Restricted mean survival time-based network meta-analysis of first-line therapies for metastatic clear cell renal...

To compare hazard ratio (HR)- and difference in restricted mean survival time (dRMST)-based network meta-analyses of first-line immune checkpoint inhibitor-based regimens for metastatic clear-cell renal cell carcinoma. We also introduce a RMST-based framework contextualizing survival benefit alongside toxicity, corticosteroid burden, and drug-acquisition cost. Five phase III trials comparing ICI-based combinations with sunitinib in mccRCC were included. Published trial-level HRs informed HR-based NMAs, while reconstructed individual patient data were used to estimate dRMST for OS at 40 to 64 months and PFS at 24 to 48 months. Frequentist common-effect models were used. Ranking concordance was assessed descriptively. Grade ≥3 treatment-related adverse events (TRAEs), high-dose corticosteroid use, and incremental drug-acquisition cost were evaluated relative to RMST-months gained. All regimens significantly improved dRMST vs. sunitinib for OS and PFS, except avelumab plus axitinib and nivolumab plus ipilimumab, respectively. For OS, nivolumab plus ipilimumab ranked first by HR, whereas nivolumab plus cabozantinib ranked first at every dRMST horizon. Lenvatinib plus pembrolizumab ranked first for PFS under both approaches. HR-dRMST concordance was greater in PFS across horizons, and concordance increased over time for both endpoints. dRMST provided clearer temporal separation and distinguished early vs. later accumulation of benefit. Nivolumab plus ipilimumab had the lowest grade ≥3 TRAE risk and the lowest drug-acquisition cost per RMST-month gained. RMST-based NMA yielded treatment rankings largely concordant to HR-based analysis while providing clearer distinction between regimens. These findings highlight the clinical value of RMST for integrating efficacy with toxicity, corticosteroid burden, and cost in treatment decision-making.