Network meta-analysis of second- and later-line therapies in advanced renal cell carcinoma: A comparative effectiveness approach.

504 Background: Despite advances with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted therapies, most patients with advanced renal cell carcinoma (RCC) progress after first-line treatment. Optimal sequencing of subsequent therapies remains uncertain due to the lack of head-to-head randomized controlled trials (RCTs). This network meta-analysis (NMA) compared the efficacy and safety of second- and later-line systemic treatments. Methods: PubMed, Embase, and Cochrane were searched for RCTs enrolling patients with advanced RCC who had received ≥1 prior systemic therapy. Eligible studies evaluated approved or investigational ICIs, VEGFR tyrosine kinase inhibitors, mTOR inhibitors, or their combinations. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). A frequentist NMA using a random-effects model (netmeta, R software ver. 4.5.0) generated pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Treatments were ranked using P-scores, and funnel plots assessed small-study bias. Results: Seventeen RCTs comprising 8,052 patients were included. Among 15 trials with available data, 62.4% of patients had only one prior line of therapy. Lenvatinib + everolimus (HR 0.49 vs placebo) and atezolizumab + cabozantinib (HR 0.56 vs placebo) demonstrated the greatest OS benefit. Compared with other active regimens, lenvatinib + everolimus significantly improved OS versus everolimus and temsirolimus monotherapy, ranking highest for OS (P-score = 0.88). For PFS, all active therapies outperformed placebo; lenvatinib + everolimus ranked first (P-score = 0.99) and improved PFS compared with all other therapies except telaglenastat + cabozantinib, ranking first (P-score = 0.89). Telaglenastat + cabozantinib (P-score = 0.89) and cabozantinib alone (P-score = 0.86) ranked second and third, respectively. Lenvatinib + everolimus also ranked first for ORR (P-score = 0.94), followed by belzutifan (P-score = 0.86). Combination regimens provided the greatest efficacy but were associated with higher rates of grade ≥3 TRAEs, whereas ICI monotherapy demonstrated the most favorable safety profile. No evidence of small-study bias was detected. Conclusions: In this NMA, lenvatinib + everolimus demonstrated the greatest overall efficacy across OS, PFS, and ORR, outperforming all other therapies except telaglenastat + cabozantinib in PFS. These findings suggest lenvatinib + everolimus as the leading option for second- or later-line therapy in advanced RCC. However, results should be interpreted with caution and warrant confirmation in future large, head-to-head randomized trials.