Future Directions in nccRCC

The treatment of nccRCC remains a significant challenge due to its rarity and biological heterogeneity. As a result, clinical trials for nccRCC often lag behind those for clear cell subtypes, with limited resources and smaller patient populations slowing progress. However, several randomized trials currently in development, such as PAPMET2 and studies under the STELLAR program, aim to better define the role of immunotherapy and targeted therapy combinations in subtypes like papillary RCC. These trials represent an important shift toward evidence-based treatment strategies rather than relying solely on extrapolating data from ccRCC.

Despite this progress, many studies still group diverse non–clear cell subtypes together—such as papillary, chromophobe, and translocation RCC—which dilutes the understanding of how each histology responds to different therapies. For instance, chromophobe RCC may respond better to mTOR inhibitors than to immunotherapy, whereas MET-driven papillary tumors may benefit more from MET inhibitors. Moving forward, the field needs more subtype-specific trials designed around the unique molecular characteristics of each variant. The goal is to eventually treat nccRCC with the same precision seen in ccRCC, using mechanistic insights to guide therapy.

In closing, there was recognition that demonstrating overall survival benefits in future RCC trials may become increasingly difficult due to variations in postprogression treatments and global access to therapies. As the therapeutic landscape expands, understanding sequencing, cross-trial comparability, and regional drug availability will be essential. Nevertheless, this conversation highlighted substantial advances in both clinical understanding and therapeutic development in RCC. Continued investment in biomarker research, mechanistically driven trial design, and international collaboration will be key to improving outcomes for all RCC subtypes, especially those that have historically received less attention.