In this issue of European Urology, experts review advancements and challenges in treating renal cell carcinoma (RCC), emphasising the complexity of managing a disease with an expanding array of therapeutic options. Despite significant progress, critical questions remain about treatment sequencing, duration, and patient selection. A major challenge is managing disease progression after adjuvant immunotherapy, which reduces relapse risk and improves survival for high-risk RCC patients post-surgery. However, some patients still experience recurrence, and optimal treatment for these cases is unclear. While retrospective studies suggest vascular endothelial growth factor receptors (VEGFR) targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitor (ICI) based regimens may help, large trials like CONTACT-03 and TiNivo-2 show that rechallenging with ICIs after initial failure does not improve survival. This raises questions about whether ICI rechallenge after a prolonged interval could restore antitumor immunity, warranting further study. In metastatic RCC, immune-based combinations are the first-line standard, leaving VEGFR TKIs as the primary option for subsequent treatment, though their efficacy may be limited. Choosing between first-line combinations – such as ICI + ICI or ICI + TKI – often relies on indirect comparisons, physician experience, and patient preferences, particularly regarding toxicity. Cross-trial comparisons are complicated by differences in patient populations, agents, and follow-up durations. Another unresolved issue is the optimal duration of combination therapy. Stopping immunotherapy after two years may reduce efficacy over time, while long-term TKI use is associated with significant toxicities. Preliminary data suggest discontinuing TKIs while continuing ICIs after an initial response may maintain efficacy and improve safety, challenging the need for continuous angiogenesis inhibition. The potential for immune exhaustion with prolonged ICI use or the utility of reinducing ipilimumab (anti-CTLA-4) in progressive disease remains unclear. Regulatory and insurance constraints further limit treatment options in later lines. Older agents like the HIF-2α inhibitor belzutifan, which showed promise in the Litespark-005 trial for post-ICI and antiangiogenic therapy, are being reevaluated in earlier treatment lines, potentially reshaping the treatment algorithm. A significant limitation is the lack of reliable biomarkers to guide treatment decisions. Additionally, the interplay between metabolism and RCC biology remains underexplored, offering a promising research avenue. While industry collaborations are valuable, academic-driven international studies are essential to address practical questions and reduce uncertainties in RCC treatment. In conclusion, despite substantial advancements, critical gaps in knowledge persist. Continued research into novel combinations, treatment durations, biomarkers, and metabolic pathways is vital to refine therapeutic strategies and improve outcomes for RCC patients.
Treatment options for renal cell carcinoma
Reviewed by Asif H Ansari
Despite an abundance of active treatment options for renal cell carcinoma, shadows still obscure the light.
