Clinical and genomic characteristics of primary resistant disease to first-line immuno-oncology plus VEGFR inhibitor therapy in metastatic renal cell carcinoma

Primary resistant disease (PRD) to immuno-oncology plus vascular endothelial growth factor receptor inhibitor (IOVE) therapy is a critical unmet need in metastatic renal cell carcinoma (mRCC), yet its clinical and molecular features remain poorly defined. We provide the first integrated clinical and genomic characterization of PRD, combining two complementary, non-overlapping cohorts: a real-world clinical cohort of 159 patients (Hiroshima Cancer Registry Project, H-CARP) and a national genomic database (Center for Cancer Genomics and Advanced Therapeutics, C-CAT). PRD (n = 20 [12.6%]) defined a distinct high-risk group with markedly shorter progression-free survival, PFS2, and overall survival (OS) and a median OS of 8.5 months. Notably, liver metastasis was a strong, readily available independent predictor of PRD (odds ratio 4.99; p = 0.011), enabling early risk stratification, and non-clear cell histology was enriched among PRD. The comparable OS with or without subsequent therapy underscores an urgent need for novel strategies. Exploratory genomic profiling revealed candidate, hypothesis-generating correlates of resistance (lower VHL and PBRM1; higher TSC2 and MSH3 alterations). By linking real-world outcomes with national genomic data, this study establishes a foundation for early identification and biomarker-guided management of PRD.