Predictive genomic markers of response to VEGF targeted therapy (TT) in metastatic renal cell carcinoma (mRCC): Role of VHL and TP53 mutation, and FLT1 germline variant

In the first-line therapy setting for mRCC, VEGF tyrosine-kinase inhibitors, mTOR inhibitors, and high-dose IL-2 are current standards. Checkpoint inhibitors are expected to garner approval soon. In the absence of head-to-head comparison of these agents, genomic markers of response to therapy are needed to guide therapy selection. The objective of this study was to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection.

Targeted sequencing of primary tumors of patients with mRCC was performed, and tumor genomic aberrations (GAs) were correlated with progression-free survival (PFS) to treatment with first-line VEGF targeted therapies by using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of all statistically significant GAs predicting PFS in the first line setting was developed.

Mutations in TP53 were associated with inferior PFS on first-line VEGF TT (HR 2.83, 95% CI 1.05-6.68; p=0.023), whereas, VHL mutations were associated with improved PFS (HR 0.40, 95% CI 0.21-0.78; p=0.0042). A trend for inferior PFS was observed with FLT1 C/C variant. A composite model of these 3 GAs was significantly associated with inferior PFS and OS in a dose-dependent manner, when controlling for IMDC risk category in a Cox proportional hazard model (Table).

A composite model of tumor GAs, including TP53 mutation, wild type VHL, and FLT1 C/C variant significantly predicted survival outcomes to first-line therapy with VEGF TT in mRCC in a dose-dependent manner.