Impact of age on outcomes in metastatic non–clear cell renal cell carcinoma (mnccRCC): A real-world TriNetX analysis

Malignancies arising in young adults often exhibit biological and clinical behaviors distinct from those in older patients (pts). Currently, little information is available regarding the prognostic impact of age in mnccRCC. This study aimed to compare survival outcomes by age group using data from the large-scale TriNetX database. Methods: We used the TriNetX research database to conduct a retrospective, large-scale outcome analysis of pts with mnccRCC who received at least one line of treatment across major healthcare institutions within an internationally connected, TriNetX-mediated network. Pts were stratified by age (< 45 vs ≥45 years), and clinical and demographic characteristics were compared using standard statistical methods. Kaplan-Meier analysis estimated progression-free survival (PFS) and overall survival (OS). Propensity score matching (PSM) was applied for sex, race, sites of metastases, type of treatment and comorbidities. Results: Among 758 pts with mnccRCC, 382 received first-line therapy between 2015 and 2025 and were included in the analysis. 257 had papillary histology, 23 chromophobe, 18 collecting duct, 60 unclassified, and 24 other rare entities. Median age was 62.7 years, and 69% were male. At diagnosis, 27% had stage IV disease and 69% underwent radical nephrectomy. First-line regimens included immune checkpoints inhibitors (ICI) monotherapy in 24.9%, tyrosine kinase inhibitors (TKI) monotherapy in 53.9%, ICI + TKI combinations in 5%, and mTOR inhibitors in 5.2%. 54 pts were < 45 years and 328 ≥45. The two age cohorts showed no significant differences in sex (p = 0.59), race (p = 0.21), comorbidities (p = 0.22), histology (all p > 0.05) or treatment categories (all p > 0.05). Lung metastases were more frequent in older pts (p = 0.018), whereas liver, bone, lymph node, and brain metastases were more common in younger pts (all p < 0.001). Pts < 45 years had shorter PFS than those ≥45 years (14.9 vs 30 months [mos]; p = 0.029) and a trend toward shorter OS (17.7 vs 36 mos; p = 0.10). After multivariate adjustment, a trend toward shorter PFS remained (14.9 vs 19.6 mos; p = 0.058), whereas OS differences were not significant (17.9 vs 40.4 mos; p = 0.16). In a subgroup analysis of papillary mnccRCC, younger pts also showed shorter PFS (20.4 vs 26.9 mos) and OS (22.5 vs 33.3 mos), with non-significant trends (PFS p = 0.11; OS p = 0.93). Conclusions: In this large, real-world cohort of mnccRCC, younger pts (< 45 years) had metastases at sites historically associated with worse prognosis (i.e., liver, brain) and exhibited significantly shorter PFS and a trend toward shorter OS, suggesting more aggressive disease biology. These findings support consideration of tailored or more intensive therapeutic strategies in younger pts.