The Role of Immunotherapy in Non-clear Cell Renal Cell Carcinoma

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.