**8. Non-clear cell RCC (nccRCC)**

Non-clear cell histology constitutes 20–25% of RCCs [94, 95]. However, this group is heterogeneous, and individually each subtype is relatively rare and thus difficult to study in large prospective trials. nccRCC includes papillary, chromophobe, sarcomatoid, collecting duct, medullary, and various hereditary forms, among which papillary is the most common subtype [94]. Patients with metastatic nccRCC have generally proven to be less responsiveness to the drugs shown to be active in ccRCC [96]. Although some patients with nccRCC may obtain some benefit from VEGF-targeting TKIs, retrospective studies have generally suggested that these agents have inferior efficacy compared with what would be expected in patients with ccRCC [97]. This was also true in the previous era of immunotherapy HD IL-2. Although included in some of the large trials of HD IL-2, patients with nccRCC rarely experienced clinical benefits [95, 98, 99]. Treatment with IFN-α has also showed limited efficacy in patients with non-clear cell histology [95]. No prospective data currently exist to characterize the response of patients with nccRCC to ICIs, though several case reports have been published identifying single responses across various histologies [100–102]. Several ongoing studies are evaluating ICIs as a single agent or in combination in patients with nccRCC.
