Trends in overall survival with evolving systemic therapies for metastatic non–clear cell RCC: An analysis over two decades.

474 Background: Metastatic non–clear cell renal cell carcinoma (nccRCC) is a rare, heterogeneous disease historically underrepresented in trials. Over the past two decades, systemic therapies including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (IO), and IO/TKI combinations have expanded, but their impact on survival in nccRCC remains poorly defined. Methods: We included patients diagnosed with metastatic nccRCC between 2004-2020 from National Cancer Database. We stratified patients based on therapy eras: pre-TKI, TKI, IO, and IO–TKI. We utilized Kaplan-Meier analysis and Cox proportional hazard models to study overall survival (OS)in patients with nccRCC. Results: We included 2,753 patients diagnosed with metastatic nccRCC from the NCDB. Among patients with nccRCC, those who did not receive systemic therapy had a median survival of 3.29 months (95% CI: 2.99–3.55 months). In contrast, patients who received systemic therapy had a longer median survival of 7.62 months (95% CI: 7.26–7.98 months). At 6 months, patients who did not receive systemic therapy had a survival probability of 32.9% (95% CI: 29.9–35.9%). By 12 months, survival declined further to 16.9% (95% CI: 14.7–19.5%). In contrast, patients who received systemic therapy demonstrated significantly better outcomes. At 6 months, survival probability was 62.1% (95% CI: 59.5–64.6%), and at 12 months, survival remained 27.6% (95% CI: 25.3–30.0%). Patients who received systemic therapy had 18% less risk of death compared to patients who did not receive systemic therapy. Additionally, each subsequent year of diagnosis had HR of 0.96 (95% CI: 0.95–0.97, p = 0.00) compared to previous year. Conclusions: Patients with metastatic nccRCC who received systemic therapy lived longer than those who did not (median 7.6 vs 3.3 months; ~18% lower mortality risk). Year-over-year survival gains (HR 0.96; p<0.001) align with wider use of TKIs, IO, and IO–TKI regimens. Given persistently modest survival, prioritizing enrollment in subtype-specific trials and ensuring timely access to active combinations should be central to care. Cox proportional hazards model evaluating factors associated with overall survival among patients with metastatic nccRCC. Variable Comparator HR (95% CI) P-value Age ≥65 years vs <65 years 1.02 (0.91–1.13) 0.78 Private insurance vs Uninsured 0.78 (0.60–1.01) 0.06 Non-academic facility vs Academic 1.13 (1.04–1.23) <0.001 Comorbidity ≥1 vs 0 1.07 (0.98–1.17) 0.13 Distance ≥50 miles vs <50 miles 0.87 (0.79–0.96) <0.001 Poor/Undifferentiated grade vs Well/Moderate 1.72 (1.50–1.97) <0.001 Cytoreductive nephrectomy: Yes vs No 0.46 (0.41–0.53) <0.001 Each Year of diagnosis vs Previous Year 0.96 (0.95–0.97) <0.001 Systemic therapy: Yes vs No 0.82 (0.76–0.89) <0.001