Long-Term Survival Outcomes of Immune Checkpoint Inhibitor-based Combination Therapies in Favorable-Risk Metastatic Renal Cell Carcinoma: An Updated Pairwise and Network Meta-Analysis.

Immune checkpoint inhibitor (ICI)-based combination therapies have transformed the management of metastatic renal cell carcinoma (mRCC). However, their benefit in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable-risk disease remains uncertain, raising concerns about potential overtreatment. We conducted a meta-analysis incorporating extended follow-up survival data to evaluate the long-term benefits of ICI-based combinations in this subgroup. PubMed, EMBASE, Web of Science, and the Cochrane Library were searched from data inception to December 18, 2025. Phase III randomized clinical trials evaluating ICI-based combination therapies in patients with IMDC favorable-risk mRCC and reporting updated or extended follow-up data were included. Endpoints were progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated in pairwise meta-analyses, and indirect comparisons across regimens were conducted using network meta-analysis. Six trials involving 5121 patients (1267 with favorable risk mRCC) were included. In pairwise meta-analyses, ICI plus antivascular endothelial growth factor therapy significantly improved PFS versus sunitinib (HR 0.68; 95% CI 0.57-0.79), whereas dual ICI therapy showed inferior PFS (HR 1.76; 95% CI 1.25-2.48). Neither therapy demonstrated a significant OS benefit (HR 0.97 [95% CI 0.79-1.19] and 0.82 [95% CI 0.60-1.12], respectively). In network meta-analysis, pembrolizumab-lenvatinib and nivolumab-cabozantinib significantly prolonged PFS versus sunitinib (HR 0.50 [95% CI 0.35-0.71] and 0.67 [95% CI 0.46-0.97]), ranking first and second (P scores .936 and.674). No ICI-based regimen demonstrated a significant OS advantage over sunitinib. These findings suggest that routine upfront ICI-based intensification may not be justified in IMDC favorable-risk mRCC and support a more selective, risk-adapted treatment approach.