Second-line therapy after ipilimumab and nivolumab in advanced renal cell carcinoma: A multicenter real-world study (GUARDIANS).

437 Background: Ipilimumab plus nivolumab is a standard first-line therapy for intermediate and poor-risk patients with metastatic or advanced renal cell carcinoma (aRCC). However, data guiding the optimal second-line treatment after progression on this regimen remain limited. In this study real-world outcomes following second line treatment in this setting were analyzed. Methods: We retrospectively evaluated the efficacy and safety of second line therapies in 356 real-world patients with advanced renal cell carcinoma who experienced disease progression on first-line ipilimumab plus nivolumab across 17 tertiary centers in Germany and Switzerland. Results: Median age was 64 years, most patients were male (69.1 %) and had a clear cell histology (74.1 %). ECOG PS was ≥ 2 in 14.3 %. IMDC risk was intermediate in 61.8 % and poor in 28.7 %. Cabozantinib was most frequently administered as subsequent therapy and showed superior median OS and PFS compared to other second-line options. Median OS was 38 months (95 %CI 20.7-55.3) and median PFS 15 months (95 %CI 8.2-21.9) with cabozantinib in second-line setting compared to a median OS of 16 months (95 %CI 10.1-21.9, p = 0.003 ) and median PFS of 7 months (95 %CI 5.1-8.9, p = 0.013 ) in the heterogeneous comparison group including sunitinib (11.3 %), axitinib, pazopanib (both 4.3 %), lenvatinib plus everolimus (3.2 %), tivozanib (2.2 %) and different IO/TKI combinations or study medication (e.g. belzutifan). Comparison of time-to-event data between the two groups revealed a hazard ratio (HR) for death of 0.515 (95% CI, 0.328–0.807; p = 0.004 ) and for disease progression of 0.608 (95% CI, 0.406–0.912; p = 0.016 ) in favor of cabozantinib. Conclusions: Our real-world data support the use of cabozantinib after disease progression on ipilimumab and nivolumab as first-line therapy of aRCC with robust efficacy. Updated results on response rate, survival data and safety will be available for ASCO GU 2026.