Management of Metastatic Renal Cell Carcinoma with Variant Histologies

Variant histology renal cell carcinoma (vRCC) encompasses rare non–clear cell subtypes that have long been associated with poor prognosis and minimal response to therapies targeting vascular endothelial growth factor and its receptor. Molecular advances have helped classify vRCC into distinct entities and identify putative targetable driver alterations, such as MET in papillary subtypes. More have since been identified in other vRCC subtypes, including alterations of tumor metabolism, chromatin remodeling genes, cell-cycle genes, and inactivation of tumor suppressors such as TP53 or NF2 . New targeted therapies, as well as immune checkpoint inhibitors, have been in development and yielded encouraging results. Collaborative clinical trials will be an essential step toward better implementation of these regimens in clinical practice.

Key points

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Variant histology renal cell carcinoma (vRCC) encompasses various entities with different molecular features.
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Systemic therapies in patients with metastatic vRCC are generally less active than in patients with conventional clear-cell renal cell carcinoma.
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Cytoreductive nephrectomy in the metastatic setting should be considered on a case-by-case basis for vRCC considering the lack of prospective data.
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Therapies targeting angiogenesis have shown substantial response rates, but comparative trials are lacking for these rare tumors.
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Immune checkpoint inhibitors are being evaluated as monotherapy or combination with early evidence of durable benefit. Ongoing trials are underway and may further improve outcomes of patients with vRCC.

Introduction

Renal cell carcinoma (RCC) affects more than 400,000 patients worldwide, and half of these patients will ultimately harbor metastatic disease. Most RCC are of the clear cell (ccRCC) subtype, characterized by alterations of VHL and subsequent activation of the hypoxia-inducible factor pathway, as well as chromatin remodeling genes BAP1 , PBRM1 , and SETD2 . Conversely, up to 25% of RCCs belong to the heterogeneous group of non–clear cell RCC, or variant histology renal cell carcinoma (vRCC), which encompasses diseases with different biology and distinct natural history. The most frequent subtypes of vRCC include papillary, chromophobe, collecting duct, renal medullary carcinomas, Xp11 translocation carcinomas, and succinate dehydrogenase deficient renal carcinomas, some of which may occur in the context of familial predisposition syndromes ( Table 1 ).

Table 1

Main biological alterations in variant histology renal cell carcinoma

RCC Type	Chromosomal Alterations	Main Molecular Alterations	Main Familial Predispositions
Papillary type I	Gain of chromosome 7, 17, deletion of 1p36	MET	Hereditary pRCC ( MET )
Papillary type II	Loss of chromosome 9p21, 3p	CDKN2A , SETD2 , BAP1, PBRM1, activation of NRF2-ARE, TFE3 fusions	HLRCC ( FH )
Chromophobe	Loss of chromosome 1, 2, 6, 10, 13, 17, and 21	TP53 , PTEN , mTOR , TERT	Birt-Hogg-Dubé syndrome ( FLCN )
Collecting duct	DNA losses at 8p, 16p, 1p and 9p; gains at 13q	Mitochondrial genome alterations
Renal medullary carcinoma		SMARCB1	Sickle cell trait
Xp11 translocation carcinoma	TFE3 or TFEB rearrangements	BIRC7 expression

vRCCs are generally associated with aggressive metastatic behavior, decreased survival, and poor response to treatment with targeted molecular therapies compared with conventional clear cell tumors. Advances in the molecular characterization of vRCC and the surge of immunotherapy-based regimens have paved the way for new therapeutic developments that may durably improve outcomes of patients with vRCC. Herein the authors discuss the biological landscape of vRCC and review current and future therapeutic options for patients with metastatic vRCC.

Main biological features of variant histology renal cell carcinoma

Papillary renal cell carcinoma (pRCC) is the most frequent type of vRCC and comprises 15% to 20% of all RCCs. These tumors had been further divided histologically into pRCC types 1 and 2, but the latter group actually encompasses tumors with heterogeneous biology. Clinical behavior of pRCC ranges from indolent localized tumors to aggressive metastatic subtypes more frequently encountered in type 2 histologies. Recurrent alterations in type 1 pRCC include gain of chromosome 7 and mutations of MET (7q31), present in 81% of tumors. Molecular characterization of type 2 pRCC identified a diverse set of alterations to include high activation of the NRF2 antioxidant response pathway, CDKN2A alterations (25%) conferring adverse outcomes, CpG island methylator phenotype associated with early and aggressive onset, silencing of CDKN2A and frequent FH mutations, as well as mutations in chromatin modifying genes SETD2 , BAP1 , and PBRM1 .

Chromophobe renal cell carcinoma (chRCC) is the second most frequent vRCC, accounting for ∼5% of all RCCs, and is notably characterized by mitochondrial alterations, multiple losses of heterozygosity involving chromosomes 1, 2, 6, 10, 13, 17, and 21, as well as TP53 (33% to 58%) and PTEN mutations (9% to 24%). ^,

Rare variants of vRCC encompass the most aggressive tumors, which often result from single somatic driver mutations and occur earlier in life. Those include translocation RCC, characterized by rearrangements of the MiTF family transcription factors TFE3 and TFEB , accounting for aggressive diseases arising in young patients; collecting duct carcinoma, notable for metabolic alterations as well as CDKN2A and Hippo member NF2 alterations; and renal medullary carcinoma, in which loss of the chromatin remodeling gene SMARCB1 has been identified as the main driver alteration.

On top of molecular alterations that could foster the development of targeted molecular therapies, new data have emerged about the immunology of vRCC. These tumors generally feature infiltration by mononuclear cells and frequent programmed death-ligand 1 (PD-L1) expression on both tumor cells and tumor infiltrating immune cells. ^, As such, many types of vRCC appear to be immunogenic tumors and potentially amenable to therapeutic strategies based on immune checkpoint inhibitors.

The role of nephrectomy in metastatic variant histology renal cell carcinoma

Cytoreductive nephrectomy (CN) has long been standard of care in the management of advanced RCC based on data from SWOG 8949 and EORTC 30947, which compared interferon-α with or without nephrectomy in metastatic ccRCC. ^, However, the benefit in overall survival (OS) demonstrated in these trials was not confirmed in the era of targeted molecular therapy. The CARMENA trial evaluated sunitinib versus immediate CN followed by sunitinib in patients with intermediate- or poor-risk ccRCC. This study enrolled 450 patients and showed a median OS of 18.4 months with sunitinib alone compared with 13.9 months in the CN arm, demonstrating noninferiority of sunitinib alone.

However, in the setting of vRCC, where therapy is less effective, the role of CN continues to be controversial. Notably, a retrospective study from the International Metastatic RCC Database Consortium (IMDC) showed that CN was associated with improved survival in advanced RCC patients (20.6 vs 9.5 months), including 196 patients with vRCC (15.3 vs 8.0 months). Additional data in 353 pRCC revealed a similar OS benefit (16.3 vs 8.6 months), whereas a study based on the Surveillance, Epidemiology, and End Results database between 2001 and 2014 in 851 advanced vRCC showed a reduction in 2-year cancer-specific mortality from 77% to 52.6% with a CN. Considering the lack of prospective data in vRCC, the role of CN remains unsettled and should be discussed on a case-by-case basis. Data from ccRCC trials suggest that upfront CN may especially benefit patients with low extrarenal tumor burden and good performance status, as well as those with significant symptoms from the primary tumor.

Systemic therapy for variant histology renal cell carcinoma

Targeted Molecular Therapies

Development of systemic therapies in vRCC has largely followed the management of ccRCC. Notably, several trials evaluating VEGFR-TKIs demonstrated some activity in vRCC ( Table 2 ), but their activity pales in comparison to that in ccRCC, because survival remains commonly less than 18 months. Two randomized phase 2 trials, ASPEN and ESPN, were conducted in a selected vRCC population to evaluate the VGFR-TKI sunitinib versus the mTOR inhibitor everolimus in the metastatic setting. ^, The ASPEN trial demonstrated a significant increase in median progression-free survival (PFS) in patients treated with sunitinib compared with everolimus (8.3 vs 5.6 months), but the effect seemed to differ between prognostic risk groups and histology. Indeed, median PFS was numerically superior with everolimus compared with sunitinib in patients with poor-risk tumors, as well as in patients with chRCC. There was no difference in OS between arms. ESPN included patients with vRCC or ccRCC with greater than 20% sarcomatoid features and did not show any difference in median PFS between sunitinib (6.1 months) and everolimus (4.1 months). Median OS was 16.2 months and 14.9 months in the sunitinib and everolimus groups, respectively. Two additional randomized trials evaluated mTOR inhibitors in an unselected RCC population, including vRCC. The RECORD-3 trial evaluated the sequence sunitinib-everolimus versus everolimus-sunitinib and included 14% of patients with vRCC, in whom OS was similar between both arms, at 16.8 versus 16.2 months, respectively. Finally, GLOBAL-ARCC evaluated temsirolimus versus interferon-α or both and included 20% of patients with vRCC, showing a median OS of 11.6 months with temsirolimus compared with 4.3 months with interferon-α in this population. ^,

Table 2

Results of selected prospective clinical trials in variant histology renal cell carcinoma

Clinical Trial	Treatment	Line of Treatment	Number of Patients Enrolled	Histology	ORR, %	PFS, mo	OS, mo
SUPAP	Sunitinib	First line	61	pRCC	13 (type I) and 11 (type II)	6.6 (type I) and 5.5 (type II)	17.8 (type I) and 12.4 (type II)
RAPTOR	Everolimus	First line	88	Metastatic pRCC	1	7.9 (type I) and 5.1 (type II)	28 (type I) and 24.2 (type II)
ESPN	Sunitinib vs everolimus	First line	68	vRCC and ccRCC with >20% sarcomatoid features	9 vs 3	6.1 vs 4.1	16.2 vs 14.9
ASPEN	Sunitinib vs everolimus	First line	108	vRCC	18 vs 9	8.3 vs 5.6	31.5 vs 13.2
RECORD-3	Sunitinib-everolimus vs everolimus-sunitinib	First line	66/238 (vRCC/total)	vRCC and ccRCC	—	7.2 vs 5.1	16.8 vs 16.2
GLOBAL ARCC	Temsirolimus vs interferon-α	First line	124/626 (vRCC/total)	vRCC and ccRCC	5 vs 8	7 vs 1.8	11.6 vs 4.3
Choueiri et al, 2017	Savolitinib	Any line	109	pRCC	7	6.2 (MET driven) and 1.4 (MET independent)	—
KEYNOTE 427 (cohort B)	Pembrolizumab	First line	165	vRCC	25	4.1	Not reached
McGregor et al, 2019	Atezolizumab and bevacizumab	Any line	60	vRCC and ccRCC with >20% sarcomatoid features	33	8.3	Not reached