Aging is associated with the outcomes of immune checkpoint blockade in renal cell carcinoma

Aging causes gradual and significant declines in immune functions and responses. However, the impact of aging on the immunotherapy outcomes in advanced renal cell carcinoma is largely unknown. Here, we conducted a pooled analysis of individual participant data from two regulatory-approved randomized controlled trials: CheckMate 214 and JAVELIN Renal 101. The overall population (n=1926) included 964 individuals treated with immune checkpoint inhibitors (ICIs) and 962 subjects treated with sunitinib. The optimal age to separate young from old was found to be 60. For young patients, immunotherapy was associated with favorable overall survival (OS; HR=0.70, 95% CI 0.56 to 0.87, p<0.001). For individuals over 60 years old, the OS benefits were marginal (HR=0.82, 95% CI 0.67 to 1.00, p=0.05). Notably, patients with Memorial Sloan Kettering Cancer Center poor risk demonstrated clear benefits from ICIs in this population. Immunotherapy failed to improve OS in patients aged 75 and above (HR=1.05, 95% CI 0.62 to 1.79, p=0.85). Further investigations indicated that young patients exhibited increased infiltration of immune cells, enhanced tumor immunogenicity, and improved immune responses. In summary, the advantage of immunotherapy diminished progressively with age. ICIs were associated with favorable outcomes in young patients. However, for patients over 60 years old, clinicians need to carefully balance efficacy, safety, and patient preferences to deliver individualized treatment.