57VHL and TP53 mutation status are not associated with response or progression-free survival in metastatic renal cell carcinoma treated with VEGF-targeted therapies

Abstract Background VHL is the most commonly altered gene in clear cell renal cell carcinoma (ccRCC), but its value as a predictive biomarker for vascular endothelial growth factor (VEGF)-targeted therapies remains uncertain. Prior studies (eg, Choueiri et al., 2017) found no association between VHL status and clinical outcomes in patients treated with early-generation VEGF inhibitors. Similarly, TP53 mutations have been associated with poor prognosis in RCC, though their relevance in the context of modern VEGF-directed therapy remains unclear. This study examined the relationship between circulating tumor DNA (ctDNA)-detected VHL and TP53 mutations and outcomes with VEGF-targeted therapies in patients with metastatic RCC (mRCC). Methods We retrospectively identified patients with mRCC who underwent Guardant360 ctDNA testing and subsequently received VEGF-targeted therapy. Patients were excluded if they did not receive a VEGF-targeted regimen after ctDNA testing. VEGF-targeted therapy was defined broadly to include newer generation vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs; excluding agents like sunitinib), belzutifan, and VEGF-TKI–based combinations with immunotherapy or everolimus. Demographic and clinical characteristics—including age, sex, histology, best overall response (BOR), current treatment, and line of therapy—were summarized by mutation subgroup. Progression-free survival (PFS) was defined as the time from the start of VEGF-targeted therapy to radiographic progression, clinical deterioration, last follow-up, or death. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Objective response rate (ORR), defined as complete or partial response (CR/PR), was stratified by mutation status and compared using Fisher’s exact test. All analyses were performed using R (version 4.3.2). Results Among the 32 patients included, 87.5% had clear cell histology. The most common VEGF-targeted therapies were cabozantinib, lenvatinib, axitinib, and tivozanib, frequently administered in combination with immunotherapy or everolimus. VHL mutations were detected in 8 patients (25%) and TP53 mutations in 8 patients (25%). The difference in proportion of responders to non-responders in patients with VHL alterations was non-significant (44.0% responders in the VHL non-mutated cohort vs. 28.6% in the VHL mutated cohort, P = .671). This was also seen in the TP53 mutated vs non-mutated cohort (47.8% responders in the TP53 non-mutated cohort vs. 22.2% in the TP53 mutated cohort, P = .249). There was no significant difference in the PFS based on VHL mutation status or TP53 mutation status (8.0 months vs 4.2 months, P = .58 and 8.0 months vs. 4.1 months, P = .46 respectively). Conclusions In this ctDNA-based analysis of patients with mRCC treated with VEGF-targeted therapies, neither VHL nor TP53 mutation status was associated with meaningful differences in clinical outcomes. These findings align with prior reports and suggest that mutation status alone may not predict efficacy of VEGF-targeted regimens, even in the context of combination therapies.