The role of immunotherapy in non-clear cell renal cell carcinoma

Abstract

The category of non-clear cell renal cell carcinoma (nccRCC) includes several clinically, histologically, and molecularly diverse entities. Traditionally, they comprise type 1 and type 2 papillary, chromophobe, unclassified, and other histologies (medullary, collecting duct carcinoma, and translocation-associated). Molecular knowledge has allowed the identification of some other specific subtypes, such as fumarate hydratase–deficient renal cell carcinoma (RCC) or succinate dehydrogenase–associated RCC. In addition, it has recognized some alterations with a possible predictive role, e.g., MET proto-oncogene receptor tyrosine kinase (MET) alterations in papillary tumors. Standard therapies for the management of advanced clear cell RCC (ccRCC), i.e., vascular endothelial growth factor receptor (VEGFR) pathway inhibitors and mammalian target of rapamycin inhibitors, have shown poorer results in nccRCC patients. Therefore, there is a need to improve the efficacy of the treatment for advanced nccRCC. Immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting programmed death 1/programmed death ligand 1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), has demonstrated a significant survival benefit in several malignant neoplasias, including ccRCC, with a proportion of patients achieving long survival. The combinations of ICI or ICI + VEGFR tyrosine kinase inhibitors (TKIs) are the standard of care in advanced ccRCC. Unfortunately, major pivotal trials did not include specific nccRCC populations. In recent years, several studies have retrospectively or prospectively evaluated ICIs alone or in combination with another ICI or with TKIs in nccRCC patients. In this article, we review data from available trials in order to elucidate clinical and molecular profiles that could benefit from immunotherapy approaches.

Case Report: A Case of Renal Cell Carcinoma Unclassified With Multi-organ Invasion

“…The potential role for chemotherapy in unclassi ed RCC is untested and at this time is not recommended outside of a clinical trial [2]. As for immunotherapy, patients with unclassi ed subtypes have shown encouraging results, with the ORR increasing to 25%-36% in the nivolumab trials or 34.6% in the pembrolizumab trial, prospective studies with combination ICI and TKI (immune checkpoint inhibitor and tyrosine kinase inhibitor) therapy also showed promising response rates [14]. For advanced unclassi ed RCC, the standard therapy reminds unclear and related reports are limited.…”

Advanced Non-Clear Cell Renal Cell Carcinoma Treatments and Survival: A Real-World Single-Centre Experience

“…Therefore, there has been an increase in data on immunotherapy and immuno-based combination therapy in recent years [20]. When used as single agents, Nivolumab [38] and Pembrolizumab [39] demonstrated short PFS (2.2-4.2 months) but promising ORR (13.6 and 26.7% respectively).…”

“…Nowadays, combination therapies based on immune checkpoint inhibitors have markedly improved the treatment of ccRCC but data on nccRCC are still scarce, taken from small or retrospective trials [19,20] where this subgroup is often described as a single entity, while it is actually composed of numerous subtypes with distinct carcinogenesis, prognosis and probably treatment sensitivity.…”

An Overview of Systemic Targeted Therapy in Renal Cell Carcinoma, with a Focus on Metastatic Renal Cell Carcinoma and Brain Metastases

“…Non-clear-cell renal cell carcinomas (nccRCC) account for nearly 25% of all kidney cancers and include a group of highly heterogeneous tumors concerning histological varieties and oncogenic abnormalities [ 36 , 37 ]. A significant number of studies assessing the efficacy of immunotherapy in this category of patients have been conducted, and they will be discussed further.…”