A Nationwide Real-world Evaluation of Upfront Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma in the Immunotherapy Era

BACKGROUND AND OBJECTIVE: Since the advent of targeted therapy, deferred cytoreductive nephrectomy (dCN) has been offered to patients with metastatic renal cell carcinoma (mRCC) who respond to systemic therapy. Transition to the immunotherapy (IO) era necessitates a re-evaluation of the role of upfront CN (uCN) in mRCC management. Our aim was to determine whether uCN improves overall survival (OS) in patients with mRCC receiving IO in comparison to tyrosine kinase inhibitor (TKI) therapy. METHODS: This nationwide historical cohort study included patients with synchronous mRCC diagnosed in the Netherlands between 2018 and 2020 who were treated with IO or TKI agents. We used propensity score-based inverse probability of treatment weighting (IPTW) to adjust for prognostic differences in Kaplan-Meier and Cox regression analyses. OS was compared for patients with versus without uCN. Analyses were stratified for IO and TKI therapy. KEY FINDINGS AND LIMITATIONS: Of 872 patients, 433 received IO (63 uCN + IO, 370 IO ± dCN) and 439 received TKI (67 uCN + TKI, 372 TKI ± dCN) therapy. The uCN treatment arms had more favourable prognostic factors than those starting with systemic therapy. In the IO cohort, the IPTW-adjusted median OS was 33 mo for uCN + IO versus 24 mo for IO ± dCN (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.40-0.97). There was no significant difference in median OS in the TKI cohort (19 mo for uCN + TKI versus 17 mo for TKI ± dCN; HR 0.76, 95% CI 0.52-1.12). Limitations include the observational nature of the study and the risk of residual confounding. CONCLUSIONS AND CLINICAL IMPLICATIONS: In the absence of randomised controlled trials (RCTs), our results indicate a preference for uCN in patients with mRCC with favourable prognostic factors in the IO era. Owing to the risk of residual confounding, strong evidence from RCTs is needed.