 At the genetic level, 2 studies investigated genomic aberrations in collecting duct carcinoma. The first study reported on targeted sequencing of 17 cases and identified frequent somatic mutations in the NF2 (29%), SETD2 (24%), and SMARCB1 (18%) genes; of note, CDKN2A also was deleted in 12% of cases.26 The second study reported on a smaller number of cases and identified frequent deletions of CDKN2A (62.5%), with only a recurrent mutation in the MLL gene in 2 of 4 cases assessed by exome sequencing.25 Larger studies are needed to clarify the role of driver mutations in this aggressive disease.
Renal Medullary Carcinoma
Renal medullary carcinoma has long been described as the seventh nephropathy in sickle cell disease, although this dogma recently has been challenged.27 For reasons that remain unknown, renal medullary carcinoma predominantly affects patients with sickle cell trait, particularly young patients of African descent. At the molecular level, renal medullary carcinoma is characterized by INI1 protein inactivation, and this is currently required to confirm the diagnosis. INI1 is a chromatin-modifying gene that belongs to the SWI/SNF complex, which has recently been described as highly mutated in ccRCC.28 For a long time, the genetic basis of INI1 loss was unknown, as only 1 allele was found to be deleted with no explanation of protein loss.29 Recently, through next-generation sequencing, Calderaro and colleagues identified translocation of the second INI1 allele as the hallmark of the disease.30 Although these data need to be confirmed in a second independent cohort, the authors have pinpointed the importance of biallelic inactivation of INI1 in these tumors.
Mucinous and Spindle Cell Carcinoma
For a long time, the biology of these tumors was unexplored. A recent report by Mehra and colleagues on 22 tumors identified the presence of either biallelic loss of the Hippo pathway and/or evidence of alteration of Hippo genes in 85% of samples.31 The most frequent mutations were in PTPN14 (31%) and NF2 (22%), followed by mutations in other members of the pathway, such as the SAV1 and HIPK2 genes.31 As a consequence, the majority of cases exhibited nuclear expression of YAP1, which is a readout of Hippo pathway inactivation.
Treatment Options for Non–Clear Cell
Renal Cell Carcinoma
Given that ccRCC is the most common subtype of RCC, more data are available for the treatment of metastatic ccRCC than of nccRCC. However, multiple studies have reported on nccRCC; these consist of randomized clinical, prospective single-arm, and retrospective studies. We review below the relevant studies that address the treatment of nccRCC to provide a guide for patients and for the clinicians who treat RCC. First, we review prospective studies that included patients with all subtypes of nccRCC; then, we review the data available for each subtype of nccRCC, primarily via retrospective review, and data on immunotherapy.
Prospective Randomized Studies
There are 3 published randomized controlled studies that have included patients with nccRCC (Table 1). In 2014, Motzer and colleagues reported the first randomized study, RECORD-3 (Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients With Metastatic Renal Cell Carcinoma), which included a cohort of patients with nccRCC and a larger cohort of patients with ccRCC.32 This study was designed to compare sequential first-line everolimus (Afinitor, Novartis) and second-line sunitinib (Sutent, Pfizer) vs first-line sunitinib and second-line everolimus in patients with metastatic RCC. A total of 66 of 471 patients (14%) had nccRCC. The median first-line progression-free survival (PFS) in the nccRCC cohort was longer in the sunitinib arm than in the everolimus arm (7.2 months vs 5.1 months), but this difference was not statistically significant. Although the nccRCC cohort was relatively small, these were the first prospective data to suggest that that frontline anti-angiogenesis therapy in the form of sunitinib may provide a slight advantage in PFS vs an mTOR inhibitor.
The ASPEN (Afinitor [RAD001] vs. Sutent (Sunitinib) in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma) phase 2 trial randomly assigned patients with metastatic nccRCC to everolimus or sunitinib.33 Overall, 108 patients were randomly assigned to sunitinib (n=51) or everolimus (n=57), with a primary endpoint of PFS. The median PFS was longer in the patients treated with sunitinib than in those treated with everolimus (8.3 vs 5.6 months; hazard ratio, 1.41 [80% CI, 1.03-1.92]; P=.16). Sunitinib resulted in an improved median PFS for patients with good-risk disease (14.0 vs 5.7 months) and intermediate-risk disease (6.5 vs 4.9 months) by Memorial Sloan Kettering Cancer Center (MSKCC) score. However, patients with poor-risk disease had a longer median PFS with everolimus than with sunitinib (6.1 vs 4.0 months). Interestingly, outcomes in the subset of patients who had chromophobe histology were better in those who were treated with everolimus than in those who were treated with sunitinib, in terms of both response rate (33% vs 10%) and median PFS (11.4 vs 5.5 months). Despite an improved objective response rate (ORR) and PFS in the sunitinib arm, the difference in overall survival (OS) between the 2 treatment groups was not statistically significantly different, with a median OS of 13.2 months in the everolimus group and of 31.5 months in the sunitinib group (P=.60); this finding was likely related to the use of second-line therapies (approximately 64% of patients received subsequent therapy). These results parallel those of RECORD-3, in which the authors demonstrated that first-line sunitinib yielded a longer PFS compared with everolimus; however, the improvement in PFS did not translate into improvement in OS in either study, suggesting that second-line therapies may affect OS. In ASPEN, it is interesting that patients with chromophobe histology (n=16) had better ORR and PFS with everolimus (n=6) than with sunitinib (n=10). However, given the relatively small number of patients and the fact that MSKCC prognostic risk grouping was not provided in this small subset, we believe it is difficult to draw the conclusion that everolimus improved outcomes in comparison with sunitinib in this small subset.
Finally, the ESPN trial (Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non–Clear Cell Renal Cell Carcinoma), which allowed a crossover after disease progression with the first-line agent, sought to determine the relative efficacy of everolimus vs sunitinib in the first-line setting in nccRCC, with a primary endpoint of PFS in the first-line setting.34 A total of 68 patients were evaluable for treatment outcomes. The ORR in both groups was low (9% in the sunitinib arm and 3% in the everolimus arm). Although the median PFS was numerically longer in the sunitinib arm (6.1 vs 4.1 months), this difference was not statistically significant (P=.6). Similarly, the median OS was numerically longer in the sunitinib arm, but the difference was not statistically significant (16.2 vs 14.9 months; P=.18).
Prospective Single-Arm Studies
In addition to the 3 prospective randomized studies involving patients with nccRCC, 7 prospective, single-arm studies have been conducted in patients with nccRCC (summarized in Table 2). These include 3 studies with single-agent sunitinib,35-37 1 study with single-agent everolimus,38 1 study with the combination of everolimus and bevacizumab (Avastin, Genentech),39 and 2 studies with cytotoxic chemotherapy.40,41
The 3 single-arm studies assessing sunitinib included patients with a variety of nccRCC subtypes; papillary RCC was the histologic subtype most frequently studied. The ORR was approximately 5% in the trials of Molina and colleagues and Tannir and colleagues, whereas the ORR was 36% in the Korean phase 2 trial by Lee and colleagues.35-37 In the subset of 5 patients with chromophobe histology, Tannir and colleagues observed 2 partial responders and a median PFS of 12.7 months.36 Conversely, the median PFS in the subset of patients with papillary histology (n=27) was shorter than that of the group as a whole. This is consistent with the trial of Molina and colleagues, in which no objective responses were found in the patients with papillary RCC.35 The median PFS times in these 3 studies were 5.5, 2.7, and 6.4 months, suggesting that sunitinib has a modest clinical activity in metastatic nccRCC compared with its activity in ccRCC.
Koh and colleagues reported a modest clinical activity with everolimus, which yielded an ORR of 10.2% and a median PFS of 5.2 months.38 In the 8 patients with chromophobe histology, the ORR was 25%, and the PFS was longer than it was in patients with the other nccRCC subtypes (P=.084), with the caveat that these subgroups included very small numbers of patients.
In a study reported by Voss and colleagues of 35 patients with advanced nccRCC, the combination of everolimus plus bevacizumab produced an ORR of 29%, a median PFS of 11 months, and a median OS of 18.5 months.39 Interestingly, patients with either papillary histology or unclassified histology with papillary features (n=19) had improved clinical outcomes, with an ORR of 43%, a median PFS of 12.9 months, and a median OS of 28.2 months. In an exploratory genomic analysis, the authors identified that 5 (36%) of 14 patients with a major papillary component harbored somatic mutations in ARID1A, and all 5 patients derived treatment benefit. The caveat of cross-trial comparisons notwithstanding, the clinical activity of bevacizumab and everolimus in this cohort of patients with nccRCC was quite impressive, with improved ORR and PFS in comparison with other prospective trials. The improved outcome in the subset of patients with papillary RCC or unclassified RCC with papillary features is intriguing and warrants follow-up. Finally, the association of ARID1A mutations with clinical benefit also deserves further evaluation.
The 2 studies investigating cytotoxic chemotherapy in this setting were designed with single-agent capecitabine and a combination of pemetrexed (Alimta, Lilly) and gemcitabine.40,41 The primary endpoint in each study was ORR. In the first trial, a total of 51 patients received capecitabine, producing an ORR of 26%, a median PFS of 10.1 months, and a median OS of 18.3 months. The majority of patients had papillary histology (76%) and an MSKCC intermediate-risk prognosis (86%). Given the rather significant clinical activity, the authors proposed an additional prospective randomized trial comparing capecitabine with a control or placebo arm.40 In the second trial, however, in which 14 patients received a combination of pemetrexed and gemcitabine, no patients showed an objective response, and the median PFS was only 3.2 months.41 Owing to its relatively high level of toxicity and poor efficacy, the authors concluded that this regimen does not warrant further study.
In addition to the randomized and prospective studies previously discussed, multiple retrospective studies are assessing the efficacy of various agents in nccRCC, and most of these studies confirm the experience of the randomized and prospective studies.42-47 Here, we focus on the retrospective studies that are specific to nccRCC subtypes, for which randomized and prospective data
Papillary RCC. In addition to prospective studies that have grouped all patients with nccRCC together, there are multiple prospective studies that are specific to papillary RCC. These include evaluation of chemotherapy (combination of carboplatin and paclitaxel),48 dual c-MET/vascular endothelial growth factor receptor (VEGFR) inhibition (foretinib),49 epidermal growth factor receptor (EGFR) inhibition (erlotinib; Tarceva, Genentech/Astellas),50 sunitinib,51 and everolimus.52 Although none of the patients treated with chemotherapy showed an objective response, the rates of response to targeted agents varied between 11% and 13.5% (summarized in Table 3).
As discussed earlier, activating mutations or amplifications in MET provide the rationale for testing foretinib in this cohort. In the foretinib phase 2 trial, 2 different dosing regimens were used, and patients were stratified by the presence or absence of MET pathway activation. In total, 74 patients were enrolled, 37 patients in each dosing cohort. The ORR was 13.5% and the median PFS was 9.3 months. The ORR in patients with germline MET mutations was 50%, but it was only 9% in those with sporadic mutations, suggesting germline c-MET mutation as a possible biomarker.43 Trials with tyrosine kinase inhibitors (TKIs), such as cabozantinib (Cabometyx, Exelixis) and savolitinib, both of which target MET, are actively recruiting patients with papillary RCC.53
Ravaud and colleagues reported on the phase 2 trial activity of sunitinib in 15 patients with type 1 papillary RCC and 46 patients with type 2 papillary RCC.51 In patients with type 1 disease, the ORR was 13%, the median PFS was 6.6 months, and the median OS was 17.8 months. In patients with type 2 disease, the ORR was 11%, the median PFS was 5.5 months, and the median OS was 12.4 months. In the everolimus study by Escudier and colleagues, patients with type 1 papillary histology had a median PFS of 7.9 months and a median OS of 28.0 months. Those with papillary type 2 histology had a median PFS of 5.1 months and a median OS of 24.2 months.52
Collecting Duct Carcinoma. Because of its rarity, little information exists on the clinical efficacy of agents for patients with collecting duct carcinomas. Below, we review 2 prospective studies and 1 retrospective review. In 2007, Oudard and colleagues published a prospective phase 2 study of gemcitabine and platinum in patients with -metastatic collecting duct carcinoma.55 A total of 23 patients were treated. The ORR was 26%, the median PFS was 7.1 months, and the median OS was 10.5 months. In 2013, Pecuchet and colleagues published a case series involving 5 patients with metastatic collecting duct carcinoma treated with the combination of bevacizumab, gemcitabine, and a platinum agent.56 In this study, the ORR was 60%, the median PFS was 15.1 months, and the median OS was 27.8 months. The authors attributed the clinical benefit in these patients to the addition of bevacizumab to the gemcitabine/platinum combination. Zhao and colleagues published a case report and a review of the literature on patients with metastatic collecting duct carcinoma treated with various targeted agents.57 In the case report, the authors reported on 1 patient who had achieved a partial remission with sorafenib (Nexavar, Bayer). In their review of the literature, the authors identified 12 patients with metastatic collecting duct tumors who were treated with targeted agents (6 with sorafenib, 4 with sunitinib, and 2 with temsirolimus [Torisel, Pfizer]), and they concluded that 33% of these patients had derived clinical benefit from these therapies.
Chromophobe RCC. Owing to the rarity of this tumor subtype, there are no studies specifically dedicated to patients with chromophobe histology. In a retrospective review, Choueiri and colleagues described the experience of treating 12 patients with metastatic chromophobe RCC with anti-VEGF regimens. Of the 12 patients with chromophobe RCC, 3 (25%) exhibited a response (2 patients treated with sorafenib and 1 patient treated with sunitinib), and the median PFS was 10.6 months.42
Renal Medullary Carcinoma. There are no published prospective studies specifically dedicated to patients with medullary histology. In 2007, Hakimi and colleagues retrospectively described their experience with 9 patients who had metastatic medullary carcinoma.58 All 9 patients had sickle cell trait, and 8 patients had a right-sided mass. In this study, 7 of the 9 patients underwent radical nephrectomy with varying neoadjuvant therapies used. The OS ranged from 4 to 16 months, with only 2 patients alive at the last follow-up visit. Given the short OS in this cohort, the authors concluded that surgery alone is inadequate in the management of patients with renal medullary carcinoma.
In 2013, Maroja Silvino and colleagues described their experience in the treatment of 5 patients with medullary carcinoma from a referral center in Brazil.59 All 5 patients had sickle cell trait, 4 were male, and 3 had a diagnosis of metastatic disease. All 5 patients were treated with platinum-based chemotherapy, and 2 patients had a partial response with gemcitabine and cisplatin.
Recently, the outcomes of 52 patients with renal medullary carcinoma were reported through a multicenter collaborative study.60 The outcomes were poor, with a median OS of 13.0 months. However, subgroup analysis showed that the median OS was better in the patients who underwent nephrectomy than in those who did not (16.4 vs 7.0 months; P<.001). Of note, in the 28 patients who received targeted therapies, no objective responses were observed. Thus, the mainstay of systemic therapy is combination cytotoxic chemotherapy, but renal medullary carcinoma remains a very difficult disease to treat, with little evidence to guide treatment regimens.
Translocation RCC. There are no prospective studies specifically dedicated to patients with translocation RCC. In 2010, through the Juvenile RCC Network, a French group examined the clinical activity of anti-VEGF agents or mTOR inhibitors in 21 patients with translocation RCC.61 The ORR in this study was 33%, and the median OS of the entire cohort was 27 months. In patients who received sunitinib as first-line therapy (n=11), the median PFS was 8.2 months. A partial response occurred in 1 patient receiving an mTOR inhibitor, and 6 patients had stable disease. In 2010, Choueiri and colleagues performed a retrospective evaluation of the efficacy of anti-VEGF targeted therapy in a total of 15 US patients.62 In this cohort, 10, 3, and 2 patients received sunitinib, sorafenib, and monoclonal anti-VEGF antibodies, respectively. The ORR was 20%, and the median PFS and OS were 7.1 months and 14.3 months, respectively.
There is a paucity of data regarding the efficacy of immunotherapy in nccRCC. We review the interleukin 2 (IL-2) and anti–programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) experience below.
Interleukin 2. The US Food and Drug Administration approved high-dose IL-2 in 1992, on the basis of its ability to produce durable responses in a small percentage of patients with mRCC.63 In these early trials, high-dose IL-2 achieved an ORR of 14% in 255 patients; however, the vast majority of these patients had ccRCC, making it difficult to draw conclusions about patients with nccRCC. In a small retrospective study, Upton and colleagues reviewed outcomes of 10 patients with nccRCC and found no responders, with a median OS of less than 1 year.64 On the basis of these data and other expert investigator experience, patients with nccRCC are not considered good candidates for treatment with high-dose IL-2.
Programmed Death 1/Programmed Death Ligand 1. At present, no data from clinical studies on the efficacy of anti–PD-1 or anti–PD-L1 agents in patients with nccRCC are available. However, there is at least a rationale and an unmet need for these studies. Choueiri and colleagues assessed PD-L1 expression in 101 nccRCC tumors and found that 11% of the tumors were positive for PD-L1 by their cutoff.65 In a separate study, investigators at the Mayo Clinic assessed PD-L1 expression in 26 patients with sarcomatoid RCC and found PD-L1 expression in 50% of tumors; they also described 1 patient with sarcomatoid RCC who responded to anti–PD-1 therapy.66 Future studies will investigate the clinical efficacy of anti–PD-1/PD-L1; several ongoing trials are currently evaluating the immuno-oncologic agents nivolumab (Opdivo, Bristol-Myers Squibb), ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with nivolumab, pembrolizumab (Keytruda, Merck), and atezolizumab (Tecentriq, Genentech) in nccRCC.67
Clinical Summary and Future Perspectives
Owing to the development of many promising novel agents and adequately powered clinical trials, the treatment landscape of ccRCC is rapidly evolving and clinical outcomes are improving. Unfortunately, advances in the treatment landscape of metastatic nccRCC have been slow, mainly because the rarity of each subtype makes it difficult to test the efficacy of novel agents robustly in clinical studies. However, we now have cumulative data about the limited utility of the anti-VEGF agents and mTOR inhibitors in nccRCC, allowing us at least to provide patients with adequate information and expectations. Insights into genomics and epigenetics, and advances in immunology and immunotherapy, allow us to be optimistic that therapeutic gains will be made in the near future against these variant RCC subtypes.
Dr Malouf has done consulting for Bristol-Myers Squibb, Pfizer, and Roche, and has received research grants from Roche and Pfizer. Dr Joseph has received research funding from Bristol-Myers Squibb, Merck, X4 Pharmaceuticals, Roche, and Syndax, and has consulted or served on the advisory board for Bristol-Myers Squibb, Merck, Exelixis, and Novartis. Dr Shah has no disclosures. Dr Tannir has received honoraria from or done consulting for Bristol-Myers Squibb, Exelixis, Nektar, Novartis, Pfizer, Argos, and Calithera, and has received research funding from Bristol-Myers Squibb, Exelixis, Epizyme, Novartis, and Miranti.
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