Systemic Treatment for Advanced and Metastatic Non-Clear Cell Renal Cell Carcinoma: Examining Modern Therapeutic Strategies for a Notoriously Challenging Malignancy

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of malignancies that represents 25% of renal cell carcinoma (RCC) cases. Treatment for non-clear cell histologies is mostly based on evidence from small phase II clinical trials or extrapolated from successful therapies in clear cell RCC because of the low incidence of non-clear cell pathology. Advances in genomic profiling have improved clinicians’ understanding of molecular targets for nccRCC, such as altered mesenchymal epithelial transition (MET) gene status and fumarate hydratase (FH) gene inactivation, but patient outcomes remain poor and optimal management of this disease remains unclear. This review assesses outcomes by histologic subtype from 27 prospective and 13 ongoing clinical trials to identify therapeutic strategies for advanced or metastatic nccRCC. Vascular endothelial growth factor tyrosine kinase inhibitors (TKI), such as sunitinib, and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, have demonstrated efficacy and remain viable treatment options, with a preference for sunitinib. However, everolimus is preferred in patients with chromophobe RCC because folliculin (FLCN) gene mutations upregulate the mTOR pathway. Novel TKIs, such as cabozantinib, show improved outcomes in patients with papillary RCC because of targeted MET inhibition. Platinum-based chemotherapy continues to be the recommended treatment strategy for collecting duct and medullary RCC. Clinically meaningful antitumor activity has been observed across all non-clear cell histologies for immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and ipilimumab. Ongoing trials are evaluating novel tyrosine kinase inhibitor and immunotherapy combination regimens, with an emphasis on the promising MET-inhibitor cabozantinib and pembrolizumab plus lenvatinib.