Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Abstract

Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.

Pembrolizumab Plus Axitinib for Metastatic Papillary and Chromophobe Renal Cell Carcinoma: NEMESIA (Non Clear MEtaStatic Renal Cell Carcinoma Pembrolizumab Axitinib) Study, a Subgroup Analysis of I-RARE Observational Study (Meet-URO 23a)

“…The choice of therapy for nccRCC is often a challenge and limited evidence is available to guide clinicians in treatment, due to its relative rarity. Although immune-checkpoint inhibitors (ICI) based combinations can be considered as standard of care for metastatic RCC [ 13 ], pivotal trials included only patents with ccRCC, therefore nccRCC have limited personalized treatments [ 14 , 15 ].…”

Kidney Cancer Models for Pre-Clinical Drug Discovery: Challenges and Opportunities

“…Since nccRCCs are relatively rare, only a limited number of randomized, prospective clinical trials exist ( 15 ). Treatment modalities that have been extrapolated from ccRCC such as VEGF- or mTOR-targeting agents have been explored in metastatic nccRCC, however, with suboptimal results ( 16 , 17 ).…”

The genomic and transcriptomic landscape of advanced renal cell cancer for individualized treatment strategies

“…Moreover, RCC with non-clear cell histology is a heterogeneous group of different subtypes, such as papillary and chromophobe RCC 18 . As holds true for advanced ccRCC, the course of non-clear cell RCC (nccRCC) differs significantly between patients 19,20 . Since the different nccRCC subtypes are considered rare diseases, randomized phase three clinical trials are lacking for nccRCC 21 .…”

“…Since the different nccRCC subtypes are considered rare diseases, randomized phase three clinical trials are lacking for nccRCC 21 . As a result, there is no clearly defined standard of care for patients with advanced nccRCC 20,22 .…”