An update on the treatment paradigm for non-clear cell renal cell carcinoma

INTRODUCTION: Non - clear cell renal cell carcinoma (nccRCC) encompasses a heterogeneous group of rare malignancies, representing approximately 20-25% of all renal cancers. Unlike clear cell RCC (ccRCC), these subtypes - papillary, chromophobe, collecting duct, translocation, molecularly defined variants and others - display distinct biological behaviors, genetic profiles, and therapeutic sensitivities, which preclude a uniform treatment approach. AREAS COVERED: This review provides an updated overview of systemic therapy for nccRCC, integrating evidence from prospective trials, retrospective series, and translational research. For most of these histologies, immune checkpoint inhibitor (ICI) - based combinations (e.g. pembrolizumab - lenvatinib, nivolumab - cabozantinib or nivolumab-ipilimumab) have demonstrated the best activity. In chromophobe RCC (chRCC), also mechanistic target of rapamycin (mTOR) inhibition appears particularly relevant, whereas in collecting duct carcinoma and renal medullary carcinoma platinum-based chemotherapy continue to have an important role, with cabozantinib showing encouraging results. Novel biomarker-driven approaches are emerging for selected molecular subsets. EXPERT OPINION: Although remarkable progress has been achieved, the optimal therapeutic strategy for nccRCC remains undefined. Future efforts should focus on histology- and biomarker-driven clinical trials, molecular stratification, to optimize efficacy across subtypes. International collaboration is crucial to overcome the challenges posed by the rarity and biological heterogeneity of these tumors.