Efficacy and safety of first-line immunotherapy in advanced renal cell carcinoma: a systematic review and network meta-analysis.

BACKGROUND: First-line treatment for advanced renal cell carcinoma (aRCC) has evolved from the cytokine era to the current standard of immune checkpoint inhibitor (ICI)-based combinations. Due to the lack of direct head-to-head comparisons among these regimens, this updated network meta-analysis (NMA) aims to provide the most contemporary evidence by integrating the latest clinical data through 2026, including emerging regimens like benmelstobart plus anlotinib. METHODS: We systematically searched PubMed, EMBASE, and Cochrane Library through January 31, 2026, for randomized controlled trials (RCTs) evaluating first-line immunotherapy in aRCC. The primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and treatment-related adverse events (TRAEs). A frequentist random-effects NMA was performed, and regimens were ranked using the surface under the cumulative ranking (SUCRA) curve. RESULTS: A total of 27 articles reporting on 21 RCTs (11,779 patients) were included. Regarding efficacy, the combination of pembrolizumab plus lenvatinib demonstrated the most significant survival benefit, ranking first in SUCRA for OS [hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.49-0.88] and PFS (HR: 0.47, 95% CI: 0.38-0.58). Notably, benmelstobart plus anlotinib achieved the highest ORR [odds ratio (OR): 7.55, 95% CI: 3.99-14.28], followed by pembrolizumab plus lenvatinib (OR: 4.18, 95% CI: 2.29-7.61). Other ICI plus tyrosine kinase inhibitor (TKI) combinations and nivolumab plus ipilimumab also significantly improved OS compared to sunitinib. Regarding safety, nivolumab monotherapy was the best-tolerated treatment (SUCRA: 0.974), while regimens containing interferon-alpha (IFN-α) or interleukin-2 (IL-2) were the most toxic. Network consistency was well-maintained, and sensitivity analysis confirmed the robustness of the primary survival rankings. CONCLUSIONS: For the first-line treatment of unstratified overall aRCC populations, pembrolizumab plus lenvatinib and benmelstobart plus anlotinib emerge as highly effective immunotherapy-based combinations. However, these global rankings from pooled cohorts should not be interpreted as absolute clinical recommendations for all subgroups. Real-world treatment selection must be highly individualized and strictly tailored to the patient's specific International Metastatic RCC Database Consortium (IMDC) risk profile alongside the efficacy-safety trade-off.