e16556 Background: Genomic alterations in RCC can serve as biomarkers for response to therapy. Wild type VHL has shown inferior response to VEGF inhibitors, while patients (pts) with mutated VHL have improved outcomes with immunotherapy (IO)/tyrosine kinase inhibitor (TKI) therapy. We describe the impact of genomic alterations on outcomes and response to front-line therapy. Methods: Pts with mRCC with genomic sequencing between 2015-2025 at Indiana University and treated with front-line systemic therapy were included. Kaplan-Meier method was used to analyze progression free survival (mPFS) and overall survival (OS) using the log rank test to compare groups. Results: 198 pts were included. Median age was 58.6 (range, 24.2-83.7). Tumor histology was 68.7% clear cell, 9.1% papillary, 8.1% unclassified, 4% chromophobe, 2.5% translocation, 1% poorly differentiated, and 6.6% other. 17.2% of pts had sarcomatoid features; 14.1% had rhabdoid. 45.5% pts had metastasis at diagnosis and 54% at relapse. Metastasis sites were lungs 57.1%, regional lymph nodes (LNs) 36.9%, bone 34.3%, distant LNs 27.8%, liver 19.7%, and brain 7.6%. IMDC risk was 22.2% good, 44.4% intermediate, 16.7% poor, and 16.7% unknown. Front-line therapy was IO/IO in 24.7%, IO/TKI in 30.3%, single-agent TKI in 22.7%, single-agent IO in 5.6%, and other in 16.7%. Genetic alterations included VHL in 53.5%, PBRM1 in 32.3%, SETD2 in 25.3%, TP53 in 14.6%, and BAP1 in 13.1%. Median follow-up was 5.0yrs (range 0.03-21.9). Overall mPFS was 0.8yrs (95%CI 0.6-1.0). 5-yr OS was 41.6% (95%CI: 33.3-49.8). mPFS was 1.3yrs (95% CI 0.8-2.1) for those treated with IO/TKI vs. 0.7yrs (95% CI: 0.4-0.9) for IO/IO (p=0.0050), though there was no difference in OS. For pts with a VHL mutation, mPFS was 1.0yrs (95% CI; 0.8-1.4) vs. 0.5yrs (0.3-0.6) for pts without (p=0.01). 5yr OS for those with a VHL mutation was 48.1% (95% CI 35.8-59.4) vs. 35.1% (24.1-46.2) for pts without (p=0.002). For pts with a VHL mutation, mPFS was 0.8yrs (95% CI 0.4-1.8) for pts treated with IO/IO vs. 1.6yrs (95% CI 0.9-4.9) for IO/TKI (p=0.05). There was no difference in OS. Table 1 outlines outcomes by genomic mutation and therapy received. Conclusions: VHL mutations were associated with improved mPFS and OS. For most mutations, IO/TKI resulted in improvements in PFS, though no difference in OS. Median PFS (yrs) 5-yr OS (%) Mutation Present Mutation Absent p-value Mutation Present Mutation Absent p-value Genomic Mutation:TP53VHLPBRM1SETD2BAP1TERT 0.91.01.20.90.50.4 0.80.50.60.70.80.8 0.45 0.01 0.01 0.320.050.10 30.148.147.235.637.721.4 44.235.138.843.842.344.5 0.41 0.002 0.080.850.690.37 Present mutation: 1L therapy IO/IO 1L therapy IO/TKI p-value 1L therapy IO/IO 1L therapy IO/TKI p-value TP53VHLPBRM1SETD2BAP1TERT 0.40.81.20.80.30.3 1.11.61.61.91.70.5 0.03 0.05 0.04 0.03 0.04 0.20 20.041.941.526.143.80 25.953.875.438.1033.3 0.930.160.050.270.800.50
Biju et al. (2026) studied this question.