The treatment of advanced non-clear cell renal carcinoma

INTRODUCTION — Although many advances have been made in the treatment of metastatic non-clear cell renal cell carcinoma (RCC), there are limited high-quality data to help inform management due to the infrequency of these tumors.

Non-clear cell RCCs (or RCCs of variant histology) are characterized by morphology, growth pattern, cell of origin, and where they are known, the histochemical and biologic bases that underlie the different types of tumors.

The most common subtypes of non-clear cell RCC include the following [1]:

●Papillary

●Chromophobe

●Collecting duct (including medullary carcinoma)

●Translocation carcinomas

●Unclassified RCC

Sarcomatoid RCC is not considered a distinct subtype because sarcomatoid features can be seen in any histologic subtype of RCC.

The kidney can also give rise to other types of malignancies, including non-Hodgkin lymphoma, soft tissue sarcomas (eg, leiomyosarcoma, liposarcoma), and carcinoid tumors; their treatment is based on the tumor type rather than their origination from the kidney. The diagnosis and treatment of these cancers are discussed separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma" and "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)

This topic will discuss the management of non-clear cell RCC. The epidemiology, pathology, and pathogenesis of these tumors are discussed separately, as is the treatment of clear cell and sarcomatoid RCC.

●(See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma".)

●(See "Overview of the treatment of renal cell carcinoma".)

●(See "Renal cell carcinoma with sarcomatoid features" and "Systemic therapy of advanced clear cell renal carcinoma".)

●(See "Renal cell carcinoma with sarcomatoid features" and "Systemic therapy of advanced clear cell renal carcinoma".)

GOALS OF THERAPY

●Localized disease – The general approach to treatment of localized (stage I to III (table 1)) non-clear cell renal cell carcinoma (RCC) is similar to that of clear cell RCC. Surgical resection offers the best chance of cure, although some small renal masses can be observed or ablated. More extensive discussions on the treatment of localized RCC are covered separately. (See "Overview of the treatment of renal cell carcinoma", section on 'Localized renal cell carcinoma' and "Definitive surgical management of renal cell carcinoma" and "Diagnostic approach, differential diagnosis, and management of a small renal mass".)

●Advanced or metastatic disease – Historically, treatment of patients with advanced, unresectable, or metastatic non-clear cell RCC has been palliative; however, prognosis and treatment of these patients are evolving in the era of checkpoint inhibitor immunotherapy, and some of these patients may have durable responses. As an example, for patients with certain histologic subtypes (ie, sarcomatoid features), immunotherapy significantly improves survival and complete response rates, suggesting the potential for cure. (See 'Non-clear cell RCC with sarcomatoid features' below.)

AVAILABLE AGENTS — Systemic therapy is usually given either as monotherapy or as combinations of agents from the following classes:

●Programmed cell death protein 1 (PD-1) checkpoint inhibitors (nivolumab and pembrolizumab)

●Programmed cell death ligand 1 (PD-L1) checkpoint inhibitors (atezolizumab)

●Anticytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibodies (ipilimumab)

●Inhibitors of the vascular endothelial growth factor (VEGF) pathway, or antiangiogenic therapy (sunitinib, cabozantinib, axitinib, lenvatinib, bevacizumab)

●Mammalian target of rapamycin (mTOR) inhibitors (everolimus and temsirolimus)

●Chemotherapy (platinum-based regimens)

Interleukin-2 (IL-2) does not have an established treatment role in those with non-clear cell renal cell carcinoma (RCC) due to limited efficacy [2-5].

The specific treatment approach for patients with non-clear cell RCC is based on histologic subtype and is discussed in further detail below:

●Papillary RCC (see 'Papillary renal cell carcinoma' below)

●Chromophobe RCC (see 'Chromophobe renal cell carcinoma' below)

●Collecting duct and renal medullary carcinoma (see 'Collecting duct and renal medullary carcinoma' below)

●Translocation RCC (see 'Translocation renal cell carcinoma' below)

●Unclassified RCC (see 'Unclassified renal cell carcinoma' below)

●RCC (clear cell and non-clear cell) with sarcomatoid features (see "Renal cell carcinoma with sarcomatoid features")

PAPILLARY RENAL CELL CARCINOMA — Tumors with papillary renal cell carcinoma (RCC) have unique histopathology, molecular alterations, and clinical presentation. These characteristics may influence treatment response to particular systemic agents, such as immunotherapy or other targeted therapies. Historically, patients with papillary RCC have been classified as type I or type II mostly based on cytopathologic findings [6-11]. We also classify papillary RCCs as MET-driven versus independent, based on molecular alterations in the MET gene and inclusion criteria from clinical trials [12,13].

Further details on the pathology of papillary renal cell tumors are discussed separately. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Papillary carcinomas' and "Hereditary kidney cancer syndromes".)

Approach to therapy — Our approach to treatment is as follows:

●For patients with treatment-naïve advanced or metastatic papillary RCC, we suggest either checkpoint inhibitor immunotherapy-based regimens or a vascular endothelial growth factor receptor (VEGFR) inhibitor as initial therapy. Both agents are reasonable options as these approaches have not been directly compared in a clinical trial in this population. A choice is based on patient comorbidities, disease risk stratification, and patient preferences. While many patients will be treated with immunotherapy, it is generally not used in patients with a poor performance status, poorly controlled autoimmune disease, or those who prefer oral therapies; such patients may be candidates for a VEGFR inhibitor.

•For those who choose immunotherapy, we suggest nivolumab plus ipilimumab rather than other immunotherapy-based regimens. extrapolating from the approach used for those with clear cell RCC. Other options include lenvatinib plus pembrolizumab, cabozantinib plus nivolumab, and single-agent pembrolizumab (table 2). (See 'Preferred immunotherapy regimens' below.)

•For those who choose targeted antiangiogenic therapy with VEGFR inhibitors or are ineligible for immunotherapy, we suggest cabozantinib rather than other VEGFR inhibitors. Sunitinib is a reasonable alternative for those who decline cabozantinib, as no overall survival benefit has been demonstrated for cabozantinib over sunitinib. For those with International Metastatic RCC Database Consortium (IMDC) poor-risk disease (table 3), alternative, but less preferred, agents include everolimus or temsirolimus (table 4). (See 'Targeted agents' below and "Systemic therapy of advanced clear cell renal carcinoma", section on 'Risk stratification'.)

•Bevacizumab plus erlotinib is preferred therapy for patients with papillary RCC due to hereditary leiomyomatosis eligible for antiangiogenic therapy. (See "Hereditary kidney cancer syndromes", section on 'Hereditary leiomyomatosis and renal cell cancer syndrome'.)

•A MET-inhibitor based approach to MET-driven papillary tumors is evolving. (See 'Experimental agents (MET inhibitors)' below.)

●Our approach to subsequent therapy depends on initial treatment:

•For patients who have progressed on initial immunotherapy-based regimens, we offer targeted antiangiogenic therapy not previously received. (See 'Targeted agents' below.)

•For those who have progressed on targeted antiangiogenic therapy without prior exposure to immunotherapy, we offer an immunotherapy-based regimen. The approach is similar to those who receive immunotherapy as initial treatment. (See 'Nivolumab plus ipilimumab' below.)

Preferred immunotherapy regimens

Nivolumab plus ipilimumab — For those with papillary renal carcinoma who choose immunotherapy as initial treatment, we offer the combination of nivolumab plus ipilimumab. This approach is extrapolated from a phase III trial (CheckMate 214) in those with clear cell RCC, where this combination conferred an overall survival benefit, high rates of complete response, and prolonged treatment-free survival [14,15]. Further randomized studies are needed to compare immunotherapy with VEGFR inhibitors in those with non-clear cell RCC to establish the optimal initial treatment approach, and patients should be encouraged to enroll in clinical trials whenever possible. Further details on the use of nivolumab plus ipilimumab in those with clear cell carcinoma are discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Nivolumab plus ipilimumab'.)

Data for nivolumab plus ipilimumab in those with papillary RCC are limited to observational studies conducted in heterogeneous populations of non-clear cell RCC [16-18]. In a phase IIIb/IV prospective study (CheckMate 920), 52 patients with non-clear cell RCC were treated with nivolumab plus ipilimumab. Among the 18 patients with papillary histology, objective responses were seen in five patients (28 percent) [19].

Lenvatinib plus pembrolizumab — The combination of lenvatinib plus pembrolizumab is effective initial therapy in patients with advanced papillary RCC. In a single-arm, international phase II trial (KEYNOTE-B61), 158 patients with systemic therapy-naïve advanced non-clear cell RCC of varying histologies were treated with lenvatinib plus pembrolizumab [20]. At median follow-up of 15 months, among the subgroup of 93 patients with papillary histology, objective responses were seen in 50 patients (54 percent), including eight complete responses (9 percent), and one-year PFS was 67 percent.

Cabozantinib plus nivolumab — The combination of nivolumab and cabozantinib is clinically effective in patients with papillary RCC. As an example, a single-arm phase II trial evaluated nivolumab plus cabozantinib in 47 patients with non-clear cell RCC of varying histologies [21]. At median follow-up of 13 months, among the subgroup of 32 patients with papillary RCC, objective responses were observed in 15 patients (47 percent). Additionally, objective responses were seen in all five patients with fumarate hydratase (FH)-deficient RCC.

Pembrolizumab — Single-agent pembrolizumab (table 2) is active in papillary RCC, as survival and response rates are higher than those previously reported with antiangiogenic agents or chemotherapy [22-24].

The efficacy of pembrolizumab (table 2) in papillary RCC was demonstrated in an open-label, nonrandomized phase II trial (KEYNOTE-427, Cohort B) [24]. In this study of 165 patients with non-clear cell histologies, of which 118 tumors (72 percent) were papillary subtype, pembrolizumab was administered at 200 mg intravenous (IV) every three weeks for up to two years, or until disease progression or toxicity. At median follow-up of approximately 11 months, objective response rates were 29 percent for those with papillary RCC, 24 percent for those with intermediate/poor-risk disease of any subtype, and 35 percent for those with a positive combined positive score (CPS) of any subtype. Among responders, the median duration of response was 29 months, and a majority (57 percent) had durable responses at 18-month follow-up. In the entire study population, estimated two-year overall survival and progression-free survival (PFS) rates were 58 and 19 percent, respectively. Grade ≥3 toxicity occurred in 17 percent of patients.

Less preferred immunotherapy regimens

Nivolumab — We do not offer single-agent nivolumab for the treatment of papillary RCC due to limited efficacy with this agent and better activity noted with other immunotherapy-based regimens. Data from observational studies [17,22,25] initially suggested response rates between 14 and 30 percent. However, in a phase II clinical trial (HCRN GU16-260, Cohort B), among the subgroup of 19 patients with papillary RCC, objective responses were only seen in one patient (5 percent) [26].

Targeted agents — Targeted therapies, such as antiangiogenic agents (VEGFR inhibitors) and mammalian target of rapamycin (mTOR) inhibitors have also demonstrated efficacy in papillary RCC. The choice of regimen depends on disease context, as follows:

●For most patients who choose VEGFR inhibitors or who are ineligible for immunotherapy, we suggest cabozantinib rather than other VEGFR inhibitors, as this approach improved PFS compared with sunitinib in a randomized trial (PAPMET). For those who decline cabozantinib, sunitinib is a reasonable alternative, as an overall survival benefit was not demonstrated for cabozantinib over sunitinib in PAPMET. In addition, the efficacy of sunitinib over the mTOR inhibitor everolimus has been established in randomized clinical trials. (See 'Sunitinib' below and 'Cabozantinib' below.)

Alternative, but less preferred, agents for those with poor-risk disease (table 3) include mTOR inhibitors such as everolimus or temsirolimus (table 4). (See 'Mammalian target of rapamycin inhibitors (everolimus and temsirolimus)' below.)

●For those with papillary RCC due to hereditary leiomyomatosis eligible for antiangiogenic therapy, we offer bevacizumab plus erlotinib. This preference is based on the results of a nonrandomized trial that demonstrated high response rates in this population. There are limited data regarding other inhibitors of the VEGF pathway in this rare subgroup. (See 'Bevacizumab with or without erlotinib' below.)

Vascular endothelial growth factor inhibitors

Cabozantinib — In patients with treatment-naïve advanced papillary RCC, cabozantinib improved PFS and objective response rates compared with sunitinib in a randomized trial.

Based on initial observational data that suggested clinical efficacy with cabozantinib [27-29], a randomized, open-label phase II trial (SWOG 1500; PAPMET) was conducted in 152 patients with papillary RCC [30]. A majority of patients had treatment-naïve disease (93 percent), IMDC intermediate- or poor-risk disease (table 3) (75 percent), and either type I and type II histology (approximately 18 and 54 percent, respectively). Patients were randomly assigned to receive either cabozantinib, sunitinib, crizotinib, or savolitinib.

Compared with sunitinib, cabozantinib improved PFS (median nine versus six months, HR 0.60, 95% CI 0.37-0.97) and objective response rates (23 versus 4 percent), which included two complete responses (5 percent). Cabozantinib also demonstrated a nonstatistically significant trend towards higher overall survival compared with sunitinib, which would be clinically meaningful if true (median 20 versus 16 months, HR 0.84, 95% CI 0.47-1.51). Clinical PFS benefit for cabozantinib was seen for patients with both type I and type II histologies, regardless of classification based on local or central pathologic assessment. Grade ≥3 treatment-related toxicities were similar between cabozantinib and sunitinib (74 versus 69 percent), and no new toxicity signals were identified.

Of note, neither of the MET inhibitors, crizotinib or savolitinib, improved PFS compared with sunitinib, and the treatment arms for these agents were closed to accrual after a prespecified futility analysis.

The use of cabozantinib in clear cell histologies is discussed separately. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Cabozantinib'.)

Sunitinib — Sunitinib is an effective initial therapy that improves survival and response rates in patients with papillary renal cell carcinoma, based on several phase II randomized trials directly comparing this agent with the mTOR inhibitor everolimus [31-35].

●In a phase II trial (ASPEN), 108 previously untreated patients were randomly assigned to either sunitinib or everolimus [32]. Two-thirds of the study population had papillary carcinoma; other patients had chromophobe, translocation, unclassified, and clear cell RCC with sarcomatoid histologies. At a median follow-up of 13 months, relative to everolimus, sunitinib improved PFS in the total study population (median PFS 8.3 versus 5.6 months, two-year PFS 23 versus 9 percent, hazard ratio [HR] 1.41, 80% CI 1.03-1.92) and had higher objective response rates (18 versus 9 percent). While the difference in overall survival was not statistically significant, it would be clinically meaningful if true (median overall survival 32 versus 13 months, HR 1.12, 95% CI 0.7-2.1).

●In a separate phase II trial (ESPN), 73 patients with metastatic non-clear cell RCC were randomly assigned to sunitinib or everolimus, with crossover to the alternate agent at disease progression [33]. At a median follow-up of approximately two years, overall survival was similar between the two treatment arms (median overall survival 16.2 versus 14.9 months). Objective responses were seen in 9 percent (3 of 33 patients) initially treated with sunitinib and in 3 percent (1 of 35 patients) initially treated with everolimus. Following crossover, four additional partial responses were observed for each agent.

Bevacizumab with or without erlotinib — There are limited data for the efficacy of bevacizumab alone or in combination with erlotinib in those with sporadic papillary RCC. One study attempted to evaluate bevacizumab in a phase II trial of patients with metastatic papillary RCC, but it was closed due to poor patient accrual [36].

However, the combination of bevacizumab plus erlotinib has substantial efficacy and is the preferred initial systemic therapy in those with papillary RCC due to hereditary leiomyomatosis. These data are discussed separately. (See "Hereditary kidney cancer syndromes", section on 'Hereditary leiomyomatosis and renal cell cancer syndrome'.)

Less preferred antiangiogenic agents — Observational studies and early phase II trials have suggested modest efficacy for the VEGFR inhibitors pazopanib and axitinib [37-40]. While some experts may reasonably offer these agents, we do not prefer pazopanib or axitinib as initial therapy in those with papillary RCC, given the stronger evidence for other antiangiogenic agents. (See 'Targeted agents' above.)

Mammalian target of rapamycin inhibitors (everolimus and temsirolimus) — Data suggest that mTOR inhibitors, such as everolimus and temsirolimus, may be effective in patients with poor-risk non-clear cell RCC. However, these agents are becoming less preferred given the demonstrated efficacy of immunotherapy in patients with intermediate- and poor-risk disease. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Intermediate- and poor-risk disease'.)

●In a single-arm open-label phase II trial (RAPTOR) of 88 patients with treatment-naïve papillary RCC treated with everolimus, the stable disease rate was 65 percent; median PFS and overall survival were approximately 4 and 21 months, respectively [41].

●In a phase III trial (ARCC) of 626 patients with advanced RCC randomly assigned to temsirolimus or interferon alfa, temsirolimus improved overall survival (median overall survival 12 versus 4 months) among the subset of 124 patients (20 percent) with predominantly papillary histology [42,43].

Experimental agents (MET inhibitors) — Although agents that inhibit the c-MET pathway have activity against papillary RCC, data are limited, and this approach remains experimental.

●Crizotinib – Crizotinib was evaluated in 23 patients with type I papillary RCC in a phase II study (CREATE) [44]. In the four patients with a MET alteration, two achieved a partial response, with durations of approximately two and three years, respectively.

●Foretinib – In a phase II trial of the investigational MET inhibitor foretinib that included 74 patients with papillary RCC, the objective response rate was 13.5 percent, and the median PFS was nine months [45]. The overall survival rate was 70 percent at one year.

●Savolitinib – In a randomized phase III trial (SAVOIR) of 60 patients with MET-driven papillary RCC, compared with sunitinib, the selective MET inhibitor savolitinib improved overall response rates (27 versus 7 percent) and had a better toxicity profile [12]. However, the study, which was prematurely terminated, did not detect a statistical difference in progression-free or overall survival between the two treatment arms.

In a single-arm phase II trial (CALYPSO) of 41 patients with advanced papillary RCC, the combination of savolitinib with the PD-L1 inhibitor durvalumab demonstrated a confirmed response rate of 29 percent, which failed to meet the primary endpoint (confirmed response rate of 50 percent or greater) [46]. However, in the subgroup with MET-driven papillary RCC, the confirmed response rate for the combination was 53 percent.

LESS COMMON SUBTYPES

Chromophobe renal cell carcinoma — For those with chromophobe tumors, we offer initial treatment with targeted agents such as mammalian target of rapamycin (mTOR) inhibitors (eg, everolimus) or vascular endothelial growth factor receptor (VEGFR) inhibitors (eg, sunitinib). Limited data also show some efficacy for bevacizumab plus erlotinib in these tumors [47]. Alternative options include combination therapy such as lenvatinib plus pembrolizumab or lenvatinib and everolimus.

●Everolimus – Some patients with chromophobe tumors have genetic alterations that lead to upregulation of the mTOR pathway, such as mutations on chromosome 17 leading to loss of the folliculin gene (ie, Birt-Hogg-Dubé syndrome). (See "Birt-Hogg-Dubé syndrome", section on 'Kidney tumors'.)

Inhibition of this pathway with agents such as everolimus represents a logical therapeutic approach in these tumors [48]. Further details on molecular alterations found in chromophobe tumors are discussed separately. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Chromophobe carcinomas'.)

The randomized phase II trial (ASPEN) comparing sunitinib with everolimus in 108 patients with non-clear cell renal cell carcinoma (RCC) included a subset of 16 patients (15 percent) with chromophobe histology [32]. In this subset, everolimus improved overall response rates relative to sunitinib (33 versus 10 percent). Median progression-free survival (PFS) for everolimus was longer relative to sunitinib (12 versus 6 months); this result was not statistically significant, likely due to the small number of patients, but it would be clinically meaningful if true.

The use of everolimus in other RCC subtypes is discussed separately. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Everolimus'.)

●Vascular endothelial growth factor inhibitors – Limited data suggest that VEGFR inhibitors have activity in patients with chromophobe RCC [32,33,49,50]. A single-arm, open-label, phase II trial evaluated sunitinib in 57 patients with non-clear clear cell histologies [49]. In this subset of five patients (9 percent) with chromophobe histologies, there were two partial responses (40 percent), and the median PFS was approximately 13 months.

●Lenvatinib plus pembrolizumab – The combination of lenvatinib plus pembrolizumab is effective initial therapy in patients with advanced chromophobe RCC. This combination was evaluated in a single-arm phase II trial (KEYNOTE-B61) of 158 patients with systemic-therapy naïve advanced non-clear cell RCC of varying histology. At median follow-up of 15 months, among the subgroup of 29 patients with chromophobe histology, objective responses were seen in eight patients (28 percent), and one-year PFS was 53 percent.

●Lenvatinib plus everolimus – Lenvatinib plus everolimus is an option in patients with chromophobe RCC either as initial therapy or subsequent therapy after progression on a VEGFR inhibitor, as this combination inhibits both the VEGF and mTOR pathway [51]. In a single-arm phase II trial of 31 patients with treatment-naïve non-clear cell RCC treated with lenvatinib plus everolimus, objective responses were seen in four out of nine patients with chromophobe RCC (44 percent) [52].

We also offer this approach extrapolating from randomized trials conducted in those with clear cell histologies, which conferred a PFS benefit compared with either sunitinib or everolimus alone. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Lenvatinib plus everolimus' and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Lenvatinib plus everolimus'.)

●Bevacizumab plus everolimus – Bevacizumab plus everolimus has also shown efficacy in those with chromophobe tumors. In a phase II trial of 35 patients with non-clear cell carcinoma, five had chromophobe tumors [47]. An objective response rate of 29 percent was seen in the total study population, with responses seen in two of five patients with chromophobe tumors (40 percent). Median PFS and overall survival were 11 and 19 months for the total study population.

●Other regimens – Other regimens have demonstrated limited efficacy in chromophobe RCC. As examples:

•Nivolumab plus cabozantinib – In one phase II trial of 47 patients with advanced non-clear cell RCC treated with nivolumab plus cabozantinib, no objective responses were noted among the subset of seven patients with chromophobe RCC [21].

•Bevacizumab plus atezolizumab – In another phase II trial of 60 patients with metastatic RCC with variant histology and/or sarcomatoid features treated with bevacizumab plus atezolizumab, objective responses were seen in one of ten patients (10 percent) with chromophobe RCC [53].

Collecting duct and renal medullary carcinoma — For those with collecting duct RCC or renal medullary carcinoma, we suggest cytotoxic chemotherapy as initial therapy rather than VEGFR inhibitors. Options for combinations of platinum-based chemotherapy include cisplatin plus gemcitabine; carboplatin plus gemcitabine; and carboplatin plus paclitaxel. There are limited data regarding immunotherapy with checkpoint inhibitors, and these agents remain investigational. The initial treatment approach for these histologies is similar to that of metastatic urothelial carcinoma, which is discussed separately. Patients are encouraged to enroll on clinical trials where available. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Initial therapy'.)

●Collecting duct renal cell carcinoma – Collecting duct RCC is an aggressive tumor that has similar biologic features to urothelial carcinoma. Unlike other types of non-clear cell histologies, collecting duct RCCs respond to cytotoxic chemotherapy using platinum-based chemotherapy [54-59]. There are limited clinical trial data evaluating treatment options in this rare tumor, and further studies are needed. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Collecting duct tumors'.)

In an open-label phase II trial of 23 patients with collecting duct RCC treated with gemcitabine plus cisplatin, objective responses were seen in six patients (26 percent), and median overall survival was approximately 11 months [54].

●Renal medullary carcinoma – Renal medullary carcinoma is an aggressive variant of collecting duct tumors predominantly found in those with sickle cell trait. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'SMARCB1-deficient renal cell carcinoma and renal medullary carcinoma' and "Sickle cell disease effects on the kidney", section on 'Renal medullary carcinoma' and "Overview of the clinical manifestations of sickle cell disease", section on 'Kidney complications'.)

Data for effective treatment options are limited to observational studies. Platinum-based chemotherapy is typically administered as initial therapy in a majority of patients, with a wide range of reported activity [60-64]. As an example, in one case series of 52 patients with renal medullary carcinoma, 85 percent (45 patients) were treated with platinum-based chemotherapy, with response rates of approximately 30 percent [64]. Two-year overall survival for the entire study population was 13 percent.

Other chemotherapy agents (eg, anthracyclines), immunomodulatory therapy (eg, bortezomib), and VEGFR inhibitors (eg, sunitinib) all have limited activity in this disease [63,65-67].

Translocation renal cell carcinoma — For those with translocation RCC, we suggest initial therapy with lenvatinib plus pembrolizumab rather than a VEGFR inhibitor, based on high objective response rates with this regimen. For patients who decline or are ineligible for decline immunotherapy, a single-agent VEGFR inhibitor (eg, sunitinib) is a reasonable alternative. Due to the rarity of translocation RCC, clinical trials are encouraged where available.

Translocation RCCs are a rare variant of non-clear cell carcinomas characterized by TFE3 gene fusions, leading to activation of microphthalmia-associated transcription factor (MITF). (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Translocation renal cell carcinoma (MiT/TFE-related RCC)'.)

There are limited data on the optimal initial therapy for advanced translocation RCC, due to the rarity of this disease. In a phase II trial, lenvatinib plus pembrolizumab demonstrated an objective response rate of 67 percent. However, lenvatinib plus pembrolizumab has not been directly compared with single-agent VEGFR inhibitors in randomized trials with this population.

●Lenvatinib plus pembrolizumab – In a single-arm, international phase II trial (KEYNOTE-B61), 158 patients with systemic therapy-naïve advanced non-clear cell RCC of varying histologies were treated with pembrolizumab plus lenvatinib [20]. At median follow-up of 15 months, among the subgroup of six patients with papillary histology, objective responses were seen in four patients (67 percent), all of which were partial responses.

●Sunitinib – Observational studies support the initial use of sunitinib in translocation RCC [68,69]. As an example, in an nonrandomized study of approximately 50 patients less than 45 years old with Xp11.2 translocation carcinomas, partial responses were seen in 3 of 11 patients (27 percent) treated with sunitinib versus one of nine patients (11 percent) treated with cytokine therapy (interferon alfa or interleukin 2) [69]. Additionally, the study demonstrated longer PFS in those treated with sunitinib relative to cytokine therapy (median PFS eight versus two months).

Unclassified renal cell carcinoma — For patients with unclassified RCC, we suggest initial treatment with immunotherapy-based regimens rather than VEGFR inhibitors due to high objective response rates with this approach. Options include combination therapy (nivolumab plus ipilimumab; lenvatinib plus pembrolizumab) or single-agent immunotherapy (pembrolizumab (table 2) or nivolumab (table 5)). Any of these options are appropriate, as there are limited data directly comparing these regimens. (See 'Immunotherapy regimens' below.)

For patients who are ineligible for or decline immunotherapy, VEGFR inhibitors are a reasonable alternative, either as single-agents (eg, sunitinib or cabozantinib) or combination therapy (lenvatinib plus everolimus). (See 'Vascular endothelial growth factor receptor inhibitors' below.)

Immunotherapy regimens — In prospective clinical trials of patients with unclassified RCC, objective responses are as high as 52 percent for combination therapy and 30 percent for single-agent immunotherapy. Data are as follows:

●Nivolumab plus ipilimumab – Some contributors offer nivolumab plus ipilimumab in those with treatment-naïve unclassified renal cell carcinomas. Observational data suggest activity of nivolumab either with or without ipilimumab in those with unclassified renal cell carcinoma, with reported objective response rates between 20 and 44 percent [17,19].

Additionally, this approach is extrapolated from a phase III trial (CheckMate 214) in those with advanced or metastatic clear cell RCC, where nivolumab plus ipilimumab conferred an overall survival benefit over sunitinib, high rates of complete response, and prolonged treatment-free survival [14,15]. Further details on the activity of nivolumab plus ipilimumab in those with clear cell carcinoma are discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Nivolumab plus ipilimumab'.)

●Lenvatinib plus pembrolizumab – The combination of lenvatinib plus pembrolizumab is effective initial therapy in patients with advanced unclassified RCC. In a single-arm, international phase II trial (KEYNOTE-B61), 158 patients with systemic therapy-naïve advanced non-clear cell RCC of varying histologies were treated with pembrolizumab plus lenvatinib [20]. At median follow-up of 15 months, among the subgroup of 21 patients with unclassified RCC, objective responses were seen in 11 patients (52 percent), all of which were partial responses.

●Pembrolizumab – In an open-label phase II trial (KEYNOTE-427, Cohort B), 165 patients with non-clear cell RCC were treated with pembrolizumab as initial therapy [24]. In the subset of 26 patients with unclassified RCC, objective responses were seen in eight patients (31 percent), and a majority had durable responses. Median PFS and overall survival were 3 and 18 months, respectively.

●Nivolumab – Nivolumab is effective in patients with unclassified RCC. In a phase II trial (HCRN GU16-260, Cohort B), 35 patients with advanced non-clear cell RCC were treated with single-agent nivolumab. Among the subgroup of 10 patients with unclassified RCC, objective responses were seen in three patients (30 percent) [26].

Vascular endothelial growth factor receptor inhibitors — Sunitinib and cabozantinib as single agents also have efficacy in patients with treatment-naïve unclassified RCC.

●Sunitinib – In two randomized trials, sunitinib improved PFS approximately twofold relative to everolimus [32,33]. In the ASPEN study, which included 22 patients with unclassified RCC, sunitinib had a median PFS of 12 versus 6 months with everolimus [32]. Similarly, in the ESPN study, which included 10 patients with unclassified RCC, sunitinib had a median PFS of nine versus five months with everolimus [33].

●Cabozantinib – A retrospective study of cabozantinib in 112 patients with non-clear cell histologies included 15 patients with unclassified RCC [29]. In this subset, objective responses were seen in two patients (13 percent), and 12-month overall survival was 36 percent.

●Other regimens – Other combinations containing VEGFR inhibitors and the mTOR inhibitor everolimus have also shown activity in unclassified RCC.

•Lenvatinib plus everolimus – In a phase II trial of 31 patients with non-clear cell RCC treated with the combination of lenvatinib plus everolimus, partial responses were seen in one of two patients with unclassified RCC [52].

•Bevacizumab plus everolimus – The combination of bevacizumab plus everolimus is an option for patients who are unable to receive lenvatinib plus everolimus. This combination was evaluated in a phase II trial that included a subset of 23 patients with unclassified RCC containing papillary features. Among these patients, the objective response rate was 43 percent and median PFS was 14 months [70].

NON-CLEAR CELL RCC WITH SARCOMATOID FEATURES — Renal cell carcinoma (RCC) with sarcomatoid differentiation occurs mainly in clear cell histologies but can also be seen in non-clear cell histologies. Patients with advanced or metastatic sarcomatoid RCC typically demonstrate clinical responses to checkpoint inhibitor immunotherapy-based regimens. Further details on the management of non-clear cell RCC with sarcomatoid features are discussed separately. (See "Renal cell carcinoma with sarcomatoid features", section on 'Initial therapy (non-clear cell RCC with sarcomatoid features)'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer of the kidney and ureters".)

SUMMARY AND RECOMMENDATIONS

●Histologic subtypes of non-clear cell renal carcinoma – The main subtypes of non-clear cell renal cell carcinoma (RCC) include papillary, chromophobe, collecting duct, unclassified, and translocation carcinomas. Sarcomatoid RCC is not considered a distinct subtype, primarily because sarcomatoid features can be seen in any histologic subtype of RCC. (See 'Introduction' above.)

●Treatment approach – The specific treatment approach to patients with advanced-stage non-clear cell RCC is based on histologic subtype. Although many advances have been made in the treatment of non-clear cell RCC, there are limited high-quality data to help inform management due to the infrequency of these tumors. Patients should be enrolled in a clinical trial whenever possible. (See 'Available agents' above.)

●Papillary renal cell carcinoma – For patients with advanced papillary RCC, some contributors offer checkpoint inhibitor immunotherapy-based therapy, while others offer a vascular endothelial growth factor (VEGFR) inhibitor as initial therapy. Recognizing that there are limited data directly comparing these approaches, we feel either option is appropriate. (See 'Papillary renal cell carcinoma' above and 'Approach to therapy' above.)

•For those who choose immunotherapy, we suggest nivolumab plus ipilimumab rather than other immunotherapy-based regimens (Grade 2C), extrapolating from the approach used for those with clear cell RCC where this combination conferred an overall survival benefit over sunitinib, high rates of complete response, and prolonged treatment-free survival. Other options include lenvatinib plus pembrolizumab, cabozantinib plus nivolumab, or single-agent pembrolizumab (table 2). (See 'Preferred immunotherapy regimens' above.)

•For those who choose targeted antiangiogenic therapy or are ineligible for immunotherapy, we suggest initial therapy with cabozantinib rather than other VEGFR inhibitors (Grade 2C). (See 'Targeted agents' above and "Systemic therapy of advanced clear cell renal carcinoma", section on 'Risk stratification'.)

•Bevacizumab plus erlotinib is the preferred therapy for patients with papillary RCC due to hereditary leiomyomatosis eligible for antiangiogenic therapy. (See "Hereditary kidney cancer syndromes", section on 'Hereditary leiomyomatosis and renal cell cancer syndrome'.)

●Chromophobe renal cell carcinoma – For patients with advanced or metastatic chromophobe RCC, available evidence is limited due to the rarity of these tumors. We offer initial treatment with targeted therapy such as a mammalian target of rapamycin (mTOR) inhibitor (eg, everolimus) or a VEGFR inhibitor (eg, sunitinib). Alternative options include combination therapy such as lenvatinib plus pembrolizumab or lenvatinib plus everolimus. (See 'Chromophobe renal cell carcinoma' above.)

●Collecting duct and renal medullary carcinoma – For patients with advanced or metastatic collecting duct or renal medullary carcinoma, we suggest cytotoxic chemotherapy as initial therapy rather than VEGFR inhibitors (Grade 2C). Options for combinations of platinum-based chemotherapy include cisplatin plus gemcitabine; carboplatin plus gemcitabine; and carboplatin plus paclitaxel. (See 'Collecting duct and renal medullary carcinoma' above.)

●Translocation renal cell carcinoma – For patients with advanced or metastatic translocation RCC, we suggest lenvatinib plus pembrolizumab rather than a single-agent VEGFR inhibitor (Grade 2C), due to high objective response rates with this regimen. For patients who decline or are ineligible for immunotherapy, a single-agent VEGFR inhibitor (eg, sunitinib) is a reasonable alternative. (See 'Translocation renal cell carcinoma' above.)

●Unclassified renal cell carcinoma – For patients with advanced or metastatic unclassified RCC, we suggest initial therapy with immunotherapy-based regimens rather than VEGFR inhibitors (Grade 2C), due to high objective response rates with this approach. Options include combination therapy (nivolumab plus ipilimumab; lenvatinib plus pembrolizumab) or single-agent immunotherapy (pembrolizumab (table 2) or nivolumab (table 5)). Recognizing that there are limited data directly comparing these regimens, we feel any of these options are appropriate. (See 'Unclassified renal cell carcinoma' above.)

For patients who decline or are ineligible for immunotherapy, VEGFR inhibitors are a reasonable alternative, either as single agents (eg, sunitinib or cabozantinib), or as combination therapy (eg, lenvatinib plus everolimus).

●Non-clear cell renal carcinoma with sarcomatoid features – For patients with treatment-naïve advanced or metastatic non-clear cell RCC with sarcomatoid features, we prefer immunotherapy-based regimens. (See "Renal cell carcinoma with sarcomatoid features", section on 'Initial therapy (non-clear cell RCC with sarcomatoid features)'.)