Efficacy of subsequent therapy in patients with metastatic renal cell carcinoma of intermediate and poor risk following first-line immuno-oncology combinations.

478 Background: In the era of immune-oncology (IO) combinations, specifically IO-IO or IO + tyrosine kinase inhibitors (TKIs), overall survival (OS) of patients (pts) with metastatic renal cell carcinoma (mRCC) of International mRCC Database Consortium (IMDC) intermediate and poor risk has significantly improved. However, disease progression makes the investigation of subsequent therapies’ efficacy challenging since no evident standard exists. Methods: This multicenter retrospective study included pts with mRCC of IMDC intermediate and poor risk who received subsequent therapy after disease progression following first-line treatment with either dual immunotherapy (ipilimumab and nivolumab) or IO-TKI since 2020. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Results: A total of 101 pts were enrolled. The following second-line regimens included: TKIs (pazopanib, axitinib or sunitinib) as monotherapy in 37 pts (37%), lenvatinib plus everolimus in 46 pts (46%), cabozantinib in 14 pts (14%) and everolimus as monotherapy in 4 pts (3%). The median follow-up time was 27 months. The ORR with TKI monotherapy was 16%, cabozantinib – 29% and lenvatinib + everolimus – 30%, p=0,1. An objective response was observed in 19 of 62 pts (31%) who received prior IO-IO combination compared to 5 of 39 patients (13%) treated with first-line IO-TKI (p=0.04). Irrespective of the first-line therapy, median PFS was 7 months (HR 0.87, 95% CI 0.5–1.4). In the overall cohort, median PFS was 11 months with lenvatinib plus everolimus, compared to 5 months with TKI monotherapy (HR 0.7, 95% CI 0.4–1.1). Median time from the initiation of second-line therapy to death from any cause was longer in the IO-IO group (24 months) than in the IO-TKI group (10 months; HR 0.56, 95% CI 0.3–0.96). However, overall survival (OS) from the start of first-line therapy did not differ significantly between groups, likely due to the longer PFS achieved with first-line immuno-targeted therapy. The 2-year OS rates were 83% and 72%, respectively (HR 0.88, 95% CI 0.58–1.34). Conclusions: In real-world clinical practice, second-line therapy demonstrates comparable progression-free survival in patients with mRCC regardless of prior IO-IO or IO-TKI treatment. The combination of lenvatinib and everolimus showed the most promising outcomes among second-line regimens, supporting its role as a preferred option in this setting.