Antonio Cigliola, Nazli Dizman, Chiara Mercinelli, Yao Zhu, Maria I Carlo, Sarah P Psutka, Stephanie A Berg, Gagan Prakash, Jeanny B Aragon-Ching, Karima Oualla, Laura Meili Linville, Charles B Nguyen, Wesley Yip, Brigida Anna Maiorano, Valentina Tateo, Philippe E Spiess, Sumanta Kumar Pal, Andrea Necchi
Younger mnccRCC patients (<45) presented with metastases at sites associated with poor prognosis and trends toward shorter PFS and OS, suggesting more aggressive disease biology. These findings support validation and consideration of tailored or more intensive strategies for younger patients.
BACKGROUND: Malignancies arising in young adults often exhibit biological and clinical behaviors distinct from those in older patients. Limited data exist on the prognostic impact of age in metastatic non-clear cell renal cell carcinoma (mnccRCC). This study compared survival outcomes by age using the large-scale TriNetX database.
METHODS: We performed a retrospective analysis of mnccRCC patients receiving ≥1 line of therapy across TriNetX-participating institutions. Patients were stratified by age (<45 vs. ≥45 years). Kaplan-Meier analysis estimated progression-free survival (PFS) and overall survival (OS). Propensity score matching (PSM) adjusted for sex, race, histological subtype, metastasis sites, cytoreductive nephrectomy, and treatment type (immune checkpoint inhibitors [ICI]-containing vs. non-ICI regimens).
RESULTS: Among 758 patients with mnccRCC, 382 received first-line therapy during the study period (2015-2025) 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; 69% male; 27% stage IV at diagnosis; 69% underwent radical nephrectomy. First-line regimens included ICI monotherapy (24.9%), tyrosine kinase inhibitors (TKI) monotherapy (53.9%), ICI + TKI (5%), and mTOR inhibitors (5.2%). Younger patients (<45, n = 54) had more liver, bone, lymph node, and brain metastases, whereas lung metastases were more frequent in older patients (P = .018). PFS was shorter in younger patients (14.9 vs. 30 months; P = .03), and OS showed a trend (17.7 vs. 36 months; P = .10). PSM analysis confirmed a PFS trend (14.6 vs. 36.5 months; P = .07), while OS differences were not significant (17.8 vs. 43.1 months; P = .12). In papillary mnccRCC, younger patients showed shorter PFS (20.4 vs. 26.9 months) and OS (22.5 vs. 33.3 months) with nonsignificant trends.
CONCLUSIONS: Younger mnccRCC patients (<45) presented with metastases at sites associated with poor prognosis and trends toward shorter PFS and OS, suggesting more aggressive disease biology. These findings support validation and consideration of tailored or more intensive strategies for younger patients.