Future Directions in ccRCC

The future of ccRCC treatment centers around optimizing the use of current therapies through smarter sequencing and combination strategies while also developing novel agents with new mechanisms of action. Several cooperative group trials are investigating how best to incorporate available drugs, as many current treatments lead to early tumor shrinkage followed by prolonged stable disease. Researchers are exploring ways to introduce additional therapies during this plateau phase to further improve patient outcomes, including innovative approaches like cellular therapies.

Ongoing clinical trials are evaluating the role of newer agents such as belzutifan, both as monotherapy and in combination with other targeted therapies or immunotherapies. These studies aim to clarify the optimal timing and combinations to maximize efficacy while maintaining tolerability. Another key question under investigation is the best treatment approach following progression on first-line immunotherapy and VEGF inhibitors. Recent and upcoming trial results will provide important guidance on whether to use cabozantinib or combinations like lenvatinib with everolimus in this setting, helping clinicians refine treatment sequencing with currently available drugs.

Looking further ahead, there is strong interest in next-generation therapies with either improved versions of existing mechanisms or completely novel approaches. Examples include new hypoxia-inducible factor 2a inhibitors and modified multikinase inhibitors with better pharmacokinetics. Additionally, cellular therapies such as chimeric antigen receptor (CAR) T and CAR natural killer cells show promise, although they come with significant toxicity concerns. Antibody-based therapies that engage immune cells in novel ways are also under investigation. Ultimately, although improving treatment sequencing will continue in the near term, breakthroughs will likely depend on introducing new mechanisms of action. Meanwhile, investigator-initiated studies are critical to answer unresolved questions that industry-driven trials may not prioritize, enabling more effective and personalized treatment strategies.